Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
533 mg of Z-Val-Gly-Ala-Pro-OtBu are hydrogenated in 10 ml of methanol in the presence of 300 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 20 minutes. The catalyst is filtered off and the filtrate evaporated in a waterpump vacuum at 30°C to give an oil. Rf = 0.52 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([Br:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1Br
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1Br

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-bromo-6-methoxyindole-2-carboxylic acid (PREPARATION 82, 0.40 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.33 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.34 g), the title compound is obtained, mp 202°-204°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([S:39]([CH3:38])(=[O:41])=[O:40])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]([CH3:31])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(S(C)(=O)=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A solution of 2.0 g (0.0045 mole) of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]6-methyl-4-(3-nitrophenyl) -5-pyrimidinecarboxylic acid, ethyl ester (see example 2A) in 15 ml of dichloromethane containing 0.71 g (0.0090 mole) of pyridine was cooled to -10° C. and treated slowly with a solution of 0.62 g (0.0054 mole) of methanesulfonyl chloride in 5 ml of dichloromethane. After stirring at room temperature overnight, a small amount of the hydrochloric acid salt of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester had precipitated. After filtration, additional dichloromethane was added and the solution was washed with water, 1N hydrochloric acid, sodium bicarbonate and brine. The dried solution was evaporated and the residue was flash chromatographed using dichloromethane to give 2.0 g of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].Cl[C:9]1[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=[CH:11][N:10]=1>>[CH3:1][O:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH:5][C:9]1[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: COC(C)(C)CN
Reactant: CSc1ncc2ccnc(Cl)c2n1
Product: COC(C)(C)CNc1nccc2cnc(SC)nc12

Procedure:
The title compound was prepared according to the method described for Preparation 175 using 2-methoxy-2-methylpropan-1-amine and 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33). The residue was purified by elution through an SCX-2 column using 50% methanol in chloroform followed by 50% chloroform in 7N NH3/MeOH followed by silica gel column chromatography eluting with EtOAc.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1.CN(C=O)C>CCOC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:26]4[CH2:29][CH2:28][CH2:27]4)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C1CNC1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1c(Cc2ccc(-n3cccn3)cc2)c(N2CCC2)nc2ccc(Br)cc12
Temperature: 100 °C

Procedure:
3-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (2.50 g, 5.77 mmol, Intermediate 4: step c), azetidine (988 mg, 17.3 mmol), and DMF (30 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The vessel was then cooled and contents were transferred to a separatory funnel with EtOAc dilution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-20% hexane/ethyl acetate) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30](O)=[O:31])=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30]([N:12]2[CH2:11][CH:10]3[CH:14]([CH2:15][CH:16]([CH3:18])[CH2:17][C:9]3([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[OH:19])[CH2:13]2)=[O:31])=[CH:21]1
Reactant: COc1ccccc1C1(O)CC(C)CC2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Product: COc1ccccc1C1(O)CC(C)CC2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Yield: 80.5 %

Procedure:
In an identical manner to Example 1, 0.78 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-6-methyl-4 perhydroisoindolol and 0.52 g of 3-indoleacetic acid are used. After chromatography on a column of silica gel (0.060-0.200 mm, diameter 3.5 cm, height 40 cm), eluting under a pressure of 0.7 bar with a mixture of dichloromethane and methanol [94/6 by volume] and collecting 45 cm3 fractions, fractions 10 to 16 are concentrated to dryness and, after drying at 40° C. at 15 Pa, 1.0 g of (3aRS,4RS,6SR,7aSR)-2-(3-indolylacetyl)-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol is obtained in the form of a white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1>C1COCC1>[OH:36][C:32]1[CH:31]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CNc1cccc(O)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (34 mg, 0.3116 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 84% yield (0.104 g, 0.2159 mmol).
Reaction SMILES: C1COCC1.[C:6]1([S:12][CH:13]=[CH:14][C:15](Cl)=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>C(N(CC)CC)C>[CH3:18][C:19]1[CH:20]=[C:21]([NH:22][C:15](=[O:16])[CH:14]=[CH:13][S:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C=CSc1ccccc1
Reactant: Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)C=CSc2ccccc2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
THF (45 ml) solution of 3-(phenylthio)acryloyl chloride (3.03 g) was added to THF (45 ml) solution of triethylamine (2.09 ml) under ice-cooling. 3-methylaniline (1.62 g) was added to the mixture under ice-cooling and stirred at room temperature for ten hours. The reaction solution was concentrated under reduced pressure. Ice cooled 1N hydrochloric acid (40 ml) and ethyl acetate (200 ml) were added to the residue and separated to two layer. The organic layer was washed with aqueous saturated sodium chloride solution (40 ml) twice, dried over anhydrous magnesium sulfate, filtered off inorganic salt and concentrated under reduced pressure to obtain N-(3-methylphenyl)-3-(phenylthio)acrylamide (3.46 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[C:10]([CH3:20])[S:9][C:4]=2[NH:5][C:6](=[O:8])[CH:7]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][C:10]1[S:9][C:4]2[N:5]=[C:6]([O:8][CH3:21])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(-c2c(C)sc3[nH]c(=O)cc(N)c23)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(C)sc3nc(OC)cc(N)c23)c1
Temperature: 90 °C
Yield: 13.1 %

Procedure:
To a suspension of 4-amino-2-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-6(7H)-one (Description 36) (120 mg, 0.419 mmol) in DMF (3 mL) was added potassium carbonate (116 mg, 0.838 mmol) and methyl iodide (0.029 mL, 0.461 mmol). The suspension was then heated to 90° C. under nitrogen atmosphere for ca. 2 hand then cooled to RT, quenched with water (ca. 25 mL) and extracted with ethyl acetate (ca. 25 mL×2). The combined organic layers were passed through a phase separator and solvent concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in DCM followed by 0-20% MeOH in DCM, to afford the title compound (16.5 mg). LCMS (A) m/z: 301 [M+1]+, Rt 1.21 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:13][C:14]([F:25])([F:24])[C:15]1[C:20]([C:21](Cl)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1>>[F:24][C:14]([F:13])([F:25])[C:15]1[C:20]([C:21]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cnccc1C(F)(F)F
Reactant: CCOC(=N)c1ccccc1Cl
Product: CCOC(=NC(=O)c1cnccc1C(F)(F)F)c1ccccc1Cl

Procedure:
starting from ethyl o-chlorobenzimidate and 4-trifluoromethyl-nicotinoyl chloride there is obtained ethyl N-(4-trifluoromethyl-nicotinoyl)-2-chlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(o-chlorophenyl)-1-methyl-5-(4-trifluoromethyl-3-pyridyl)-1H-1,2,4-triazole, 1H-NMR(CDCl3): 3.85 (s, N-CH3), 7.6-8.1 (5 aromatic H), 8.9-9.2 (2 aromatic H); mass spectrum: 338 (100), 319 (5), 166 (94), 138 (95);
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)(=[O:3])[CH3:2]>COC(OC)N(C)C>[CH3:6][N:16]([CH3:21])/[CH:17]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:3]
Reactant: COc1ccc2cc(C(C)=O)cc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: COC(OC)N(C)C
Product: COc1ccc2cc(C(=O)/C=C/N(C)C)cc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 185.4 %

Procedure:
tert-butyl 4-(3-acetyl-7-methoxynaphthalen-1-yl)piperazine-1-carboxylate (107) (1.5 g) and N,N-dimethylformamide dimethylacetal were charged in a flask and heated at 100° C. for 36 hours. More N,N-dimethylformamide dimethylacetal (10 ml) was added to the reaction, the temperature was raised to 120° C. and the reaction was allowed to proceed overnight. The reaction was cooled and poured onto water. The solid was extracted with ethyl acetate (2×100 ml), the organics combined, washed with water (1×100 ml) and brine (1×100 ml), dried over sodium sulfate and concentrated. Column chromatography (100% ethyl acetate) gave (E)-tert-butyl 4-(3-(3-(dimethylamino)acryloyl)-7-methoxynaphthalen-1-yl)piperazine-1-carboxylate (108) as a light yellow foam (1.59 g) LCMS (m/z): 440 [M+H].
Reaction SMILES: O=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>CCOCC>[CH2:21]([O:28][N:29]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CCC1CCCCCCCCCCC1=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)CCC1CCCCCCCCCCC1=NOCc1ccccc1
Temperature: 140 °C
Yield: 92.4 %

Procedure:
A heavy walled reaction tube was charged with 3-(2-oxocyclododecyl)-propionic acid, methyl ester (6.0 g, 22.3 mmol), benzyloxyamine hydrochloride (3.99 g, 25 mmol), and pyridine (30 mL). The tube was sealed and heated in an oil bath at 140° C. for 2 hours. Upon cooling, the reaction mixture was diluted with ether (1L) and extracted with 2NN HCl until the aqueous layer was acidic, followed by extraction with water (2×50 mL). The organic phase was dried over magnesium sulfate, filtered through a silica gel plug, and the solvent removed in vacuo to afford 8.1 g (97%) of a crude oil. Purification by flash column chromatography on silica gel (100:1 ratio) and by elution with hexane/ethyl acetate (95/5) afforded 7.7 g (92% yield) of the title compound as a colorless oil with a 4:1 (E/Z) isomer ratio. 1H NMR (CDCl3, 400 Mhz) δ: 7.23-7.36 (m, 5H), 5.03 (s, 2H, (E) major isomer), 5.02 (s, 2H, (Z) minor isomer), 3.63 (s, 2.4H, (E) major isomer), 3.61 (s, 0.6H, (Z) minor isomer), 2.63 (ddd, J=13.3, 9.8, 4.8 hz, 1H), 2.36 (m, 1H), 2.24 (m, 2H), 2.05 (m, 1H), 1.75 -1.84 (m, 2H), 1.69 (m, 2H), 1.52-1.62 (m, 1H), 1.40-1.51 (m, 1H), 1.26 (m, 14H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[C:8]=[S:9].[C:10](#[N:12])[CH3:11]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8](=[S:9])[N:7]2[CH:2]=[CH:3][CH:4]=[CH:11][C:10]2=[N:12][C:8]1=[S:9]
Reactant: CC#N
Reactant: S=C=Nc1ccccn1
Product: S=c1nc2ccccn2c(=S)n1-c1ccccn1

Procedure:
10 G. of freshly distilled 2-pyridylisothiocyanate is dissolved in 100 ml. of acetonitrile and the reaction mixture stirred at room temperature for 2 days. The solid precipitate is filtered and washed with fresh acetonitrile affording 3-(2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 107°-109° C.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]O.O>ClCCl>[N+:1]([O-:4])([O:3][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: OCCCCBr
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])OCCCCBr
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
In reactor cooled to −5 to 5° C., nitric acid fuming (8.5 g-135 mmol) was slowly added to a solution of 98% sulfuric acid (13.0 g-130 mmol) in dichloromethane (18.0 g-212 mmol). 4-bromobutanol (10.2 g-66.6 mmol) was then added to this mixture and the reaction medium was stirred at −5 to 5° C. over a period of 2-5 hours. The mixture was poured into cold water (110 g) keeping the temperature between −5° C. and 3° C. After decantation, the upper aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, adjusted to pH=6-7 by addition of 27.65% sodium hydroxide, washed with brine and dried over magnesium sulfate. Dichloromethane was distilled off under vacuum and crude 4-bromobutyl nitrate (12.7 g-64.1 mmol) was recovered in a yield of about 96%.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[NH4+].[OH-].[NH4+]>>[N+:15]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][NH2:9])=[CH:4][CH:5]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: NCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: NCCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
24.2 g. (0.20 mol) Phenethylamine are carefully mixed in an ice-bath with 125 ml. concentrated sulphuric acid. After stirring for 1 hour, 16.8 g. (0.21 mol) ammonium nitrate in 125 ml. concentrated sulphuric acid are carefully added dropwise thereto at 0° to 5° C. After a further hour, the reaction mixture is poured on to 1.5 liters of ice and the pH adjusted to 9 with a concentrated aqueous solution of ammonium hydroxide. The aqueous phase is extracted several times with diethyl ether, the combined organic phases are dried over anhydrous magnesium sulphate, evaporated to dryness and the residue is distilled. There are obtained 14.5 g. (44% of theory) of a colourless oil; b.p. 110°-115° C./0.01 Torr. 1H-NMR (60 MHz, CDCl3, ppm): δ=2.99 (q, 2H, J=2.0 Hz, CH2); 3.05 (t, 2H, J=2.0 Hz, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
4-Chloro-2-fluoroaniline (23 g) was dissolved in conc. sulfuric acid (120 ml), and the resultant mixture was cooled to -20° C., followed by dropwise addition of fuming nitric acid (15 g). The reaction mixture was stirred at -20° to -15° C. for 1.5 hours, poured into ice-water and then extracted with ether. The ether extract was washed with water and a saturated sodium bicarbonate solution, dried and concentrated. The residue was crystallized from a mixture of toluene and hexane (2:1) to obtain 20 g of 4-chloro-2-fluoro-5-nitroaniline. m.p., 83°-84.5° C.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1>>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:40]([C:36]2[S:35][C:34]([N:31]3[CH2:32][CH2:33][N:29]([CH2:28][C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:45][CH:44]=4)[C:30]3=[O:43])=[N:38][C:37]=2[CH3:39])=[O:41])=[CH:49][CH:48]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 38 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, the title compound was obtained as a white powder in 38% yield: mp 177-178° C.; 1H NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 4H), 7.04-6.96 (m, 4H), 5.98 (s, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.4, 160.8, 155.3, 153.2, 133.8, 131.3, 129.9, 129.5, 117.2, 115.7, 115.4, 47.2, 43.2, 42.0, 41.6, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: O1C=NC=N1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C@H:16]([CH2:26][N:27]3[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]=[N:28]3)[O:15][C:14]2=[O:35])=[CH:9][CH:8]=1.[C:36](=[N:39]O)([NH2:38])[CH3:37]>O1CCOCC1.C(#N)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C@H:16]([CH2:26][N:27]3[CH:31]=[C:30]([C:32]4[O:33][N:39]=[C:36]([CH3:37])[N:38]=4)[N:29]=[N:28]3)[O:15][C:14]2=[O:35])=[CH:11][CH:12]=1
Reactant: CC(N)=NO
Reactant: COc1cccc([C@H]2[C@H](Cn3cc(C(=O)O)nn3)OC(=O)N2c2ccc(Cl)cc2)c1
Agent: c1ncon1
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cccc([C@H]2[C@H](Cn3cc(-c4nc(C)no4)nn3)OC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Reference for 1,2,4-oxadiazole formation: Bioorg. Med. Chem. Lett. 1999, 9, 209. A solution of 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (32 mg, 0.07 mmol) in dioxane (0.5 mL) is treated with N,N′-carbonyldiimidazole and stirred at room temperature for 30 min. Acetamide oxime (10 mg, 0.13 mmol) is then added and the mixture stirred for 2 h at room temperature then at 100° C. for 18 h. The reaction solution is then diluted with acetonitrile and filtered through a Whatman 0.42 μM and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)) HPLC to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 8.93 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.28 (m, 3H), 7.05-7.00 (m, 2H), 6.88 (ddd, J=7.9, 2.5, 0.8 Hz, 1H), 5.62 (d, J=5.0 Hz, 1H), 5.25-5.24 (m, 2H), 5.03 (ddd, J=5.7, 5.5, 4.9 Hz, 1H) 3.76 (s, 3H), 2.40 (s, 3H); HPLC-MS calculated C22H19ClN6O4 (M+H+) 467.1, found 467.1.1.
Reaction SMILES: CS[C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:48]([NH2:50])[CH3:49].C1COCC1>ClCCl.C1COCC1>[CH2:48]([NH:50][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1)[CH3:49]
Reactant: CCN
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
(S)-9-Methylthio-5-(1-tert-butoxycarbonylpiperidin-4-yl)methyl-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (2.51 g, 5.61 mmol) obtained in Step 1 was dissolved in dichloromethane (40 mL), and the mixture was stirred at room temperature for 20 minutes after adding 3-chloroperbenzoic acid (65%; 1.94 g, 7.29 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was dissolved in THF (10 mL), and the mixture was stirred overnight after adding a 2.0 mol/L ethylamine/THF solution (14.0 mL, 28.1 mmol). The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography to give the title compound (Compound 23) (2.09 g, 84%) as a yellow oily substance.