Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:8]([N:13]2[CH2:18][CH2:17][C:16](O)([C:19]#[N:20])[CH2:15][CH2:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1>N1C=CC=CC=1>[Cl:6][C:7]1[C:8]([N:13]2[CH2:14][CH:15]=[C:16]([C:19]#[N:20])[CH2:17][CH2:18]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC1(O)CCN(c2ncccc2Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1=CCN(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., phosphoryl trichloride (10 g, 68 mmol) was slowly added into a solution of 1-(3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonitrile (compound 22) (8 g, 33 mmol) in pyridine. After stirred at RT for 30 minutes, the reaction was washed by a HCl solution, and extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product.
Reaction SMILES: [F:1][CH:2]1C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3]1.[CH3:19][O:20][CH:21](OC)[O:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:20][C:21]1([O:22][CH3:23])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3][CH:2]1[F:1]
Reactant: COC(OC)OC
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Temperature: 45 °C
Yield: 78 %

Procedure:
The mixture of 4-(3-fluoro-4-oxo-piperidin-1-yl)-3-fluoronitrobenzene (65 mmol), trimethylorthoformate (130 mmol), p-toluene-sulphonic acid monohydrate (67 mmol) in methanol was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 78% yield.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[C:17](=[O:27])[C:18]([CH3:26])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:12]3=[CH:11][C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:28].[Na+]>>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:19][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:26])[C:17]([OH:28])=[O:27])=[CH:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [OH-]
Reactant: CCCCCCOc1ccc2c(c1)cc1n2C(=O)C(C)(c2ccccc2)S1
Agent: [Na+]
Product: CCCCCCOc1ccc2[nH]c(SC(C)(C(=O)O)c3ccccc3)cc2c1
Yield: 93 %

Procedure:
To 7-hexyloxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3(2H)-one (3.92 g), 2N sodium hydroxide (70 ml) was added, and the mixture was heated and refluxed for 1.5 hours. The reaction mixture was allowed to cool, and the deposited crystalline matter was collected by filtration. The crystalline matter was dissolved in methanol. The solution was made acidic by adding concentrated hydrochloric acid under ice cooling, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to give 3.81 g (yield: 93 %) of the desired compound as a colorless powder. The melting point was 100°-102° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][CH3:20])=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c2ccccc2nc2ccccc12
Yield: 77.6 %

Procedure:
A solution of acridine-9-carboxylic acid 81 (2.0 g, 8.96 mmol), methyl iodide (3.82 g, 26.9 mmol) and potassium carbonate (4.95 g, 35.8 mmol) in DMF (25 mL) was stirred at room temperature for 3 h then diluted with brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to afford compound 82 (1.65 g, 78%) as a light yellow solid. LRMS (ESI): (calc) 237.25 (found) 238.2 (MH)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=O)[CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][NH:30][C:31]([NH:33][OH:34])=[NH:32].[ClH:35]>C(O)C>[ClH:35].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14]2[N:13]=[CH:12][CH:11]=[C:10]([CH3:16])[C:9]=2[C:8](=[N:29][NH:30][C:31](=[NH:32])[NH:33][OH:34])[CH2:7]1
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1ccco1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccco1)C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-furyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (227 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (314 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. The residue in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 3 hours and cooled, and crystals precipitated while stirring was filtered, washed with ethanol and dried to give 7-(2-furyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 97) (154 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:5]C=C1.C1C(=O)N([Br:24])C(=O)C1.C([O:28][CH2:29][CH3:30])(=O)C>C1COCC1.O>[Br:24][CH:30]1[CH:29]([OH:28])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:7][CH:2]1[CH3:1]
Reactant: CC1C=CC=C(c2ccncc2[N+](=O)[O-])C1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O)C1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 4-(5-methylcyclohexa-1,3-dienyl)-3-nitropyridine (1.0 equiv.) in THF and water (1:1, 0.13M) was added NBS (1.5 equiv.) and the reaction was stirred at room temperature for 30 min. Upon completion, ethyl acetate and water were added to the reaction, the organic phase was dried with brine, then sodium sulfate, filtered, and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to give (+/−)-6-bromo-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol as a yellow oil in 80% yield. LC/MS=315.0/313.0 (M+H), LC=2.966 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13]S)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:9]([O:8][C:6]([NH:5][C:4](=[CH2:13])[C:3]([O:2][CH3:1])=[O:15])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Yield: 99.4 %

Procedure:
MSH 1 (439 mg, 2.0 mmol) was added to a 10 mL round bottom flask and dissolved in DMF (3 mL). In a separate vial, N-(tert-butoxycarbonyl)-L-cysteine methyl ester 2 (48 mg, 0.20 mmol) was added and dissolved in DMF (3 mL). The vial was cooled to 0° C. and a solution of potassium carbonate (138 mg, 1.0 mmol) in water (3.0 mL) was added. The resulting solution was added dropwise by pipette over a period of 3 min to the stirred MSH solution at room temperature. The vial was rinsed with DMF (2×1 mL) to ensure complete transfer. TLC (petrol:ethyl acetate, 4:1) analysis after completion of the addition revealed a single, UV active product (Rf 0.6). The reaction mixture was transferred to a separatory funnel and diluted with diethyl ether (150 mL) and water (100 mL). After separation, the organic layer was washed successively with water (80 mL) and brine (80 mL) before drying (MgSO4) and filtering. The solvent was removed under reduced pressure and the resulting residue purified by column chromatography to provide methyl 2-[(tert-butoxycarbonyl)amino]acrylate 3 as a clear oil (40 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH3:23][CH2:24][OH:25].[H-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([O:25][CH2:24][CH3:23])=[CH:8][CH:9]=1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOc1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 9.3 %

Procedure:
In a similar fashion using route 51 general procedure 119, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (0.3 g, 0.89 mmol), EtOH (0.12 g, 2.6 mmol), NaH (60% in mineral oil; 0.1 g, 2.6 mmol) and NMP (2 ml) gave the title compound (30 mg, 9%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:29]1(B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[C:29]1([C:14]2[N:15]=[C:11]([C:10]3[C:2]([CH3:1])=[N:3][N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=34)[S:12][C:13]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C1=CCCCC1
Yield: 95.8 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (220 mg, 0.5 mmol) produced in Example 15(i), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (620 mg, 3.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (72 mg, 0.088 mmol), cesium carbonate (620 mg, 1.9 mmol), water (0.5 mL) and 1,2-dimethoxyethane (15 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (176 mg, 95%) was obtained as a yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:22](=[O:23])[CH2:21][CH2:20][CH:19]1[C:24]#N.C(O)(=[O:28])C>C1C=CC=CC=1.C(OCC)C>[OH:23][CH:22]1[CH2:21][CH2:20][CH:19]([CH:24]=[O:28])[CH:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: CC(=O)O
Reactant: N#CC1CCC(=O)C1CCCCCCO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CC1CCC(O)C1CCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diisobutylaluminum hydride (19.3 g., 0.125 mole) in benzene (170 ml.) was added, with rapid stirring, to a solution of 2-(6-hydroxyhexyl)-3-oxocyclopentanecarbonitrile (8.8 g., 0.042 mole) in dry diethyl ether (200 ml.) at 10°-15°C. Stirring at ambient temperature was continued for 15 minutes and the mixture was added to 2N aqueous acetic acid (170 ml.) at a temperature lower than 15°C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over magnesium sulphate and the solvents were removed in vacuo to give crude 3-hydroxy-2-(6-hydroxyhexyl)cyclopentanecarbaldehyde (8.6 g.). It was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(CCl)NCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ccc(F)cc1)NCc1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of N-benzyl-2-chloroacetamide (8.3 g—obtained as described for intermediate 1), DIPEA (9.31 mL) and 4-fluoro-aniline (4.28 mL) in anhydrous DMF (60 mL) was stirred at 100° C. for 24 hours under a Nitrogen atmosphere and then left at r.t. for two days. The solution was poured into water (100 mL) and extracted with AcOEt (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 7:3) to give the title compound (7.73 g) as a beige solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1.C(N(CC)CC)C.[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1.O>C(#N)C>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:47])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ccc(Cl)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
To a solution of the compound (0.55 g) obtained in step 4 and triethylamine (439 μL) in acetonitrile (5 mL) was added 4-chlorobenzoyl chloride (177 μL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 25→50% ethyl acetate/hexane) to give the title compound (0.51 g, 99%) as a white powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:23])([CH3:22])[CH:14]1[C:24](O)=[O:25])=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH2:30]>N1C=CC=CC=1.O>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH:30][C:24]([CH:14]1[C:15]([CH3:22])([CH3:23])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])=[O:25]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1c2ccccc2C(C)(C)C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Phosphorus oxychloride (74.0 mg, 0.045 mL, 483 μmol, Eq: 2.2) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylindoline-2-carboxylic acid (64 mg, 220 μmol, Eq: 1.00) and 2,6-difluoroaniline (54.0 mg, 0.045 mL, 418 μmol, Eq: 1.9) in pyridine (1 mL) and the resulting dark yellow suspension stirred at rt overnight. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (10 mL), 0.1 M aqueous HCl (10 mL) and brine (5 mL) and concentrated in vacuo to give tert-butyl 2-(2,6-difluorophenylcarbamoyl)-3,3-dimethylindoline-1-carboxylate as a white solid (42 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[N:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:13][N:12]=[C:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: ON=C1CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(ON=C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
The core molecule was synthesized following method A. Potassium t-butoxide (12 g, 110 mmol) was added in portions to a cooled (0° C.) solution of cyclopentanone oxime (9.9 g, 100 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-fluoro-4-nitrobenzene (14 g, 100 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water to provide cyclopentanone O-(4-nitro-phenyl)-oxime (17 g). Cyclopentanone O-(4-nitro-phenyl)-oxime (14 g, 62 mmol) was dissolved in glacial acetic acid (40 mL) and 1.9 N hydrochloric acid (40 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes and then concentrated. The solid was mixed with water (250 mL) and allowed to stand for 1 hour. The crude mixture was extracted with ethyl acetate and the combined organic phases were dried (Na2SO4) and concentrated. The crude material was dissolved in toluene (350 mL) and p-toluenesulfonic acid (2.0 g, 10 mmol) was added. The reaction mixture was heated to reflux for 4 hours and water was removed with a Dean-Stark trap. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated to give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (10 g). A mixture of give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (5.4 g, 27 mmol) and Raney nickel (˜5 g wet weight) in ethanol (50 mL) was hydrogenated at 50 PSI on a Parr shaker for 2 hours. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by column chromatography to provide 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (4.0 g). Mp 86.5-88.5° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH2:19][CH3:20])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:57][CH2:58][C:59]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:63])[CH2:60][CH2:61][CH3:62]>O1CCCC1>[C:67]([O:66][C:65](=[O:71])[NH:64][C:59]([CH3:63])([CH2:60][CH2:61][CH3:62])[CH2:58][NH:57][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:7][C:8]([CH2:19][CH3:20])=[CH:9][C:10]=12)=[O:16])([CH3:70])([CH3:69])[CH3:68]
Reactant: CCc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19 %

Procedure:
A solution of 280 mg (0.19 mmol, 23% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-ethyl-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 168A) in 4 ml of tetrahydrofuran was admixed with 43 mg (0.22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS: 25952-53-8) and 30 mg (0.22 mmol) of 1-hydroxy-7-azabenzotriazole (CAS: 39968-33-7). The solution was stirred at room temperature for 20 minutes. The reaction mixture was admixed with 0.097 ml (0.56 mmol) of N,N-diisopropylethylamine and 48 mg (0.22 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester (Example 152A). The mixture was stirred at room temperature for a further 24 hours, and the reaction mixture was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Method 21), which gave 19 mg (19% yield, 95% purity) of product.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].Cl[CH2:11][CH:12]=[CH:13][CH3:14]>>[CH2:11]([N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[CH:4][N+:1]([O-:3])=[O:2])[CH:12]=[CH:13][CH3:14]
Reactant: CC=CCCl
Reactant: O=[N+]([O-])C=C1NCCN1
Product: CC=CCN1CCNC1=C[N+](=O)[O-]

Procedure:
Method B, 2-(nitromethylene)imidazolidine was reacted with 1-chloro-2-butene. Melting point: 82°-85°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:3]=1.[N+:18]([O-:21])([OH:20])=[O:19]>CO.C(#N)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=1.[N+:18]([O-:21])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Agent: Cc1cc(NS(=O)(=O)c2ccc(N)cc2)no1
Solvent: CC#N
Solvent: CO
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared by starting from a Sulfamethoxazole solution (2 g, 7.9 mmoli) in methanol (100 ml), addition of a 65% nitric acid solution (0.500 ml) in acetonitrile (5 ml), following the procedure reported in Example 5. Sulfamethoxazole nitrate as amorphous solid is obtained. Yield 60%.
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:31])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@:9]([CH3:31])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCCCCCOc1ccc(CC[C@](C)(CCC(=O)O)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(CC[C@@](C)(N)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a stirred solution of (R)-4-tert-butoxycarbonylamino-6-(4-heptyloxy-phenyl)-4-methyl-hexanoic acid (24 mg, 0.06 mMol) in CH2Cl2 (2 ml) is added trifluoroacetic acid (0.1 ml). The mixture is stirred at RT for 6.5 hours. After that time, the reaction mixture is concentrated under reduced pressure to give the title compound as an amorphous white powder. The crude product is sufficiently pure to be used without further purification.