Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Br[C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1>N1C=CC=CC=1.[Cu]Br>[CH:3]1([N:7]2[CH2:8][CH2:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]5)=[N:22][CH:21]=4)=[CH:14][C:11]=3[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Brc1cnc(N2CCCCC2)nc1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1cc2c(cc1Oc1cnc(N3CCCCC3)nc1)CCN(C1CCC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 44 mg, 1.1 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.92 mmol) and copper (I) bromide (184 mg, 1.3 mmol) in pyridine (10 ml) at 0° C. After stirring for 0.5 hour at room temperature, 5-bromo-2-(1-piperidinyl)pyrimidine (D32) (0.669 g, 2.8 mmol) was added and the reaction mixture heated at reflux for 2 hours. The reaction was allowed to cool, filtered and the filtrate was concentrated in vacuo. The crude residue was dissolved with ethyl acetate and washed with water and brine. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Purification of the resulting residue by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) afforded the title compound (E140). MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14]([C:16]1[S:17][C:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:20]=1)=[O:15])[CH2:9]2>N1C=CC=CC=1.O>[CH:12]12[CH2:13][CH:8]1[CH2:9][N:10]([C:14]([C:16]1[S:17][C:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:5](=[O:7])[CH3:6])(=[O:36])=[O:35])=[CH:30][CH:29]=3)=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[N:20]=1)=[O:15])[CH2:11]2
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccc(-c2sc(C(=O)N3CC4CC4C3)nc2-c2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-c2sc(C(=O)N3CC4CC4C3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
Acetic anhydride (0.66 g, 0.65 mmol) was added to stirred solution of 44243-azabicyclo[3.1.0]hexane-3-carbonyl)-4-(4-chlorophenyl)thiazol-5-yl)benzenesulfonamide (Compound 73, 0.3 g, 0.65 mmol) in pyridine (5 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The progress of reaction was monitored by TLC. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 25% ethyl acetate in hexanes as an eluent to obtain the title compound (0.07 g, 21.4%). MS: m/z 502 (M+1).
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].C[O:12][C:13](=O)[CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=O>>[F:10][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([F:1])[C:8]=1[OH:9])[O:4][C:13](=[O:12])[CH:14]=[C:15]2[C:17]([F:20])([F:19])[F:18]
Reactant: COC(=O)CC(=O)C(F)(F)F
Reactant: Oc1ccc(F)c(O)c1F
Product: O=c1cc(C(F)(F)F)c2cc(F)c(O)c(F)c2o1
Temperature: 0 °C
Yield: 29.1 %

Procedure:
A solution of Compound 4 (0.46 g, 3.1 mmol) and methyl-4,4,4-trifluoroacetoacetate (0.55 g, 3.2 mmol) in 7 mL CH3 SO3H is stirred at 20° C. for 48 hours. The reaction mixture is poured into 70 mL ice water, and the resulting precipitate is collected by filtration, washed with water, dried in vacuo at 60° C. for 16 hours to yield 240 mg (30%) of Compound 20 as an off-white powder. 1 H-NMR (DMSO-d6) δ 7.33 (d, 1 H), 6.99 (s, 1H). 19F-NMR (DMSO-d6) Φ 59.38 (s, 3F), 129.93 (t, J=9.9 Hz, 1H), 147.78 (d, J=9.3 Hz, 1F).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2ccc(Cl)nn2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 10.4 %

Procedure:
To a suspension of 3,6-dichloropyridazine (2.98 g), 3-nitrophenylboronic acid (1.67 g) and tetralis(triphenylphosphine)-palladium (578 mg) in 1,2-dimethoxyethane (30 ml) was added an aqueous solution of sodium carbonate (2M, 15 ml), and the mixture was stirred at 80° C. for 3 hours. The mixture was diluted with ethyl acetate, and then washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 30% ethyl acetate in n-hexane to give 3-chloro-6-(3-nitro-phenyl)-pyridazine (0.246 g, 10.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].[CH3:17]C1C=CC(S(C)(=O)=O)=CC=1.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[N:7]([CH3:17])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2cc(Cl)ccc2c(=O)[nH]1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cc(Cl)ccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A mixture of 0.96 g (5.0 mmol) of 7-chloro-2-methyl-4(3H)-quinazolinone and 0.20 g (4.8 mmol) of lithium hydroxide monohydrate in 25 ml of tetrahydrofuran is heated at reflux with stirring for 0.5 h. After cooling to room temperature, 0.89 g (4.8 mmol) of methyl p-toluene sulfonate is added and the reaction mixture heated at reflux for 4 hours. The reaction mixture is neutralized with con. HCl and the solvent removed in vacuo to give a residue. The residue is slurried with 50 ml of water, filtered, washed with 50 ml of 0.5M sodium hydroxide, followed by (3×50 ml) of water. The solid is dried to give 0.73 g (73%) of the desired product, m.p. 162°-165° C. None of the isomeric O-alkylated product is detected by HPLC.
Reaction SMILES: [CH2:1]([N:3]1[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]2[CH:11]=[C:12]([CH2:15]O)[CH:13]=[N:14][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:15][C:12]3[CH:13]=[N:14][C:4]4[N:3]([CH2:1][CH3:2])[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]=4[CH:11]=3)[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CCN1c2ncc(CO)cc2NC(=O)[C@@H]1C
Product: CCN1c2ncc(CN3CC=C(c4ccc(Cl)cc4)CC3)cc2NC(=O)[C@@H]1C

Procedure:
Compound 63 was prepared using a procedure analogous to that described in connection with compound 1D, except that (5)-4-ethyl-7-(hydroxymethyl)-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one was used instead of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was used instead of 1-(4-chlorophenyl)piperazine. 1H NMR(CHLOROFORM-d) δ (ppm): 7.79 (d, J=1.5 Hz, 1H), 7.68 (br. s., 1H), 7.27-7.34 (m, 4H), 7.02 (s, 1H), 6.06 (br. s., 1H), 4.21 (q, J=6.8 Hz, 1H), 3.98-4.12 (m, 1H), 3.44-3.61 (m, 2H), 3.07-3.26 (m, 3H), 2.75 (t, J=5.2 Hz, 2H), 2.55 (br. s., 2H), 1.36 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H); [M+H] calc'd for C22H25ClN4O, 397; found, 397.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:16]([CH3:20])(I)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>C(#N)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([CH3:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)I
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1=C(C)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Yield: 27.1 %

Procedure:
A mixture of methyl 7-(2-phenoxyacetamido)-3-methyl-3-iodocepham-4-carboxylate (0.25 g.) in dry acetonitrile (10 cc) and sodium acetate (45 mg.) was heated under reflux for 4 hours and concentrated. The residue was mixed with water and extracted with chloroform. The chloroform layer was washed with an aqueous sodium thiosulfate solution and then with water, dried and concentrated. The residue was subjected to chromatography on silica gel and eluated with chloroform to yield crystals (50 mg.) of methyl 7-(2phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 124°-125° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][O-:19].[Na+]>CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11](=[NH:12])[O:19][CH3:18])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1cn(COCCO)c2ncnc(N)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cn(COCCO)c2ncnc(N)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-amino7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]-pyrimidine-5-formimidate was prepared by first dissolving compound (17a) (0.5 g; 2.15 mmole) in dry MeOH (15 ML). A sodium methoxide (1 M) solution (5 mL) was added and the mixture was stirred at room temperature for 3 hours. This solution was adjusted to pH7 by adding small portions of Dowex 50 (H+ form, prewashed with dry CH3OH). The solution was then quickly filtered to remove the ion-exchange resin followed by concentration of the filtrate in vacuo to a semisolid mass. The residue was purified by a column (2×60 cm; prepacked in CH2Cl2) of silica gel (15 g; 60-200 mesh). Elution of the column with CH2Cl2 :CH3OH (96:4, V:V) afforded the desired nucleoside which was crystallized from dry CH3OH-ET2O to afford the pure imidate (0.13 g; yield 23%); mp. 124° C.; IR (KBr)γ3350 (OH) and 1600 cm-1 ; UVλmax nm:(pH 1), 237 (14700) 280 (12710); (MeOH), 278 (15770); (pH 11), 217 (26100) 278 (13880). 1H NMR (DMSO-d6): δ3.50 (nm, 4, CH2), 3.75 (s, 3, OCH3), 5.58 (s, 2, C1 ''CH2), 7.25 (brs 1, NH2), 7.75 (s, 1, C6 --H), 8.06 (s, 1, C2 --H), 8.20 (brs, 1, C=NH, 9.98 (brs,1,NH2). Anal. (C11H15N5O3) C,H,N.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@H:16]([OH:18])[CH2:15][N:14]2[C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C:16](=[O:18])[CH2:15][N:14]2[C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:27])([F:28])[F:29])=[CH:21][N:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@H](O)CN2c2ncc(C(F)(F)F)cc2Cl)no1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CC(=O)CN2c2ncc(C(F)(F)F)cc2Cl)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S,4S)-1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (183 mg, 0.423 mmol) in dimethyl sulfoxide (5 mL) is added triethylamine (0.118 mL, 0.846 mmol) and sulfur trioxide pyridine complex (115 mg, 0.72 mmol). The reaction is stirred at room temperature for 4 hours. More triethylamine (0.18 mL, 1.27 mmol) and sulfur trioxide pyridine complex (155 mg, 0.97 mmol) are added to the reaction mixture and the stirring is continued for another 2 hours. The reaction is quenched with 1N hydrochloric acid aqueous solution and the solid precipitated out of the solution is filtered and dissolved in dichloromethane and washed with saturated sodium bicarbonate aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with ethyl acetate/hexanes and further purification using pre LC-MS provides the title compound, ESI m/z 431 [M+H+].
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([C:27]#[N:28])([CH2:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25])[CH2:6][CH2:7][CH:8]=[CH2:9])C.[Li+].[OH-].Cl>CO.O>[C:27]([C:5]([CH2:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25])([CH2:6][CH2:7][CH:8]=[CH2:9])[C:4]([OH:29])=[O:3])#[N:28]
Reactant: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid ethyl ester (2.84 g, 7.20 mmol) was dissolved in methanol (42 mL). In a separate flask LiOH (1.5 g, 36.0 mmol) was dissolved in water (21 mL). The LiOH solution was added to the methanolic solution containing 2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid ethyl ester and the reaction was allowed to stir at room temperature for 2 hours. Next, 12N HCl (3 mL) was added to the reaction mixture followed by removal of the methanol under reduced pressure. The reaction mixture was poured into a separatory funnel, ethyl acetate was added and the organic layer washed 2 times with 1N HCl and one time with saturated brine solution. The organic layer was separated, dried with sodium sulfate, filtered and the solvent was removed to yield a residue.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nc2cccc(Br)n2n1
Product: Nc1nc2cccc(-c3ccccc3)n2n1

Procedure:
5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3.00 g, 14.0 mmol) and phenyl boronic acid (1.8 g, 15.0 mmol), in a manner analogous to Step 73c. The product was isolated as a white powder (0.567 g, 19%) after chromatography on an Isco silica gel column (80 g) using methanol in dichloromethane as the eluent. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.94 (d, J=6.9 Hz, 2H), 7.52 (m, 4H), 7.37 (m, 1H), 7.02 (d, J=6.5 Hz, 1H), 6.02 (s, 2H). MS=210 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]=[C:13]=[S:12])=[O:10])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)N=C=S
Reaction time: 1.5 h

Procedure:
4-Fluorophenylacetylchloride (Aldrich, 0.017 mL, 0.126 mmol, 2.5 eq) was added to a solution of sodium thiocyanate (0.014 g, 0.176 mmol, 3.5 eq) in ethyl acetate (1.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to afford a 2-(4-fluorophenyl)ethanoyl isothiocyanate solution (0.126 M). 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 0.011 g, 0.050 mmol, 1.0 eq) was dissolved in CH2Cl2 (1.0 mL) and 2-(4-fluorophenyl)ethanoyl isothiocyanate (0.126 M, 0.50 mL, 0.063 mmol, 1.3 eq) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 0-6% MeOH in CHCl3) to afford the title compound (0.008 g, 38%) as a solid. 1H NMR (CD3OD) δ 7.85-7.95 (m, 1H), 7.67-7.69 (m, 1H), 7.13-7.28 (m, 4H), 6.95-7.00 (m, 2H), 6.05-6.15 (m, 1H), 5.90-5.91 (m, 1H), 3.65 (s, 2H); MS(ESI+) m/z 415 (M+H)+; HRMS(ESI+) calculated: 415.1040, found: 415.1041.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)[CH:5]=1.[OH-].[K+].Cl>CO.O>[O:23]([CH2:22][C:21]([N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]1[C:13]1[N:14]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:31])=[O:2])[S:11][CH:12]=1)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3C(=O)COc3ccccc3)cs2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2nc([C@H]3CCCCN3C(=O)COc3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
A solution of 3-{4-[(R)-1-(2-phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid methyl ester (0.030 g, 0.069 mmol) (prepared as illustrated in example 24) in methanol (0.5 mL) was treated with 1N KOH (0.14 mL, 0.14 mmol). The mixture was stirred at room temperature for 16 h, then diluted with water (0.5 mL) and acidified to pH 1 with HCl 0.5N. A white solid precipitated, which was filtered to yield 3-{4-[(R)-1-(2-phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid (0.022 g, 76%), MS (ISP): 421.3 (M−H). 1H-NMR (CDCl3, 300 MHz): 13.33 (1H, bs), 8.44 (1H, s), 8.15 (1H, d), 8.04 (1H, d), 7.65 (1H, m), 7.23 (2H, m), 6.92 (3H, m), 5.76+5.33 (1H, bs), 4.94 (2H, m), 4.34+3.80 (1H, bd), 3.32 (3H, m), 1.64 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([N:29]2[CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28]2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1cc(Br)c2cccnc2c1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-8-hydroxyquinoline-7-carboxylic acid of Preparation 4 (150 mg, 0.56 mmol) and di(1H-imidazol-1-yl)methanone (90.7 mg, 0.56 mmol) in THF (10 mL) was heated to reflux for 3 h, under nitrogen. The reaction mixture was allowed to cool to RT and isoindoline (53 mg, 0.45 mmol) was added. The resulting mixture was stirred at RT overnight. The reaction mixture was then quenched with H2O and an aqueous saturated solution of sodium hydrogen carbonate, and twice extracted with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SPE-SI cartridge (2 g, DCM to DCM:MeOH 99:1) affording the title compound (39.1 mg, 0.11 mmol) as a light brown solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]=[N+:13]=[N-:14])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[F:28])[CH3:2].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[C:30]#[CH:31]>C(O)C>[CH2:34]([O:33][C:29]([C:30]1[N:14]=[N:13][N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4]([CH2:15][N:16]4[CH:20]=[CH:19][N:18]=[C:17]4[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[F:28])=[N:5][C:6]=3[CH:11]=2)[CH:31]=1)=[O:32])[CH3:35]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N=[N+]=[N-])ccc21
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc3c(c2)nc(Cn2ccnc2-c2cc(F)ccc2F)n3CC)nn1

Procedure:
A mixture of crude 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole (143 mg) and ethyl propiolate (1 eq.) in ethanol (10 mL) is heated at reflux for 6 h. The mixture is cooled, concentrated, and the residue purified by preparative silica gel chromatography to give 1-{2-[2-(2,5-Difluoro-phenyl)-imidazol-1-ylmethyl]-1-ethyl-1H-benzoimidazol-5-yl}-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 8.51s, (1H), 8.05(s, 1H), 7.74(m,1H), 7.50-7.39(m,4H), 7.21-7.17(m,2H), 7.06(s,1H), 5.54(s,2H), 4.47(q,2H), 3.86(q,2H), 1.43(t,3H), 1.04(t,3H), LCMS MH+ 460.6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>>[OH:29][C@:25]([C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)no1
Yield: 28 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (35 mg, 28%)
Reaction SMILES: Cl.[CH2:2]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][O:20][C:21]([CH2:23][CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>>[CH2:2]([N:9]1[C:25]2[CH:24]([CH2:23][C:21]([O:20][CH2:19][CH3:18])=[O:22])[CH2:29][CH2:28][CH2:27][C:26]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccccc1)c1ccc(F)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccccc1)c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(benzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[OH:30]>[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[OH:30])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)/C=C(/C)c1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CO
Agent: [Pd]
Product: CCOC(=O)CC(C)c1ccc(C2CCN(C(=O)OC(C)(C)C)C(O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 12-1 (400 mg, 1.0 mmoles), 10% Pd/C (160 mg), and CH3OH (5 mL) was stirred at ambient temperature under a hydrogen atmosphere for 3.0 hours. The reaction mixture was filtered through a celite pad and the filtrate concentrated to give 12-2 as a yellow oil. Rf 0.33 (silica, 30% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:12][N+](C)=C.[I-]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:12])[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: C=[N+](C)C
Reactant: CC(=O)Cc1ccc(Cl)cc1
Agent: [I-]
Solvent: CC(=O)O
Product: C=C(C(C)=O)c1ccc(Cl)cc1
Temperature: 125 °C
Yield: 42.6 %

Procedure:
1-(4-Chloro-phenyl)-propan-2-one (8.6 g, 51 mmol) and Eschenmoser's salt (12.3 g, 66.3 mmol) were dissolved in glacial acetic acid and heated in a closed pressure tube at 125° C. under nitrogen for 1 h. After cooling to room temperature, the solution was concentrated. The residue was dissolved in EtOAc, washed with saturated NaHCO3 aqueous solution, dried (MgSO4), concentrated, and chromatographed (SiO2, 39:1-19:1 hexane/EtOAc) to give 3-(4-chloro-phenyl)-but-3-en-2-one as yellow oil (3.92 g, 43%).