Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:28])[C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:25]([C:24]2[C:23]([Cl:28])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:18])=[O:26])[NH2:17])=[CH:12][CH:11]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NN(C(=O)c1c(Cl)cncc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 96 %

Procedure:
Triethylamine (1.40 mL, 1.02 g, 10.1 mmol) was added to a suspension of 4-chlorophenylhydrazine hydrochloride (1.83 g, 98%, 10.0 mmol) in THF (75 mL). The mixture was stirred under nitrogen at room temperature for 2.75 h. More triethylamine (3.0 mL, 21.6 mmol) was added followed by dropwise addition of a solution of freshly-prepared 3,5-dichloropyridine-4-carbonyl chloride (10.0 mmol) in THF (20 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were shaken together and allowed to separate. The organic phase was dried (Na2SO4) and concentrated, leaving 3.04 g of a tan solid, mp 201-203.5° C. Recrystallized from ethyl acetate/cyclohexane and then from ethanol furnished crystals which melted at 206-207.5° C.
Reaction SMILES: CC(C)(C(=O)[N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9]([C:14]1[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2)C#N.C(N(CC)CC)C.[CH3:32][C:33]([S:36](Cl)=[O:37])([CH3:35])[CH3:34]>C1COCC1>[CH3:32][C:33]([S:36]([N:6]1[CH2:7][CH2:8][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][C:11]21[CH2:12][CH2:13]2)=[O:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C#N)C(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reactant: CC(C)(C)S(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reaction time: 16 h

Procedure:
Intermediate 2 (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-methylpropane-2-sulfinyl chloride (0.06 mmol) was added. The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][S:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])=[O:6].[F:19][C:20]([S:23][CH2:24][CH2:25]OS(C(F)(F)F)(=O)=O)([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[F:18][C:2]([F:1])([C:14]([F:15])([F:16])[F:17])[CH2:3][CH2:4][S:5]([CH:8]([CH2:25][CH2:24][S:23][C:20]([F:22])([F:21])[F:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:6])=[O:7]
Reactant: CCOC(=O)CS(=O)(=O)CCC(F)(F)C(F)(F)F
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CCSC(F)(F)F)S(=O)(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (3,3,4,4,4-pentafluoro-butane-1-sulfonyl)-acetate (J. Fluorine Chem. 1985, 28(4), 425-440) (2.00 g, 6.70 mmol), trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester (1.50 g, 5.36 mmol), and potassium carbonate (2.77 g, 5.36 mmol) in 1,2-dimethoxyethane (100 mL) was stirred overnight at room temperature under nitrogen. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/CH2Cl2 1:1) to provide compound II-3 (0.28 g, 37%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:3][CH2:2]1.Cl[Si](C)(C)C>CO>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1CC1CC1
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of tert-butyl 4-((1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)methyl)piperidine-1-carboxylate (STEP C, 1.39 g, 2.76 mmol) in methanol (15 mL) was added chlorotrimethylsilane (1.41 mL, 11.0 mmol). After stirring for 18 h, the mixture was concentrated in vacuo. The residue was diluted ethyl acetate and basified with saturated sodium bicarbonate aqueous solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to give the title compound (809 mg, 73%) as an amorphous.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[S:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.Cl.[OH-:23].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[S:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)S[C@H]1n1ccc2c(Cl)nc(N)nc21
Agent: Cl
Agent: [Na+]
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)S[C@H]1n1ccc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of the compound from Step F in 2N aqueous NaOH is stirred at reflux temperature for 1.5 h. The solution is cooled in an ice-bath, neutralized with 2 N aqueous HCl and evaporated to dryness. The residue is suspended in MeOH, mixed with silica gel and evaporated. The solid residue is placed onto a silica gel column (packed in a solvent system of CH2Cl2/MeOH). The compound is eluted with a solvent system of CH2Cl2/MeOH. The fractions containing the product are collected and evaporated to dryness to yield the title compound 2-7.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][C:29](=O)C)C=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:35]CCCCCCCC(O)=O>>[Br:35][CH2:29][CH2:28][CH2:24][CH2:25][CH2:26][CH2:27][CH2:22][C:21]([NH:20][CH2:19][C:10]1[C:11]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][C:9]=1[CH2:33][CH3:34])=[O:32]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCBr

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using 8-bromo-octanoic acid in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C24H39BrN5O2+ 508.2. found m/z=508.2 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][O:13]C(=O)C)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>>[CH2:1]([C@H:8]([CH2:12][OH:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H](Cc1ccccc1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H](CO)Cc1ccccc1

Procedure:
The product of stage c above is treated with aqueous lithium hydroxide solution as described in Example 1, stage d.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][N:27]=[C:28]=[O:29].CCN(CC)CC.Cl>C1COCC1>[O:29]1[CH2:25][CH2:26][N:27]=[C:28]1[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]=[CH:10]2)[CH3:23]
Reactant: CNCCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: O=C=NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1)C1=NCCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 16.4 %

Procedure:
300 mg (0.96 mmol) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methylamine in 10 ml THF were treated with 150 mg (1.4 mmol) 2-chloroethylisocyanate and the mixture stirred at room temperature during 10 hours. After addition of 0.2 ml NEt3 the mixture was stirred for an additional hour and treated with 0.1 M aqueous HCl. Extraction with Et2O, drying of the combined organic layers with Na2SO4, Evaporation of the solvent, and column chromatography on silica gel with CH2Cl2/MeOH/NEt3 10:1:0.1 gave 60 mg (16%) (4,5-Dihydro-oxazol-2-yl)-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine, MS: 382 (MH+).
Reaction SMILES: C1(C(OC)C[C:6]([O:8][CH3:9])=[O:7])CC1.C(=O)([O-])[O-].[K+].[K+].C[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO>[CH:21]1([C:20](=[CH2:19])[C:6]([O:8][CH3:9])=[O:7])[CH2:22][CH2:23]1
Reactant: CCCCCC
Reactant: COC(=O)CC(OC)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=C(C(=O)OC)C1CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 62 %

Procedure:
To a solution of the mixture of methyl cyclopylacrylate and methyl 3-cyclopropyl-3-methoxypropionate (59.6 g, from Example 1, Example 2, Example 3 or Example 4) in methanol (120 ml) was added potassium carbonate (32.24 g) and stirred for 13 hours at room temperature. After addition of hexane, the upper hexane's layer was separated, filtered and concentrated. The residue was diluted with hexane, filtered, concentrated, and distill (50 mmHg, 101° C. to 102° C.) to give methyl cyclopropylacrylate (23.3 g, yield 62%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C(N[C@H]1CCCNCC1)C(F)(F)F
Product: CCn1ncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Yield: 44 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (S)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (S)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.12 g, 44%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.42-6.40 (m, 1H), 4.22-4.18 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:22]([CH:24]([CH3:29])[C:25](OC)=O)=[O:23]>>[CH2:1]([NH:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[CH:24]([CH3:29])[CH:25]=[N:21][CH2:20][CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)C(C)C=O
Reactant: CCCCCCCCCCCCCCNCCNCCN
Product: CCCCCCCCCCCCCCNCCN1CCN=CC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 299.5 g (1 mole) of N-tetradecyldiethylenetriamine and 116.1 g (1 mole) of methyl 2-formylpropionate. At 130° to 135° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-tetradecylaminoethyl-6-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [OH:1][C@H:2]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)/[CH:3]=[CH:4]/[C:5]#[C:6]/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C@H:11]1[O:15]C(C)(C)[O:13][C@H:12]1[CH2:18][O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].Cl>CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C@@H:2]([OH:1])/[CH:3]=[CH:4]/[C:5]#[C:6]/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C@@H:11]([OH:15])[C@@H:12]([OH:13])[CH2:18][O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:29]=1
Reactant: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Reaction time: 48 h
Yield: 145.4 %

Procedure:
A solution of 2-[[(4S,5R)-5-[(1E,3E,7E,9S)-9-hydroxy-1 0-(4-fluorophenoxy)-1,3,7-decatrien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (1.1 g, 1.8 mmol) in methanol (25 mL) was treated with 1 mL of 1 N hydrochloric acid and the reaction was stirred for 2 days. The pH of the reaction was adjusted to neutrality. Purification on preparative reverse phase semi-prep column using a gradient of acetonitrile in water yielded 1.1 g of (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-1 1-ynoic acid, methyl ester, as an oil; 1H NMR (CDCl3) δ3.67 (m, 2H), 3.75 (s, 3H), 3.83 (m, 1H), 3.95 (m, 1H), 4.13 (m, 2H), 4.37 (m, 1H), 4.58 (m, 1H), 5.73 (dd, 1H), 5.86 (dd, 1H), 6.04 (dt, 1H), 6.17 (m, 1H), 6.40 (m, 1H), 6.58 (m, 1H), 6.9 (m, 4H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:16]2[NH:17][C:18]([NH:20][C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:22])=[N:19][C:15]=2[CH:14]=[CH:13][CH:12]=1)=O>CC(O)=O>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:11]1[C:16]2[NH:17][C:18]([NH:20][C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:22])=[N:19][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1NC(=O)c1cccc2nc(NC(=O)c3nccc4ccccc34)[nH]c12
Solvent: CC(=O)O
Product: O=C(Nc1nc2cccc(-c3nc4ccccc4[nH]3)c2[nH]1)c1nccc2ccccc12
Temperature: 130 °C
Yield: 74.2 %

Procedure:
To a solution of 169 mg (0.4 mmol) of isoquinoline-1-carboxylic acid [7-(2-amino-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-amide in AcOH (15 mL) was added NH4OAc (0.5 g). The mixture was heated at 130° C. for 30 min. After cooling to room temperature, the AcOH was removed under reduced pressure, extracted with EtOAc (50 mL), washed with sat. aq. sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in DCM (3 mL), and 5 mL of hexane was added. The resulting solid was filtered and dried to afford 120 mg (75%) of isoquinoline-1-carboxylic acid (1H,3′H-[2,4′]bibenzoimidazolyl-2′-yl)-amide. LCMS: 405 (M+1)+.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Azidobenzoic acid (855 mg, 5.14 mmol), HOBt (701 mg, 5.14 mmol, 1.0 eq.) and 3-phenylpropylamine (0.969 ml, 6.68 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.21 g, 6.16 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][CH2:6][N:5]=1)C.[CH3:9][CH:10]([CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]1)[CH3:11]>C(O)(C)C>[CH3:11][CH:10]([CH:12]1[CH2:13][C:14](=[O:19])[C:15](=[C:4]2[CH2:8][CH2:7][CH2:6][NH:5]2)[C:16](=[O:18])[CH2:17]1)[CH3:9]
Reactant: CC(C)C1CC(=O)CC(=O)C1
Reactant: CCOC1=NCCC1
Solvent: CC(C)O
Product: CC(C)C1CC(=O)C(=C2CCCN2)C(=O)C1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of 2-ethoxy-1-pyrroline (9.05 grams, 0.08 mole), and 5-(1-methylethyl)-1,3-cyclohexanedione (12.34 grams, 0.08 mole), in 50 mL of isopropyl alcohol solvent is heated under reflux for 2 hours. After standing overnight, the cooled reaction solution will deposit white, crystalline product which is collected, washed with cold solvent and dried to give 2.2 grams of solid, m.p. 143°-145° C. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution extracted with three portions of 3N NaOH followed by three portions of 3N hydrochloric acid. Addition of 3N NaOH to the acid solution causes precipitation of an 0.87-gram portion of product, m.p. 143.5°-145° C. The latter is recrystallized from ethyl acetate for an analytical sample.
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[CH3:18]COCC.CO>>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of phenylmalonic acid (3.6 g, 0.02 mol), boron trifluoride etherate (2.4 mL, 0.02 mol) and 0.8 mL of anhydrous methanol (0.02 mol) was refluxed and stirred for 24 hours. After cooling to room temperature, the reaction mixture was filtered and 20 mL of water was added.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]3[O:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:35]=3[CH:46]=2)=[CH:12][CH:11]=1)(O)=[O:8]>ClCCl.CN(C)C=O>[Cl:4][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]3[O:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:35]=3[CH:46]=2)=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)O)cc3)cc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.190 ml of oxalyl chloride are added dropwise to a solution of 0.600 g of tert-butyl 4-(4-carboxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 6 ml of dichloromethane. The reaction solution is subsequently stirred at room temperature over 1 hour and then admixed with 2 drops of N,N-dimethylformamide and stirred at room temperature for a further 35 minutes. The reaction mixture is concentrated by evaporation to dryness and used further as the crude product without purification. Reddish oil, Rt=5.50.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:44][CH:41]1[CH2:42][CH2:43][N:38]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:39][CH2:40]1
Reactant: OC1CCNCC1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 47 mg (0.47 mmol) of piperidin-4-ol and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 62 mg (83% of theory)
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=2.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CN(C)C=O>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[Cl:13])[N:4]1[C:14]([CH2:17][CH3:18])=[N:15][N:16]=[C:3]1[C:2]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[N:11]2
Reactant: CCNCC
Reactant: CCc1nnc2c(Cl)nc3cc(Cl)c(Cl)cc3n12
Solvent: CN(C)C=O
Product: CCc1nnc2c(N(CC)CC)nc3cc(Cl)c(Cl)cc3n12
Reaction time: 0.25 h
Yield: 16 %

Procedure:
4,7,8-Trichloro-1-ethyl-[1,2,4]-triazolo[4,3-a]quinoxaline (2.9 g., 0.0096 mole) and 2.1 g. (0.0388 mole) of diethylamine in N,N-dimethylformamide (50 ml.) were stirred at room temperature for 2 hours. The reaction mixture was poured over ice and stirred for 15 minutes. The precipitate was separated by filtration, washed with water and air dried. Recrystallization (three times) from isopropanol then afforded 500 mg. (16% yield) of pure 7,8-dichloro-4-diethylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 147°-149° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:2].[H][H]>[Pd].C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)Oc1cccc(C=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1cccc(CO)c1
Yield: 62.3 %

Procedure:
Into 100 ml of ethyl acetate was dissolved 5.09 g of methyl 2-(3-formylphenoxy)propionate; 0.57 g of 10% palladium on carbon was added; the mixture was stirred for 30 minutes in a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered; the filtrate was concentrated and the residue was subjected to silica gel column chromatography to give 3.20 g of methyl 2-[3-(hydroxymethyl)phenoxy]propionate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH2:14][O:15][CH:16]([F:18])[F:17])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:19][O:20][C:21](Cl)=[O:22]>ClCCl>[F:18][CH:16]([F:17])[O:15][CH2:14][CH2:13][C@H:2]([NH:1][C:21]([O:20][CH3:19])=[O:22])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
(S)-Benzyl 2-amino-4-(difluoromethoxy)butanoate (116 mg, 0.448 mmol) was dissolved in anhydrous dichloromethane (2.5 mL) and cooled down to 0° C. and TEA (181 mg, 1.79 mmol) and methylchloroformate (51 mg, 0.538 mmol) were added respectively. The mixture was stirred for 30 minutes and then it was stirred at room temperature overnight. The resulting product mixture was quenched with saturated NaHCO3 and extracted with dichloromethane. The organic layer was washed with saturated NH4Cl solution and brine and dried over Na2SO4. The volatiles were removed in vacuo to afford 56 mg (40%) of desired product after column purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][C:3]=1[O:18][CH3:19].Br[CH2:21][C:22]([C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])=[O:23]>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]([C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])=[O:23]
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCC(=O)c1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 4-bromoacetyl-5-methyl-2-phenyloxazole to obtain 5-[3-[3-methoxy-4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propyl]-2,4-oxazolidinedione as an oily product.