Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:14](O)=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:13]2[C:12]([N:11]=[C:3]3[C:4]=1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]3[CH3:1])=[CH:20][CH:19]=[C:18]([O:21][CH3:22])[CH:17]=2
Reactant: COc1ccc(Nc2cc([N+](=O)[O-])ccc2C)c(C(=O)O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc3c(C)ccc([N+](=O)[O-])c3c(Cl)c2c1
Yield: 68 %

Procedure:
N-(2′-methyl-5′-nitrophenyl)-5-methoxyanthranilic acid (7.2 g) is heated in phosphorous oxychloride (60 ml) at 120° C. for 1 hour. Excess phosphorous oxychloride is distilled off under reduced pressure, and the residue is poured slowly into a stirred mixture of chloroform, concentrated ammonium hydroxide and ice. The separated chloroformic layer is washed with water and dried using magnesium sulfate. Chloroform is evaporated to dryness, and the residue is crystallized from benzene to give 9-chloro-7-methoxy-4-methyl-1-nitroacridine (6.1 g, 68% yield), m.p. 227-228° C. 1H NMR (d6DMSO): δ 8.23 (d, 1H, J=9.3 Hz), 8.13 (d, 1H, J=7.3 Hz), 7.79 (bd, 1H, J=8.3 Hz), 7.71 (dd, 1H, J1=9.3 Hz, J2=2.9 Hz), 7.58 (d, 1H, J=2.9 Hz), 4.02 (s, 3H), 2.85 (s, 3H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.C(N(CC)CC)C.O>C(Cl)Cl>[I:21][C:22]1[CH:23]=[N:24][N:25]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1
Reactant: Ic1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Ic1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 8 h
Yield: 26.4 %

Procedure:
Trityl chloride (885 mg, 3.2 mmol) was added to a stirred cold (0-5° C.) solution of 4-iodo pyrazole (513 mg, 2.6 mmol) and triethylamine (401 mg, 0.55 mL, 0.4 mmol) in DCM (10 mL). Stirring was continued at room temperature overnight. Cold water was then added and the product was extracted with DCM and the organic layer was washed with sat. sodium bicarbonate solution followed by brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using neutral alumina and 2% EtOAc in Hexane as eluent) to afford 300 mg (26% yield) of 4-iodo-1-trityl-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2
Reactant: OB(O)c1ccccc1
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 70.2 %

Procedure:
A 100-mL round-bottom flask equipped with a balloon filled with air was charged with (5)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.800 g, 2.58 mmol), phenylboronic acid (0.937 g, 7.68 mmol), pyridine (0.83 mL, 10.30 mmol), dichloromethane (50 mL), and copper (II) acetate (0.934 g, 5.14 mmol). The resulting mixture stirred at 40° C. for 1 day. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (gradient elution with 5-10% ethyl acetate/petroleum ether) to afford (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.700 g, 70%) as a white solid. MS (ESI, pos. ion) m/z 386, 388 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:14][CH2:15][N:16](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([NH:16][CH2:15][CH3:14])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)c1c[nH]c(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added DIPEA (0.193 ml, 1.105 mmol), HATU (0.168 g, 0.442 mmol), and ethyl amine (0.045 g, 0.553 mmol) and the reaction stirred at RT for 2 h. Purification was accomplished by HPLC to afford methyl 3-chloro-4-[(ethylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.035 g, 41% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s., 1H) 7.81 (t, 1H) 7.48 (d, 1H) 3.80 (s, 3H) 3.20 (dd, 2H) 1.08 (t, 3H). MS: m/z 231.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21].O.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>CC(C)=O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: C[C@H](CO)CBr
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](CO)CN1CCC(c2nsc3cc(F)ccc23)CC1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.6 g, 20 mmol), (R)-(-)-3-bromo-2-methyl-1-propanol (3.0 g, 20 mmol), K2 CO3 (2.7 g, 20 mmol), tetrabutylammonium sulfate (0.058 g), CH3 CN (95 ml) and H2O (19 ml) was stirred and refluxed for 4.5 hours. After standing at ambient temperature for 16 hours, the reaction was poured into H2O, and subsequent extractive workup of the aqueous with EtOAc yielded 6.8 g of a partially solidified oil. The product was purified by flash chromatography on silica gel, eluting the column with CH2Cl2, then 2% MeOH--CH2Cl2 and finally 5% MeOH--CH2Cl2. Concentration of the appropriate fractions yielded 5.2 g of a waxy solid. The solid was dissolved in acetone and fumaric acid (1.9 g, 1.0 eq) was added and the reaction briefly heated at reflux. The resultant fumarate salt precipitated from solution yielding 4.8 g of white solid. The compound was recrystallized from acetonitrile to yield 3.1 g (36%) of the alcohol as a white solid, m.p.=151°-153° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN1C(=O)CCC1>[O:21]1[CH2:22][CH2:23][N:18]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=2)[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1Nc1ccccc1
Yield: 82.5 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.50 g, 1.7 mmol) and morpholine (0.59 g, 6.8 mmol) in 15 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 5-Morpholino-2-nitro-N-phenylbenzenamine (0.42 g, 80%) was obtained by flash column chromatograph (30% acetyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.26 (t, J=5.2 Hz, 4H), 3.81 (t, J=5.2 Hz, 4H), 6.37 (d, J=2.7, 9.7 Hz, 1H), 6.45 (d, J=2.7 Hz, 1H), 7.25-7.47 (m, 5H), 8.18 (d, J=9.7 Hz, 1H), 9.87 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 47.5, 66.7, 96.6, 105.9, 125.0, 126.0, 129.4, 130.2, 139.4, 145.8, 156.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([Cl:32])=[CH:21][N:20]=1>CS(C)=O>[Cl:32][C:22]1[CH:23]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=3)=[CH:29][CH:30]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: Fc1cc(C(F)(F)F)ccn1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of potassium carbonate (376 mg), 2-fluoro-4-(trifluoromethyl)pyridine (269 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 120° C. for 2 hr. The mixture was neutralized with sat.NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (484 mg) as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.N.C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O1CCOCC1>[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([NH2:41])=[O:37])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(N)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 74.8 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.5 g, 0.86 mmol) was reacted with a dioxane solution (0.5 M) of ammonia (2 mL, 1 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid amide as a white solid (0.3 g, 75%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25]C(=O)C)[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[CH:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[N:4]=[N:3]1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25][S:34]([CH:31]5[CH2:33][CH2:32]5)(=[O:36])=[O:35])[CH:17]=[C:18]([N:20]5[CH:21]=[CH:22][CH:23]=[CH:24]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[N:4]=[N:3]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cn(C)nn4)ccc32)c1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-n3cccc3)c2)nn1

Procedure:
The compound was prepared from the compound of Example 99 using the procedures of Example 100 and cyclopropane sulfonyl chloride. 1H NMR, 300 MHz: (DMSO-d6): δ 10.3 (s, 1H), 8.8 (s, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.46-7.43 (m, 4H), 6.34 (t, 2H), 4.12 (s, 3H), 2.94 (m, 1H), 1.04-1.02 (m, 4H); LC-MS (ESI): Calculated mass: 459.52; Observed mass: 460.1 [M+H]+ (rt: 1.22 min).
Reaction SMILES: [NH2:1][C:2]1[N: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.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:28][C:26]1[CH:27]=[C:22]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 101h (1.3 g, 4.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.24 g, 4.7 mmol), and cesium carbonate (3.8 g, 12 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, XantPhos (272 mg, 0.47 mmol) and tris(dibenzylideneacetone)dipalladium(0) (430 mg, 0.47 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (100 mL) and water (100 mL), and filtered. The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with brine (50 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 50:1 methylene chloride/methanol to afford 101i (1.3 g, 59%). MS: [M+H]+ 464.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3C2)CC1
Reaction time: 16 h
Yield: 97.1 %

Procedure:
First 3.76 g (24 mmol) of piperidine-4-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction by shaking is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.8 g (100%) of crude product are obtained which are chromatographed on 200 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.7 g (97.3%) of 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are then obtained in the form of a colourless oil. The 1-[2-chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced thereform using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182°-186°.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:45][CH:44]=1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cc2ccc(F)cc2)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of MTBE and heptanes.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCN(C2CCNCC2)CCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was coupled with 1-piperidin-4-yl-[1,4]diazepan-5-one (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3243.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:49][O:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:10]([NH:12][CH:13]2[C:47](=[O:48])[N:15]3[C:16]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[C:17]([O:20][S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].ClC1C=CC=C(C(OO)=[O:67])C=1>C(Cl)Cl>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:49][O:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:10]([NH:12][CH:13]2[C:47](=[O:48])[N:15]3[C:16]([C:31]([O:33][CH:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:32])=[C:17]([O:20][S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:22])=[O:23])[CH2:18][S:19](=[O:67])[C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c4csc(NC=O)n4)[C@H]3SC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c4csc(NC=O)n4)[C@H]3S(=O)C2)cc1

Procedure:
To a solution of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-tosyloxy-3-cephem-4-carboxylate (syn isomer) (3.2 g) in methylene chloride (20 ml) was added m-chloroperbenzoic acid (1.62 g) at ambient temperature. The mixture was stirred for an hour. The resulting solution was concentrated under reduced pressure and the residue was subjected to column chromatography on silica gel (eluent: benzene-ethyl acetate) to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-tosyloxy-3-cephem-4-carboxylate-1-oxide (syn isomer), 0.6 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([NH:13][NH2:14])=[O:12])[N:10]=2)[CH:7]=1.[C:16](OCC)(OCC)(OCC)[CH3:17]>CC(O)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]3[O:12][C:16]([CH3:17])=[N:14][N:13]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1c(C(=O)NN)nc2ccc(I)cn12
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: Cc1nnc(-c2nc3ccc(I)cn3c2C)o1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carbohydrazide (200 mg) in AcOH (0.5 ml) was added triethyl orthoacetate (2 ml) at room temperature, and the reaction mixture was heated at reflux for 4 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, and the EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (100 mg) as a light yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]([CH3:18])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCOCC1.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([CH:16]([OH:17])[CH3:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2ccc(C(C)=O)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccc(C(C)O)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 22 g (0.090 mole) of methyl 5-(p-acetamido-phenyl)-2-furyl ketone and 345 ml of 95% dioxane/H2O was added portionwise 3.4 g (0.090 mole) of NaBH4 while maintaining the temperature at 15°-20°. The resulting mixture was stirred overnight at room temperature and then added to ice/water. The solid was filtered and dried at 60° to yield 21 g (95%), m.p. 175°-177°, of title compound.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.C(=O)=O.S1C(S(N)(=O)=O)=CC2C=CC=CC1=2.C1(C)C=CC(S([C:42]#[N:43])(=O)=O)=CC=1>O1CCCC1.[Zn+2].[I-].[I-]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:42]#[N:43])[S:13][C:12]=2[CH:16]=1
Reactant: COc1ccc2ccsc2c1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: NS(=O)(=O)c1cc2ccccc2s1
Agent: O=C=O
Agent: [I-]
Solvent: C1CCOC1
Product: COc1ccc2cc(C#N)sc2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
A 2.5 M solution of n-BuLi (39.65 mL, 99.13 mmol) was added at −20° C. to a stirred solution of 14.8 g (90.12 mmol) of 6-methoxybenzo[b]thiophene (S. L. Grahm, et al. Topically Active Carbonic Anhydride Inhibitor. 2. Benzo[b]thiophenesulfonamide Derivatives with Ocular Hypotensive Activity. J. Med. Chem. 1989, 32 2548-2554) in 100 mL of anhydrous tetrahydrofuran with 5 mg of 2,2′-dipyridyl over 15 min. The resulting solution was stirred at −78° C. for 10 min and a tetrahydrofuran (100 mL) solution of ZnI2 (31.63 g, 99.12 mmol) was added during 30 min. After warming up to 0° C. for 5 min and cooling back to −78° C. p-toluenesulfonyl cyanide (17.15 g, 94.64 mmol) in tetrahydrofuran (100 mL) was added over a period of 30 min, and the reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with NH4Cl solution (300 mL) and then extracted with Et2O (3×250 mL). The combined Et2O layers were washed with H2O, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica-gel:450 g; hexane-EtOAc 95:5) to give 3.2 g (16%) of 6-methoxybenzo[b]thiophene-2-carbonitrile as a pink solid, mp 82-83° C. (Et2O).