Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1.Cl[CH:33]([C:39](=O)[CH3:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1>[CH:1]1([C:7]2[S:19][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:39]([CH3:40])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CCCCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C2CCCCC2)nc1C
Temperature: 25 °C
Yield: 184.2 %

Procedure:
To 90 ml of tetrahydrofuran, 11.1 g (87 mmol) of cyclohexanecarboxamide and 17.6 g (43.5 mmol) of Lawesson's reagent were suspended, followed by heating under refluxing for 3 hours. The reaction liquid was cooled to room temperature, followed by adding 14.4 g (87 mmol) of ethyl 2-chloro-3-oxobutanate and heating under refluxing for further 3 hours. The reaction liquid was poured into ice water and extracted with diethyl ether. The organic layer was washed with water, dilute hydrochloric acid, an aqueous solution of sodium carbonate and saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 20.3 g (yield: 92%) of ethyl 2-cyclohexyl-4-methylthiazole-5-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][OH:20])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][O:20][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(F)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (APCI) m/z 379 (M+1).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][C:9](N)=[CH:8][CH:7]=1.[S:13](=[O:15])=[O:14].O.[ClH:17]>C(O)(=O)C.[Cu](Cl)Cl>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([S:13]([Cl:17])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: O=S=O
Reactant: Nc1ccc(Cl)nc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
Sodium nitrite (3.45 g, 0.05 mol) was added portion wise to a stirred solution of 6-chloro-pyridin-3-ylamine (6.4 g, 0.05 mol) in acetic acid (56 ml) and HCl (conc) (9.92 ml) while maintaining the temperature below 15° C. This solution was then added drop wise to a stirred solution of sulfur dioxide (17.2 g, 0.27 mol), copper (II) chloride (1.85 g, 0.011 mol) and water (2.2 ml) in acetic acid (37 ml) at 5° C. The reaction mixture was allowed to warm to room temperature and poured over ice water and stirred for a further 15 min. The resultant precipitate was collected by filtration, washed with water and dried overnight in a vacuum oven to give 6-chloro-pyridine-3-sulfonyl chloride (6.41 g, 60.5% yield); (400 MHz; d6-DMSO) 8.54 (1H, d), 7.96 (1H, dd), 7.50 (1H, d).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Solvent: O
Product: CN(C)C(=N)NC(=N)N

Procedure:
Metformin hydrochloride is screened through a 1 mm sieve. Screened metformin hydrochloride is granulated in fluid bed granulator with the solution of povidone in demineralized water and dried in the same device. The dried granulate is screened through a 1 mm sieve. The obtained granulate, microcrystalline cellulose and hydrogenated castor oil are homogenously blended in a bin blender. Pre-sieved magnesium stearate is added to the obtained blend and blended in a bin blender so that the final blend is obtained. The final blend is compressed into a bilayer tablet as disclosed in Examples 14 and 15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C[N:13]([C:15]1[CH:20]=[CH:19]C=C[N:16]=1)C.C.C([O:25][CH2:26][CH3:27])(=O)C>>[CH3:19][C:20]1[C:15]([NH:16][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])(=[O:10])=[O:9])=[N:13][O:25][C:26]=1[CH3:27]
Reactant: CN(C)c1ccccn1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CCOC(C)=O
Product: Cc1onc(NS(=O)(=O)c2ccccc2Br)c1C
Temperature: 9 °C

Procedure:
A 500 mL flask was charged with 2-bromobenzene sulfonyl chloride (153.3 g) and dimethylaminopyridine (7.37 g, 0.1 equiv), purged with argon and cooled in an ice-brine bath. Pyridine (300 mL) was added, and the mixture stirred. A separate flask containing 3-amino-4,5-dimethyl isoxazole, (73.95 g) in anhydrous pyridine3 (300 mL) under argon was cooled in an ice bath. When the internal temperature of the pyridine-bromobenzenesulfonyl chloride solution was ˜−3° C., the isoxazole-pyridine solution was added dropwise by cannula. The addition required ˜90 min. Quantitative transfer of the isoxazole was achieved with a 10 mL pyridine rinse. Upon completion of addition, the ice was removed from the brine-ice bath, and the internal temperature of the reaction vessel warmed to approximately 8-10° C. over 1 h. The reaction vessel was then immersed in a preheated oil bath at 42° C. and maintained at this temperature for 24.5 h. The warm solution was cannulated dropwise into ice cold 6N HCl (8 L) with vigorous stirring over approximately 90 min. Immediate precipitation occurred. The mixture was stirred in the ice-water bath for approximately 1 h, and the yellow solid collected by suction filtration on a medium porosity glass frit. The filter cake was washed with cold deionized water (4×0.5 L), taking care to mix the filter cake with each wash. The solid was air suction dried for 24 h affording a yellow powder: 185.5 g, 93.4%, HPLC area percent 97.7. The solid was dissolved in ethyl acetate (3.7 L or 20 mL/g), charcoal (46.1 g, Darco KB, lot 1F-074) added, the mixture heated briefly to 58° C., cooled to RT and stirred for 12 h, filtered through celite, the celite pad rinsed with ethyl acetate (5×200 mL) and evaporated to dryness.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27](Cl)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1.Cl.Cl.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C@H:19]([C:27]([N:42]3[CH2:41][CH2:40][N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])[CH2:44][CH2:43]3)=[O:28])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:16])=[O:17])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2c1
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N3CCN(c4ccccc4Cl)CC3)cc2c1
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
The thus obtained N2 -(7-methoxy-2-naphthalene-sulfonyl)-L-arginyl chloride (2.4 g) is immediately added to a solution of 1.64 g (0.00608 mole) 1-(2-chlorophenyl)piperazine dihydrochloride and 2.56 g (0.0253 mole) triethylamine in 50 ml chloroform under ice chilling. After 10 minutes, the mixture is brought to room temperature, and allowed to stand overnight. Then the reaction mixture is washed with water and the solvent is distilled off. The residue is washed with ethyl ether and dissolved in a 30%-ethanol/50 ml water mixture, and made basic with a 2N sodium hydroxide aqueous solution to pH 10. Thus an oily substance is deposited and is crystallized on standing. The crystals are collected by filtration, dried, and recrystallized from 20 ml THF, and 0.83 g of 1-[N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl]-4-(2-chlorophenyl)piperazine is obtained. Yield 28%. m.p. 219°~221° C. (decomp.) IR(KBr): 3330, 1625, 1480 cm-1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1.C([O-])(=O)C.[Na+]>ClCCCl>[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][C:21]([CH:8]=[O:9])=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1
Reactant: COc1c(Br)cc(Br)cc1-c1ccc[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(Br)cc(Br)cc1-c1ccc(C=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Phosphorus oxychloride (0.18 ml, 1.9 mmol) was added to N,N-dimethylformamide (0.15 ml, 1.9 mmol) at 0° C. under argon with constant stirring. The resulting mixture was allowed to warm to room temperature and was then stirred for 1.5 h. 1,2-Dichloroethane (1.5 ml) was added and a solution of 2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole (0.30 g, 0.91 mmol) in 1,2-dichloroethane (3 ml) was then added at 0° C. The reaction mixture was stirred at room temperature for 16 h. On cooling, the mixture was poured onto crushed ice and basified with aqueous sodium acetate (50%, 20 ml). The organic phase was separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with aqueous sodium hydrogen carbonate, dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on alumina (Brockmann grade 1) with ether - methanol (0-1% ) gradient elution gave the title compound (D29) as a beige solid (0.18 g).
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:5][CH2:6][CH3:7])[CH3:4].[N+:8]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9]>CCO>[CH2:3]([N:5]([CH2:6][CH3:7])[CH2:1][C:13]1[N:12]=[C:11]([N+:8]([O-:10])=[O:9])[NH:15][CH:14]=1)[CH3:4]
Reactant: CCNCC
Reactant: C=O
Reactant: O=[N+]([O-])c1ncc[nH]1
Solvent: CCO
Product: CCN(CC)Cc1c[nH]c([N+](=O)[O-])n1
Temperature: 25 °C

Procedure:
Formaldehyde (36% in H2O, 1.0 mL, 13.3 mmol, 1.5 equiv) and diethyl amine (0.92 mL, 8.8 mmol) were added sequentially to a suspension of 2-nitro-imidazole (1 g, 8.8 mmol) in EtOH (20 mL). The resulting mixture was heated to reflux for 18 h, allowed to cool to rt, and concentrated. Trituration of the residue in Et2O afforded an impure sample of the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11]([CH3:13])=O)[N:3]=1.SC[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH2:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Cl)nc(N)nc1SCCc1ccccn1
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a stirred suspension of 1.00 g (4.62 mmol) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile in 10 ml DME were added 642 mg (4.62 mmol) 2-mercapto-ethylpyridine and 1.05 ml (6.92 mmol) DBU and stirring continued for 1 hour at room temperature. 50 ml water was then added and the resulting crystals collected by filtration and washed with ether. Chromatography (ethyl acetate/hexane 111 then ethyl acetate) followed by trituration in ether afforded 300 mg (22%) 2-amino-4-chloro-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 294 (M{37Cl}+H+, 30), 292 (M{35Cl}+H+, 100).
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:22](Br)[CH3:23].CO>O1CCOCC1>[CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][CH2:22][CH3:23])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCBr
Reactant: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(C(=CC1CCCCC1)n1cncn1)C(C)(C)C
Temperature: 50 °C
Yield: 37.7 %

Procedure:
A solution of 26.3 g (0.1 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (Example 2) in 50 ml of dioxan was added dropwise to a suspension of 3 g of 80% strength sodium hydride in 100 ml of dioxan. When the addition had ended, the mixture was warmed to 50° C. for 1 hour. After cooling, 10.9 g (0.1 mol) of ethyl bromide were added dropwise and the reaction mixture was heated under reflux overnight. After cooling, 10 ml of methanol were added and the mixture was concentrated in a rotary evaporator. The residue was taken up in methylene chloride and the methylene chloride mixture was washed with water. After drying the organic phase over sodium sulphate, it was filtered and the filtrate was concentrated. The residue was distilled. 11.0 g (37.8% of theory) of 1-cyclohexyl-3-ethoxy-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene of boiling point 110° C./0.07 mm Hg were obtained.
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[H][H].[C:14]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24][CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O>[C:14]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][O:10][CH2:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:24][CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)c3ccccc3)CC2)cc1
Reactant: [H][H]
Reactant: OCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCC(CCOC/C=C/c2ccccc2)CC1
Reaction time: 18 h
Yield: 64.6 %

Procedure:
Cinnamyl alcohol (1.52 g, 11.3 mmol) an sodium hydrode (0.56 g, 14 mmol, 60% oil disp.) were stirred in dry N,N-dimethylformamide (15 mL) at room temperature under a nitrogen atmosphere for 45 minutes. After the hydrogen gas evolution had ceased, a solution of 1-benzoyl-4[(p-toluene sulfonyl)oxyethyl]piperidine (3.93 g, 11.3 mmol) in dry DMF (40 mL) was added, and the mixture was stirred for 18 hours. Additional sodium hydride (0.53 g) was added, and the reaction was further stirred for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (500 mL). The organic phase was extracted with water (5×50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with hexanes to 50% ethyl acetate in hexanes, then concentrated under vacuum to yield (E)-1-benzoyl-4-[(3-phenyl-2-propenyloxy)ethyl]piperidine (2.55 g, 65%) as a yellow oil. IR (neat): 1630 cm-1. HRMS: Calculated for C23H27NO2 : 349.2042; found: 349.2050.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21](I)[C:3]=12.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>C(#N)C.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])[C:3]=12
Reactant: OB(O)c1ccccc1F
Reactant: CN(C)C(=O)c1cncc(-c2cnc3c(c(I)cn3COCC[Si](C)(C)C)c2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cncc(-c2cnc3c(c(-c4ccccc4F)cn3COCC[Si](C)(C)C)c2Cl)c1
Temperature: 110 °C

Procedure:
78 mg (0.14 mmol) of (5-[4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide, 21 mg (0.15 mmol) of 2-fluoro-phenylboronic acid and 6 mg (7 μmol) of (1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct were dissolved in a mixture of 2.6 mL of acetonitrile, 2.6 mL of toluene and 1.5 mL of a saturated aqueous solution of sodium bicarbonate. The resulting mixture was heated to 110° C. in a closed vial for 22 h. The resulting mixture was diluted with ethyl acetate, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of 10% v/v methanol in ethyl acetate and hexanes to afford 56.6 mg (0.10 mmol) of 5-[4-chloro-3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide. 1H-NMR [500 MHz, d6-DMSO] δ: 8.73 (d, 1H), 8.67 (d, 1H), 8.41 (s, 1H), 7.99 (t, 1H), 7.97 (s, 1H), 7.49-7.41 (m, 2H), 7.30-7.25 (m, 2H), 5.74 (s, 2H), 3.62 (t, 2H), 3.01 (s, 3H), 2.97 (s, 3H), 0.86 (t, 2H), −0.06 (s, 9H); MS [MH+] m/z: 525.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])P(OC)(OC)=O.CN(C)C(=N)N(C)C.[N+:28]([C:31]1[C:32]([CH:37]=O)=[N:33][CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C:4](=[CH:37][C:32]1[C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:3]([O:2][CH3:1])=[O:19])=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=Cc1ncccc1[N+](=O)[O-]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=Cc1ncccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Methyl[(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (1.33 g, 4.46 mmol) was dissolved in dry THF (20 mL) and cooled to −78° C. under nitrogen. Tetramethylguanidine (490 mg, 4.26 mmol) was added and the solution stirred at −78° C. for a further 10 mins. A solution of 3-nitropyridine-2-carbaldehyde (Tetrahedron vol 0.54 (1998) p 6311) (618 mg, 4.06 mmol) in dry THF (5 mL.) was added drop wise. After stirring the solution for 2 hours. at −78° C. (50 mL) it was diluted with water (150 mL) and extracted with ethyl acetate. The combined extracts were washed with water (2×20 mL) and brine (20 mL), dried (MgSO4) and evaporated under reduced pressure to give a yellow oil, which was purified by column chromatography (DCM) to give the title compound as a 4:1 mixture of Z/E isomers (1.1 g, 84%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[F:30][C:29]([F:32])([F:31])[C:27]([O-:33])=[O:28].[N:1]1([C:6]2[CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][NH2+:17][CH2:18][CH2:19]3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cccc(-n3cnnn3)c2)CC1
Product: O=C([O-])C(F)(F)F
Product: c1cc(CCN2CC[NH2+]CC2)cc(-n2cnnn2)c1

Procedure:
The t-butyl 4-{2-[3-(1H-tetrazol-1yl)phenyl]ethyl}piperazine-1-carboxylate (280 mg, 2.15 mmol) was stirred in TFA (5 ml) for ½ hr then concentrated and dried to yield 4-{2-[3-(1h-tetrazol-1yl)phenyl]ethyl}piperazin-1-ium trifluoroacetate. LC-MS (IE, m/z): 259 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2C(O)=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.[OH:35][C:36]1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:36](=[O:35])[C:18]1[CH:17]=[CH:13][C:12]([S:9](=[O:10])(=[O:11])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:24])([F:23])[F:22])[CH:4]=2)=[CH:20][CH:19]=1)[CH3:27]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up in analogous fashion. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C:16]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:28][C:27]1[C:16]([NH:15][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[C:17]([CH:24]=[CH:25][CH:26]=1)[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 1 h
Yield: 82.9 %

Procedure:
4-(trifluoromethoxy)benzoyl chloride (0.29 g, 1.3 mmol) was added dropwise to a mixture of the aniline from Step B (0.25 g, 1.3 mmol) and triethylamine (0.13 g, 1.3 mmol) in 5 mL of methylene chloride at room temperature. After stirring for one hour the reaction was poured into water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated under reduced pressure. The resulting solids were washed with hexane/ether and filtered to afford 0.41 g of the title compound, a compound of the present invention, as a solid melting at 207-209° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].BrBr.C([OH:23])(C)(C)C>>[C:12]([C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])[CH:16]=[O:23])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)O
Agent: BrBr
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O

Procedure:
In a 5 l., four-neck, round-bottom flask equipped with a thermometer, mechanical stirrer, dropping funnel and vent tube were placed 600 gm. of 2.6-di-t-butyl-p-cresol and 3600 ml. of t-butyl alcohol. To this stirred solution at 25°-35° C were added 908 gm. of Br2 over a period of ten hours. The resulting solid was separated by filtration, washed with hexane and dried. The yield was 440 gm. (71%) of aldehyde melting at 187°-189° C.