Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([NH:8][C:9]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([N:26]2[CH2:30][C@@H:29]([N:31]3[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][CH2:32]3)[CH2:28][C@H:27]2[C:41]([NH:43][C:44]2[CH:56]=[CH:55][C:47]([C:48]([O:50]C(C)(C)C)=[O:49])=[CH:46][CH:45]=2)=[O:42])=[O:25])[CH2:20][CH2:19]1)=[N:10]C(OC(C)(C)C)=O)=O)(C)C.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[C:9]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]([N:26]2[CH2:30][C@@H:29]([N:31]3[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][CH2:32]3)[CH2:28][C@H:27]2[C:41]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:48]([OH:50])=[O:49])=[CH:55][CH:56]=2)=[O:42])=[O:25])[CH2:22][CH2:23]1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)Nc3ccc(C(=O)O)cc3)N(C(=O)C3CCN(C(=N)N)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a solution of the compound prepared in Example 8 (0.11 g, 0.13 mmol) in dichloromethane (15 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). The reaction was warmed to room temperature and stirred for 18 h. The solvent and excess trifluoroacetic acid was removed under reduced pressure. The solid was dissolved in water and lyophilized to dryness to afford the title compound (0.030 g, 40%) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:3]1=[O:20].[CH3:21][N:22]([CH3:30])[C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C1COCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([N:22]([CH3:30])[CH3:21])[CH:28]=2)=[O:18])=[CH:4][C:3]1=[O:20]
Reactant: CN(C)c1cccc(O)c1
Reactant: O=C(O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CN(C)c1cccc(OC(=O)CCCCOC2=CC(=O)C(=O)c3ccccc32)c1
Reaction time: 2 h
Yield: 35.6 %

Procedure:
A mixture of acid 3 (137 mg, 0.5 mmol), 3-dimethylaminophenol (82 mg, 0.6 mmol), DCC (103 mg, 0.5 mmol), and DMAP (12 mg, 0.01 mmol) in THF (2 mL) was stirred for 2 h. The reaction mixture was concentrated in vacuo, the residue dissolved in benzene, washed with H2O and dried (Na2SO4). Column chromatography (10% EtOAc) in benzene gave 13 as a yellow solid (70 mg, 36%), 1H NMR (CDCl3) 8.13, (d, J=7.3 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.69 (t, J=6.1 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.22 (dd, J=8.1, 8.1 Hz, 1H), 6.30-6.70 (m, 2H), 5.96 (s, 1H), 4.21 (t, J=5.6 Hz, 2H), 2.69 (t, J=6.5 Hz, 2H), 1.90-2.15 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:28]C(C)([O-])C.[K+].IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH3:28])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: COc1ccc(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Reactant: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(F)cc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To an ice-cold suspension of 0.07 g (0.17 mmol) 4-(2,5-dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-nicotinamide in 1 mL tetrahydrofuran were added 0.019 g (0.17 mmol) potassium tert-butoxide followed by 10 μl (0.18 mmol) iodomethane. The suspension was stirred at room temperature for 16 hours, poured onto 10% aqueous citric acid solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give 32 mg (44%) of the title compound as a white solid. MS (ESI): m/z=421.052 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[C:27](B(O)O)[CH:28]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[C:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: CC(C)S(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1cc(F)ccc1OCc1cccc(F)c1
Product: CC(C)S(=O)(=O)Cc1cccc(Nc2ncnc(-c3cc(F)ccc3OCc3cccc(F)c3)n2)c1

Procedure:
A suspension of crude 4-chloro-N-{3-[(prop-2-ylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (876 mg, 37% by weight) and {5-fluoro-2-[(3-fluorobenzyl)oxy]phenyl}boronic acid (264 mg) was treated as described in example 34. One obtained pure product (299 mg).
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C:14]2[O:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH:22](Cl)(Cl)Cl.CO>CO.O>[CH3:22][O:20][C:19]([C:17]1[O:18][C:14]([CH2:13][O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[CH:15][CH:16]=1)=[O:21]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc(CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)o1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)o1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To produce diazomethane, 1.0 g (10 mmol) N-methyl-N-nitrosourea was added portionwise with cooling to 20 ml diethyl ether to which 7 ml of 40% KOH had been added to form a lower layer, in such a way that the reaction temperature did not exceed +5° C. 30 min after the last addition the yellow organic phase was separated off and allowed to stand for 3 h over a little solid KOH. Enough of the ethereal solution of diazomethane thus obtained was added at room temperature with stirring during a period of 15 min to a solution of 500 mg (1.6 mmol) GMF carboxylic acid (formula 4, product of Example 4) in 18 ml methanol and 2 ml water for the yellow colour just to remain and no further evolution of gas to be observed. After a further 15 min stirring the reaction was complete (TLC monitoring with mobile solvent chloroform/methanol (2:1), Rf (educt)=0, Rf (product)= 0.41), whereupon the solvent was removed under vacuum and the crude product was purified by elution from a silica gel column (3×20 cm) with chloroform/methanol (2:1). Concentration of the fractions containing the product gave 440 mg (84%) of colourless syrup with [α]D20 =+113° (c=0.8, methanol), which gradually crystallised on scratching; m.p. 72° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[CH:21]>C(NCC)C.C(Cl)CCl.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.[Cu]I>[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[C:21][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: C#CC(C)(C)C
Reactant: CN1Cc2c(Br)ncn2-c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)C)ncn2-c2ccccc2C1=O

Procedure:
2.92 g (10 mmol) of 3-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 80° in a pressure tube for 24 hours with 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride, 30 mg of copper(I) iodide and 2.5 ml (20 mmol) of 3,3-dimethyl-1-butyne in 30 ml of diethylamine and 10 ml of ethylene chloride. The reaction mixture was evaporated, the residue was taken up in methylene chloride and washed with water. The organic solution was dried over magnesium sulphate and filtered through a silica gel pad. By crystallization from hexane there was obtained 3-(3,3-dimethyl-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 148°-150°.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH2:13][Br:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C)C=CC=1[Cl:34])(=O)C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:34])[CH2:13][Br:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Reactant: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1
Yield: 62 %

Procedure:
The title compound was prepared by adapting the method for 3-benzoyloxy-4-fluorobenzyl bromide using 3-benzoyloxy-4-chlorotoluene (2.47 g, 10.0 mmol), NBS (1.96 g, 11.0 mmol) and benzoyl peroxide (10 mg) in carbon tetrachloride (25 mL). The residue was purified by flash column chromatography [SiO2, EtOAc/n-hexane (1:40)] to give 3-benzoyloxy-4-chlorobenzyl bromide as a colourless oil (2.012 g, 62%) which solidified on standing and was used without further purification; δH (400 MHz, CDCl3) 4.48 (s, 2H), 7.27 (dd, J=8.2, 2.0, 1H), 7.36 (d, J=2.0, 1H), 7.46 (d, J=8.2, 1H), 7.50-7.58 (m, 2H), 7.64-7.71 (m, 1H), 8.22-8.28 (m, 2H). LRMS (FAB+) m/z (rel. intensity) 325.0 (81, [M+H]+), 327.0 (100, [M+H]+);
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29]>Cl>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: COC(=O)CCCCCCCCN1C(=O)C(c2ccccc2)N(c2ccccc2)C1=O
Agent: Cl
Product: O=C(O)CCCCCCCCN1C(=O)C(c2ccccc2)N(c2ccccc2)C1=O
Yield: 37.1 %

Procedure:
A mixture of methyl 2,5-dioxo-3,4-diphenyl-1-imidazolidinenonanoate (3.00 g, 7 mmol) and 6N HCl solution (30 mL) was heated at reflux for 22 hours. The mixture was cooled, extracted with CH2Cl2 and the combined extracts washed with water and twice with saturated sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated and the residue chromatographed on a column of silica gel using a mixture of hexanes and ethyl acetate (2:1) as eluent. Elution gave 2,5-dioxo-3,4-diphenyl-1-imidazolidinenonanoic acid (1.06 g, 36%) after recrystallization from a mixture of hexanes, diethyl ether and CH2Cl2 (6:2:2), mp 111.5°-112.5° C. Anal. Calcd. for C24H28N2O4 : C, 70.57: H, 6.91: N, 6.86. Found: C, 70.45: H, 7.05: N, 6.75%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([CH2:21][SH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:21]([S:22][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: SCc1ccccc1
Reactant: O=C1CCc2cc([N+](=O)[O-])c(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])c(SCc3ccccc3)cc21
Yield: 38.3 %

Procedure:
Following General Procedure A, the title compound (672 mg, 79%) was prepared from 6-bromo-5-nitro-2,3-dihydro-1H-inden-1-one (1.5 g, 5.86 mmol), phenylmethanethiol (1 ml, 8.79 mmol) and K2CO3 (4.0 g, 29.29 mmol) in DMF (20 ml).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1B(O)O.C([O-])(O)=O.[Na+].Br[C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:28](=[O:36])[C:27]=1[C:37]#[N:38]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:33]1([CH2:32][N:29]2[CH:30]=[CH:31][C:26]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=4[CH3:16])=[CH:7][C:2]=3[F:1])=[C:27]([C:37]#[N:38])[C:28]2=[O:36])[CH2:34][CH2:35]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: Cc1nccc(Oc2ccc(B(O)O)c(F)c2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nccc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)c(F)c2)c1C
Yield: 15.5 %

Procedure:
To a solution of intermediate 22 (0.34 g 1.321 mmol) in 1,4-dioxane (5.5 ml) and a saturated solution of NaHCO3 (5.5 ml) was added intermediate 5 (0.28 g, 1.123 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.15 mg, 0.132 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with EtOAc, and then it was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/AcOEt 1:1 as eluent). The desired fractions were collected and evaporated in vacuo to give a residue that was triturated with Et2O to yield compound 10 (0.068 g, 16%)
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH2:16][CH3:17])[CH:3]=1.[N+](=[CH2:20])=[N-]>O1CCCC1.CCOCC>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([S:11]([CH3:14])(=[O:12])=[O:13])[C:2]([Cl:1])=[CH:3][C:4]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of 4-chloro-2-ethoxy-5-methanesulfonylbenzoic acid (2.5 g, 9.0 mmol) in tetrahydrofuran was cooled to 5° C. and treated with excess diazomethane in ether solution (prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) and stirred for 10 min. Solvent and excess diazomethane was removed by rotary evaporation. The resulting residue was dissolved in dichloromethane and filtered through a plug of silica gel and evaporated. The solids were triturated with ether/hexane to give 4-chloro-2-ethoxy-5-methanesulfonyl-benzoic acid methyl ester (2.1 g, colorless solids).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[N:33]1(C(OC(C)(C)C)=O)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:15]1([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:21]2[CH:22]=[CH:23][C:24]([CH2:25][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCNCC3)cc1)C2c1ccccc1
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (196 mg, 3.24 mmol) and tert-butyl piperazine-1-carboxylate (304 mg, 1.63 mmol) at room temperature and stirred overnight. Then NaBH(OAc)3 (173 mg, 0.81 mmol) was added to the mixture at 0° C., stirred for one day. The reaction mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated to give the crude product which was purified by flash chromatography to obtain a solution. To the solution obtained (concentrated to about 50 mL) was added conc. HCl (10 mL) at room temperature and stirred overnight. The mixture was extracted with ethyl acetate for three times, the aqueous phase was concentrated to give 9-phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (127 mg, yield 46%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.47 (br s, 7H), 3.60 (m, 1H), 4.32 (s, 2H), 4.38 (d, 1H), 4.83 (d, 1H), 5.41 (br s, 2H), 7.19 (m, 6H), 7.24 (m, 3H), 7.55 (m, 4H), 9.87 (br s, 2H), 12.20 (s, 1H); LC-MS (ESI) m/z: 438 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1>CO>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N:9]=[CH:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Reactant: O=Cc1cccnc1
Solvent: CO
Product: Fc1ccc(Oc2ccc(N=Cc3cccnc3)cc2)c(F)c1
Temperature: 55 °C

Procedure:
4-(2,4-Difluorophenoxy)aniline (2.21 g, 10.0 mmol) and pyridine-3-carboxaldehyde (1.12 g, 10.5 mmol) were dissolved in anhydrous methanol (35 ml) and the solution was heated at 55° C. for three hours. The solution was cooled and concentrated in vacuo to a residual oil, which was maintained under a 90 μm Hg vacuum for twenty-four hours. N-(4-(2,4-Difluorophenoxy)phenyl)pyrid-3-ylmethyleneamine was obtained in quantitative yield. 1H NMR(400 MHz): 6.83-6.90(1H,m), 6.93-7.00(3H,m), 7.05-7.13(1H,m), 7.21-7.27(2H,m), 7.40(1H,dd, J=8.1, 4.9), 8.27(1H,dd,J=8.1, 1.7), 8.50(1H,s), 8.69(1H,dd,J=4.9, 1.7), 9.00(1H,d,J=1.7); MS(ESI)m/z 311.1([M+H]+,100); Anal. Calcd. for C18H12F2N2O C,69.67; H,3.90; N,9.03. Found: C,69.28; H,3.99; N,8.91.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:43][O:44][C:45]1[CH:64]=[CH:63][C:48]([C:49]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([C:59]([O:61][CH3:62])=[O:60])[CH:52]=2)=O)=[CH:47][C:46]=1[C:65]([O:67][CH3:68])=[O:66]>C1COCC1>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[C:49]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([C:59]([O:61][CH3:62])=[O:60])[CH:52]=1)[C:48]1[CH:63]=[CH:64][C:45]([O:44][CH3:43])=[C:46]([C:65]([O:67][CH3:68])=[O:66])[CH:47]=1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C(=O)c2ccc(OC)c(C(=O)OC)c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCCC=C(c1ccc(OC)c(C(=O)OC)c1)c1ccc(OC)c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
n-Hexyltriphenylphosphonium bromide (0.427 g, 1 mmol) was dried by azeotropic distillation from a benzene solution and then stirred in dry THF (10 mL) under nitrogen atmosphere. Sodium bis(trimethylsilyl)amide (1 M in THF, 1 mL, 1 mmol) was added and the ylide produced was stirred under nitrogen at 0° C. for 30 min. Intermediate 35 (0.276 g, 0.77 mmol) was added as a solution in THF (10 mL) under nitrogen. The mixture was stirred at rt overnight and partitioned between 1 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, and evaporated to afford an oil which was chromatographed on SiO2 (230-400 mesh, 50 g), eluting with hexanes/ethyl acetate (4:1) to give the product (36) (0.15 g, 46%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.63 (d, J=2.3 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.20 (dt, J=2.3 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.7H, 1H), 5.96 (t, J=7.5 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H), 2.05 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.2 Hz, 2H), 1.22 (m, J=1.9 Hz, 2H), 0.83 (t, J=6.7 Hz, 3H); IR (neat) 2927, 2853, 1732, 1606, 1500, 1435, 1263 cm−1. Anal. (C25H30O6) C, H.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13].Cl.Cl[CH2:32][C:33]1[N:37]([CH3:38])[CH:36]=[N:35][N:34]=1.C[O-].[Na+]>CO>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][N:20]([CH2:32][C:33]2[N:37]([CH3:38])[CH:36]=[N:35][N:34]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13]
Reactant: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCNCC1
Reactant: Cn1cnnc1CCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCN(Cc2nncn2C)CC1
Temperature: 70 °C
Yield: 25.8 %

Procedure:
In methanol (6 ml) were dissolved 1-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine-dihydrochloride (Compound 20, 0.40 g) and 3-chloromethyl-4-methyl-4H1,2,4-triazole.hydrochloride (255 mg). To the solution was added 1N-methanol solution of sodium methylate (3.69 ml), and the mixture was heated at 70° C. for 14 hours, then the reaction mixture was concentrated. The concentrate was dissolved in dichloromethane (30 ml), washed with water, dried and concentrated. The concentrate was recrystallized from ethyl acetate to give 1-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl)-2-butylsulfonyl]-4-(4-methyl-4H-1,2,4-triazol-3-ylmethyl) piperazine (Compound 26, 108 mg) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@@H:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[C@@H:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Yield: 76 %

Procedure:
3-(4-Benzyloxyphenyl)-(S)-2-ethoxypropanoic acid ethyl ester was hydrogenated at atmospheric pressure for 2 hours in ethyl acetate using Pd/C as catalyst. Purification by chromatography on silica gel using toluen:ethyl acetate as eluant gave 3.83 g (yield in 3 steps 76%) of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([CH:29]2[CH2:31][O:30]2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[OH:30][CH:29]([C:27]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([O:20][CH3:19])[CH:28]=1)[CH2:31][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(C2CO2)ccc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Product: COc1cc(C(O)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
4-(1-Hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one and 2-(methyloxy)-4-oxiran-2-ylbenzonitrile.