Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].C(COC)OC.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14]2.S([CH2:32][N:33]=C=O)(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[C:32]([CH:15]1[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1)#[N:33]
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of potassium tert-butoxide (18.27 ml) in 1:1 (v/v) mixture of dimethoxyethane and ethanol (100 ml) was added slowly to a stirred mixture of 3-quinuclidinone (8.14 g), tosylmethylisocyanate (16.53 g) in dry ethanol (6.5 ml), and dry dimethoxyethane (228 ml) under an atmosphere of argon whilst maintaining the temperature below 10° C. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 30 minutes. The reaction mixture was then stirred at 40° C. for 3 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by flash column chromatography on alumina (Brockmann Grade I) using a 2:98 (v/v) mixture of methanol/ethyl acetate as eluant to give 3-cyanoquinuclidine (6.6 g), microanalysis, found: C, 67.6; H, 8.5; N, 18.7%; C8H12N2 requires: C, 70.6; H, 8.8; N, 20.6%; NMR (CDCl3): 1.4-1.7 (3H, m), 1.85-2.0 (1H, m) 2.0-2.1 (1H, m) and 2.6-3.4 (7H, m); m/z 137 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([CH3:15])(O)[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].NC(N)CS(F)(F)[F:29].[OH-].[K+].C(OCC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([F:29])([CH3:15])[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reactant: NC(N)CS(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of 1-(6-Bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)-2-methylpropan-2-ol (19.8 g, 49.8 mmol) in DCM (150 mL) was cooled with a dry-ice acetone bath to −73° C. (Diaminoethyl)sulfur trifluoride (6.9 mL, 52.3 mmol) was added dropwise over 2 min; the temperature rose to −62° C. The resulting solution was stirred in the bath for a further 1 hr, then at ambient temperature for 1 hour. The reaction mixture was poured into a separatory funnel containing cold 10% KOH (250 mL), and then diethyl ether (500 mL) was added. After shaking, the organic layer was washed with brine (150 mL), dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 85/15 hexanes/EtOAc as eluent. Fractions containing product were pooled and the solvent removed under reduced pressure to afford the title compound as an orange oil (13.4 g, 78%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NCC(N1CCC[C@H]1C(O)=O)=O)(OC(C)(C)C)=[O:17]>C1COCC1>[CH:10]1([NH:9][C:8](=[O:17])[NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.75 h

Procedure:
A portion (10.3g= 0.05 mole) of dicyclohexylcarbodiimide (DCC) was added dropwise under stirring at 0° C. to a solution of N-Boc-glycyl-L-proline prepared in accordance with the method described in J. Chem. Soc. (C), 954 (1969) (27.2g= 0.1 mole) in dried THF (100ml) and the reaction mixture was kept under continuous stirring for 45 minutes. To the filtrate obtained by filtering-off of dicyclohexyl urea precipitated in the mixture, was added at 0° C. a solution of 7-amino-4-methylcoumarin (8.75g= 0.05 mole) in dimethylformamide (DMF) (60ml). After standing overnight at room temperature, the reaction mixture was concentrated in vacuo to give a residue which was dissolved in ethyl acetate (300ml.). The solution was washed successively with 1 N hydrochloric acid, aqueous 5% sodium bicarbonate and water, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from a binary mixture of ethyl acetate (150ml) and n-hexance (70ml) to give 20.1g (yield, 93.4%) of crystalline 7-(n-BOC-glycyl-L-prolyl)-amino-4-methylcoumarin.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: COCCN
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCNc1ccc([N+](=O)[O-])c(N)c1
Temperature: 135 °C
Reaction time: 48 h
Yield: 60.6 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (21.6 g, 125 mmol), 2-Methoxy-ethylamine (28.1 g, 375 mmol) and anhydrous potassium carbonate (18.9 g, 137 mmol) in N,N-dimethylacetamide (40 ml) was stirred at 135° C. under nitrogen for 2 days. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 30 minutes The resulting precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford N1-(2-methoxy-ethyl)-4-nitro-benzene-1,3-diamine (16 g, 61%) as a yellow-orange powder, and used in the next step without further purification.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[O:43]=[C:38]1[NH:39][C:40](=[O:42])[CH2:41][N:37]1[S:34]([C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:5][CH2:6][C@@H:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=3)[OH:8])[CH2:23][CH2:24]2)=[CH:33][CH:32]=1)(=[O:36])=[O:35]
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CC(=O)NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CC(=O)NC4=O)cc3)CC2)ccc1O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
Acetic acid (0.15 mL, 2.6 mmol) was added dropwise into a mixture N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (320 mg, 1.3 mmol), 1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imidazolidinedione (440 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (331 mg, 1.56 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 4/1) to produce a white solid (496 mg, 67% yield): mp 200-202° C.; c 1.35-1.42 (m, 2H), 1.81-1.97 (m, 2H), 2.7-2.82 (m, 2H), 2.83-2.97 (m, 6H), 3.95-3.97 (m, 2H), 4.22 (s, 2H), 4.57-4.6 (m, 1H), 6.82 (m, 1H), 7.1 (m, 3H), 7.2 (m, 1H), 7.75 (m, 2H), 8.4 (brs, 2H); MS m/e 566 (M−H)+;
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[F:1][C:2]([F:17])([F:16])/[C:3](/[C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:25]/[OH:26]
Reactant: NO
Reactant: CCOC(=O)c1cccc(C(=O)C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(/C(=N\O)C(F)(F)F)c1
Temperature: 57 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57° C. for 3 hours. The reaction mixture was cooled and passed through an ion exchange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0° C. 4-methylbenzene-1-sulfonyl chloride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to −78° C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to −33° C. and stirred for 2 hours after which it was allowed to warm to room temperature overnight with stirring.
Reaction SMILES: Br[C:2]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl>C(OCC)C.CCCCCC>[CH:19]1[C:14]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]=3[CH:3]=[C:2]([B:25]([OH:30])[OH:26])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cc2ccc3ccccc3c2c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A flask was charged with 10.1 g of 5-bromobenzo[c]phenanthrene in an argon atmosphere. 400 mL of dehydrated diethyl ether was then added to the flask. After cooling the reaction solution to −40° C., 22 mL of a 1.6 M hexane solution of n-butyllithium was added to the reaction solution. The mixture was heated to 0° C., and stirred for 1 hour. After cooling the reaction solution to −60° C., a dehydrated diethyl ether (10 mL) solution of 14.4 g of triisopropyl borate was added dropwise to the reaction solution. The reaction solution was stirred for 5 hours while warming the reaction solution up to room temperature. After the addition of 100 mL of a 10% hydrochloric acid aqueous solution, the mixture was stirred for 1 hour. After removing the aqueous phase, the organic phase was washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic phase was concentrated. The resulting solid was washed with hexane to obtain 5.37 g of the target benzo[c]phenanthrene-5-boronic acid (yield: 60%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]([O:16][C:17](=[O:23])[N:18]([CH2:20][CH2:21][NH2:22])[CH3:19])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC(O)C>[C:12]([O:16][C:17](=[O:23])[N:18]([CH2:20][CH2:21][NH:22][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(CCNc1ccc2ncc(Br)n2n1)C(=O)OC(C)(C)C
Yield: 58.9 %

Procedure:
A solution of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (1.4 g, 6.3 mmol), N-(2-aminoethyl)-n-methyl carbamic acid tert-butyl ester [121492-06-6] (961 mg, 5.5 mmol), and Hunig's base [7087-68-5] (1.1 mL, 6.4 mmol) in 2-propanol (28 mL) was heated to reflux for 4d, cooled, preloaded onto silica gel and flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate). The isolated light yellow solid product was recrystallized (ethyl acetate/heptane) to yield 1.2 g of [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester as a white powder, mp. 128-129° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotamers present) 1.16 (s, 6H) 1.33 (br. s., 3H) 2.84 (s, 2H) 2.90 (br. s., 1H) 3.34-3.44 (m, 3H) 3.45-3.52 (m, 1H) 6.68 (d, J=9.60 Hz, 1H) 7.31 (br. s., 1H) 7.49 (s, 1H) 7.72 (d, J=9.35 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.22, 28.45, 34.02, 35.07, 39.02, 39.97, 46.23, 47.06, 78.52, 78.87, 99.57, 113.35, 125.92, 130.80, 137.01, 154.37, 155.39. LRMS (ESI) m/z 370.1/372.1 [(M+H)]+, calc'd for C14H20BrN6O2: 370.25.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC)CCCc1cccc(-c2ccc(CN)cc2)n1
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCc1cccc(-c2ccc(CNCc3ncc[nH]3)cc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.1 %

Procedure:
An anhydrous methanol solution (0.50 ml) containing the compound (30.1 mg) obtained in Example 36-5 and 2-imidazole carboxaldehyde (10.1 mg) was added with trimethyl orthoformate (0.029 ml), and the whole was stirred at room temperature for 14 hours. Sodium borohydride (17.0 mg) was added thereto and the whole was stirred for 30 minutes. The solvent was distilled off. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining the subject compound (30.4 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29](=O)[CH2:30]Br)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:30]=2)=[CH:27][CH:26]=1)#[N:24]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Product: N#Cc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Yield: 37 %

Procedure:
4-[4-(4-Cyano-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (100 mg, 37%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 4-cyanophenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.44-8.47 (m, 2H), 8.27 (d, J=8.5 Hz, 2H), 7.94-8.00 (m, 4H), 7.63-7.68 (m, 1H), 7.47-7.52 (m, 1H), 7.28 (dd, J=7.6, 1.4 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16]([O:20][C:21](=[O:33])[CH2:22][N:23]([C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27](Cl)[N:26]=1)[CH3:24])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>>[C:16]([O:20][C:21](=[O:33])[CH2:22][N:23]([C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:26]=1)[CH3:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(N(C)CC(=O)OC(C)(C)C)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nc(C)cc(N(C)CC(=O)OC(C)(C)C)n2)ccc1-n1cnc(C)c1
Yield: 79 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and [(2-chloro-6-methyl-pyrimidin-4-yl)-methyl-amino]acetic acid tert-butyl ester, using potassium carbonate as a base. The title compound was isolated as a slightly yellow foam in a yield of 79%. MS ISP (m/e): 439.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (s broad, 1H), 7.60 (d, 1H), 7.12 (d, 1H), 7.05-6.95 (m, 2H), 6.85 (s, 1H), 5.94 (s, 1H), 3.87 (s, 3H), 3.12 (s broad, 3H), 2.30 (s, 3H), 2.29 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:46]1([CH2:51][C@@H:52]2[CH2:56][CH2:55][CH2:54][NH:53]2)[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O>[N:46]1([CH2:51][CH:52]2[CH2:56][CH2:55][CH2:54][N:53]2[CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[N:13]=[C:12]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCN4CCCC4CN4CCCC4)cccc32)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and (S)-(+)-2-(pyrroldin-1-ylmethyl)pyrrolidine (28.7 mg, 0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1>>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:15][C:16]=2[NH2:21])=[O:9])=[CH:10][CH:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: NCc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2N)cc1
Yield: 31.5 %

Procedure:
The title compound (195 mg, 63% yield) was prepared as a grey solid from 4-cyano-benzoic acid (294 mg, 2 mmol) and 4-trifluoromethyl-o-phenylenediamine (422 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 310 (M+1).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19]O)=[C:15]([CH3:17])[N:16]=1)[CH3:11].[OH-].[Na+]>CCCCCC.O>[CH2:10]([C:12]1[S:13][C:14]([CH2:18][CH2:19][O:2][N+:1]([O-:4])=[O:3])=[C:15]([CH3:17])[N:16]=1)[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCc1nc(C)c(CCO)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Product: CCc1nc(C)c(CCO[N+](=O)[O-])s1
Reaction time: 2 h
Yield: 58 %

Procedure:
Fifteen (15) ml of nitric acid of (85–90%) were added dropwise to 15 ml of sulfuric acid (95–98%) over a time period of 20 minutes while keeping the temperature at 0–5° C. After 2 hours, 14.3 grams (83.60 mmole) of 2-ethyl-4-methyl-5-thiazoleethanol, prepared as described above, were added, while the temperature was still maintained at 0–5° C., the reaction mixture was stirred for 2 hours at the same temperature, and was then poured carefully onto 125 ml of cold water. The water solution was made basic with a 20% aqueous solution of sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of dichloromethane. The extracts were combined and dried over sodium sulfate, filtered and evaporated to dryness. Chromatography of the crude product on silica gel (using a mixture of 75:25 ethyl acetate:hexane as an eluent) yielded 10.5 grams (58% yield) of colorless liquid having a purity of 98%, as determined by gas chromatography.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[SH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)c1ccc(S)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(Sc2nccs2)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromothiazole (3.9 g) and ethyl 2-(4-mercaptophenyl)propionate (4.56 g), potassium carbonate powder (4.9 g) and dimethylformamide (50 ml) is stirred at 85° C overnight. The reaction mixture is treated in the same manner as in Example 6 to give 2-[4-(2-thiazolylthio)phenyl]-propionic acid melting at 85°-87° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:23])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:2][CH2:3][CH3:4].[S:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>B(F)(F)F.CCOCC.C(Cl)Cl>[CH2:1]([O:5][C:6](=[O:23])[CH:7]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OC(C)=O
Reactant: c1ccsc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OCc1ccccc1)c1cccs1
Reaction time: 16 h

Procedure:
A solution of 1.6 g. (5.0 mmol.) of N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester and 1.0 ml. of thiophene in 10 ml. of methylene chloride was treated with three drops of boron trifluoride etherate and left to stir at 25° for 16 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride and chromatographed on silica gel with methylene chloride containing increasing amounts of ethyl acetate to give the title compound, m.p. 37°.