Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[S:26])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[N:9]=[CH:8][C:7]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:15])=[C:6]2[OH:25].C1COCC1.C(Cl)Cl.O(C)S(C(F)(F)F)(=O)=O.[N:44]1C=CC=CC=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:25])=[CH:4][C:3]([C:2]([NH:1][NH2:44])=[S:26])=[CH:12][C:11]=3[F:13])=[O:15])=[CH:19][CH:20]=1
Reactant: c1ccncc1
Reactant: NC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: NNC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.75 h

Procedure:
To a suspension of the title compound of Example 52 (0.60 g) in 20 mL 1:1 THF:CH2Cl2 at room temperature is added methyl triflate (0.2 mL). The reaction is stirred for 45 minutes after which time everything goes into solution. Pyridine (0.38 mL) is added and then H2S is bubbled in for 1 hour. Nitrogen is then purged through the reaction for 30 minutes. Hydrazine monohydrate (0.28 mL) is added dropwise to the reaction mixture. The reaction is stirred for 1 hour after which time the solution turned from an orange to a pale yellow color and a precipitate is observed. The solid in the reaction is filtered and dried to give the desired product (0.26 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:43])[CH2:34][NH:35]C(OC(C)(C)C)=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC(=O)NC1CCCN(CC2NC(C3C=CC(C4C=CC(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)=CC=4)=CC=3)=CN=2)C1=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:44])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:43])[CH2:34][NH2:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CNC(=O)OC(C)(C)C)cc3)cc2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CN)cc3)cc2)[nH]1)C(C)C

Procedure:
[1-(2-{5-[4′-(2-Amino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared using method 804 substituting [1-(2-{5-[4′-(2-tert-butoxycarbonylamino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C28H33N5O4 calculated 503.3 observed [M+1]+504.2; rt=1.42 min
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[O:7][N:6]=1)=O.O.[NH2:12][NH2:13]>C(O)CCC>[CH3:10][C:8]1[O:7][N:6]=[C:5]([C:3]([NH:12][NH2:13])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(C)on1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1cc(C(=O)NN)no1
Yield: 64 %

Procedure:
As described for example 112a, 5-methyl-isoxazole-3-carboxylic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) at 100° C. for 2 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 64%). 1H-NMR (300 MHz, DMSO): δ=2.44 (d, J=1 Hz, 3H), 4.57 (s, 2H), 6.52 (d, J=1 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.[F:8][C:9]([F:26])([F:25])[C:10](=O)[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O>C(O)(=O)C.O>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[C:10]([C:9]([F:8])([F:26])[F:25])=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)=[N:1][C:2]=12
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1Br
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A stirred mixture of commercially available 3-amino-4-bromo-pyrazole (14.00 g, 86.4 mmol) and 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (Example C.1 step 1) (24.56 g, 86.4 mmol) in acetic acid (170 mL) was heated under reflux conditions for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water (340 mL), the precipitate was filtered off, washed with water and dried in air at 60° C. to give the 3-bromo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (31.77 g, 90%) as a yellow solid. MS (EI) 410.0 [(M)+], 412.0 [(M+2)+]; mp 136° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Li]CCCC.CN([CH:36]=[O:37])C>>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:36]=[O:37])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of 1-(4-bromophenyl)-4-(tert-butoxycarbonyl)piperazine (9.98 g, 29.2 mmol, prepared as described in Example 1) in TI (70 mL) and toluene (70 mL) was added nBuLi (1.6 M in hexanes, 19 mL, 30.4 mmol) at a rate to maintain an internal temperature below −65° C. The resulting solution was stirred 15 min, then treated with DMF (5 mL). The mixture was stirred 30 min at −78° C., then allowed to warm to 0° C., quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated. The crude material was crystalized from dichloromethane/ether/hexanes to give 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzaldehyde. The filtrates were purified by flash chromatography (30% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) to provide an additional 2.16 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 69.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.95 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(OC)C=CC=1.[Mg].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Brc1ccccn1
Reactant: COc1cccc([Mg]Br)c1
Agent: COc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccccn2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
That is, as shown in the reaction scheme below, (3-methoxyphenyl)magnesium bromide was synthesized from 22.4 g (120 mmol) of 3-bromoanisole with 3.4 g of magnesium in dry tetra hydrofuran (THF) in an argon stream by a conventional manner. This was slowly added to a dry THF solution of 15.8 g (100 mmol) of 2-bromopyridine and 1.8 g of (1,2-bis(diphenylphosphino)-ethane)dichloronickel (II) (Ni(dppe)Cl2) and the mixture was stirred at 50° C. for 1 hour. After adding 250 ml of 5% hydrochloric acid aqueous solution to the reaction mixture, the reaction mixture was extracted with chloroform to obtain a target substance and the organic layer was distilled under reduced pressure. 17.4 g (93.9 mmol) of 2-(3-methoxyphenyl)pyridine (3-MeO—PPy) was obtained as a color less transparent liquid. Identification was performed by CHN elementary analysis and 1H-NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Sn](C)(C)C)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([S:12](=[O:14])(=[O:13])[NH:15][CH3:16])[CH:3]=2)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C[Sn](C)(C)c1cc(CCCOCc2ccccc2)nc(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cc(-c2cc(CCCOCc3ccccc3)nc(C#N)n2)cc(C(F)(F)F)c1
Yield: 35 %

Procedure:
3-Bromo-N-methyl-5-trifluoromethyl-benzenesulphonamide (37 mg), 4-(3-benzyloxy-propyl)-6-trimethylstannanyl-pyrimidine-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium(II) (7 mg) in DMF (1 mL) were heated in a microwave to 180° C. for five minutes. The mixture was diluted with ethyl acetate (20 mL) and washed with water (3×20 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield crude product. Purification by preparative-HPLC afforded 4-(3-benzyloxy-propyl)-6-(3-methylsulphamoyl-5-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (16.5 mg).
Reaction SMILES: Cl[CH2:2][S:3][C:4]#[N:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[S:12])=[CH:9][CH:8]=1.O>CO>[S:3]([CH2:2][O:13][C:11](=[S:12])[C:10]1[CH:14]=[CH:15][C:7]([Cl:6])=[CH:8][CH:9]=1)[C:4]#[N:5]
Reactant: N#CSCCl
Reactant: OC(=S)c1ccc(Cl)cc1
Solvent: O
Solvent: CO
Product: N#CSCOC(=S)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
16 g (0.15 mol) of chloromethyl thiocyanate were added dropwise to 31.5 g (0.15 mol) of the K salt of 4-chlorothiobenzoic acid in 200 ml of methanol at 0°-10° and the mixture was then first warmed to room temperature and then to 50°-60°, until the reaction had taken place. The cooled mixture was poured onto 1 liter of cold water, whilst stirring vigorously, and the precipitate was filtered off and dried. Light pink-coloured crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:35])[C@H:23]([CH2:32][CH2:33]O)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:35])[CH:23]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:32][CH2:33][Br:37]
Reactant: COC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CCBr)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A solution of triphenylphosphine (2.20 g, 8.39 mmol) in dry CH2Cl2 (20 mL) was added dropwise via syringe to a solution of N-Boc homoserine methyl ester 18 (8.39 mmol) and carbon tetrabromide (4.18 g, 12.60 mmol) in dry CH2Cl2 (20 mL). The resulting dark solution was stirred at room temperature for 16 h. Hexanes was added and precipitates were removed by suction filtration. The filtrate was concentrated under reduced pressure and subject to flash silica gel column chromatography using ethyl acetate/hexanes (1:10, v/v then 1:6, v/v) to give the desired product 19 as a yellow oil (501 mg, 20% overall yield from homoserine). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 2.12-2.48 (m, 2H), 3.39-3.47 (m, 2H), 3.78 (s, 3H), 4.33-4.48 (m, 1H), 5.10-5.22 (m, 1H). m/z (ESI) 296 [C10H18BrNO4+H]+.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:7][S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)C1CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cyclopropanesulfonamide (6.51 g, triethylamine (40 mL) and DMAP (0.656 g) in DCM (150 mL) was slowly added benzyl chloroformate (12 mL). The mixture was stirred at room temperature for 18 hours. The mixture was washed with 1 N HCl. The aqueous layer (pH 1) was extracted with EtOAc (×2). The combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated. The resulting residue was purified by flash chromatography (ISCO, 0-10% methanol in dichloromethane) to afford the desired product (7.8 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.56-7.44 (m, 1H), 7.38 (s, 5H), 5.22 (s, 2H), 2.92-2.84 (m, 1H), 1.40-1.35 (m, 2H), 1.12-1.06 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[C:10]([O-])([O-])=[O:11].[K+].[K+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O.C1(C)C=CC=CC=1>[C:4]([C@@H:5]1[CH2:7][O:8][C:10](=[O:11])[NH:6]1)([O:3][CH3:2])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1COC(=O)N1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To (S)-serine methyl ester hydrochloride (20 g, 128.64 mmol) in water (230 ml) was added KHCO3 (14.16 g, 141.52 mmol) and K2CO3 (19.56 g, 141.52 mmol) at room temperature. It was then cooled by an ice bath and triphosgene (19.04 gm, 64.32 mmol) was added in toluene (192 ml) via an addition funnel over 25 minutes. The reaction mixture turned cloudy. After 2 h, reaction phases were separated and the aqueous layer was lyophilized to yield (S)-4-carbomethoxy-2-oxazolidinone as a white solid (16.5 g) in 88% yield.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[CH:14][C:13]=12>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:18]([C:16]1[CH:15]=[CH:14][C:13]2=[N:9][O:10][N:11]=[C:12]2[CH:17]=1)=[O:19]
Reactant: CNc1ccccc1
Reactant: O=C(Cl)c1ccc2nonc2c1
Product: CN(C(=O)c1ccc2nonc2c1)c1ccccc1

Procedure:
Prepared from N-methylaniline and [2,1,3]-benzoxadiazole-5-carbonylchloride using the procedure described for Example 7. N-Methyl-N-phenyl-[2,1,3]-benzoxadiazole-5-carboxamide was isolated as a yellow oil. LC-MS, MH+=254; 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H); 7.64 (d, 1H, J=9.6 Hz); 7.34 (d, 1H, J=9.6 Hz); 7.29-7.09 (m, 5H); 3.54 ppm (s, 3H).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(=NO)c1ccccc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
329 mg (1.0 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 149 mg (1.1 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 235 mg (55% of theory)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17]([C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[CH:22]=[CH:23]C=2O)=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Cl>O1CCCC1.N1C=CC=CC=1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[C:21]1[CH:22]=[CH:23][C:5]2[O:4][C:2](=[O:3])[N:16]([C:10]3[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=3)[C:17](=[O:18])[C:19]=2[CH:20]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)cc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 43 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 11 (1.54 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 23.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[ClH:49]>CO>[ClH:49].[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:24]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Cc1ccnc(F)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(-n2c(/C=C/c3ccccc3)nc3ccccc32)c1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-fluoro-4-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]([CH3:30])[CH:26]=[CH:27][CH2:28][OH:29])=[CH:22][CH:21]=1>CS(C)=O>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH3:30])[CH:26]=[CH:27][CH2:28][OH:29])=[CH:31][CH:32]=1)[CH:11]=[N:10]2
Reactant: Fc1ccc2nc(Cl)cnc2c1
Reactant: CC(C=CCO)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
A mixture of 1.28 g (7 mmol) of 2-chloro-6-fluoroquinoxaline, 1.16 g (8.4 mmol) of anhydrous, powdered potassium carbonate, 1.55 g (8 mmol) of 4-(4-hydroxyphenoxy)-2-penten-1-ol and 20 ml of DMSO was warmed, under nitrogen, at 110° C. for a period of 2 hours. The mixture was cooled to room temperature, poured into dilute, aqueous HCl and extracted with two portions of ether. The combined organic layers were washed twice with 1 percent aqueous NaOH and with water, dried over MgSO4 and evaporated to dryness. The residue was purified by preparative scale HPLC, eluting with 3:1 hexane:acetone. After removal of solvent the resulting tan crystals were recrystallized from methylcyclohexane to give 1.05 g of crystals which were further purified by recrystallization from toluene to leave nearly colorless crystals, m.p. 109°-111° C. (Compound F)
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30](NCC)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30]([NH:18][CH:15]2[CH2:17][CH2:16]2)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: NC1CC1
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1cc(S(=O)(=O)NC2CC2)c(F)cc1Cl

Procedure:
1.005 g (3.6 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 0.76 mL (10.9 mmol) cyclopropylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])[CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[I:24]I>O1CCCC1>[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])[CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[I:24]
Reactant: Cc1ccc(C)n1C(C)c1ncccc1F
Reactant: II
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A dry 250 ml 3-neck roundbottom flask equipped with a thermometer, rubber septum, magnetic stirrer, and nitrogen inlet was charged with 30 ml of anhydrous tetrahydrofuran and 2.1 ml (14.67 mmole) of dry diisopropylamine. The stirring solution was cooled to −78° C. After which 9.5 ml (15.11 mmole) of 1,6 n-butyllithium in hexanes was added over 10 minutes by syringe. The solution was stirred 30 minutes longer and 3.2 g (14.67 mmole) of N-[(3-Fluoropyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole in 30 ml of dry tetrahydrofuran was added dropwise via syringe over 30 minutes, keeping the internal temperature below −65° C. After stirring 30 minutes longer, a solution of 4.0 g (15.80 mmole) of iodine in 30 ml of dry tetrahydrofuran was added by canula over 10 minutes. The mixture was warmed to room temperature (a color change, quenching, occurred at −30° C.) and stirred overnight under nitrogen. The solution was diluted to 200 ml with ethyl ether, extracted with aqueous saturated sodium bicarbonate (IX), brine (IX), and dried over sodium sulfate. Filtration and concentration gave a dark solid which was purified by flash silica gel chromatography (20% ethyl acetate in hexanes) to give the titled compound as a white solid, 3,9 g (77%): mp 156-158° C.; IR (KBr, cm−1) 3000, 2950, 1574, 1408, 752; 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H) 7.85 (t, 1H), 5.60 (s, 2H), 4.05 (t, 2H), 3.00 (dt, 2H), 2.10 (s, 6H); MS (FD) m/e 344 (Mt). Anal. Calc'd. for C13H14FIN2: C, 45.37; H, 4.10; N, 8.14. Found: C, 45.07; H, 4.03; N, 8.06.