Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([OH:38])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][OH:16])=[CH:35][CH:36]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Reactant: O=CC=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28° C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55° C. The reaction mixture is stirred at 60° C. for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HCl and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH3:42][N:43]=[C:44]=[O:45].N12CCCN=C1CCCCC2>C(Cl)Cl>[CH3:42][NH:43][C:44]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:45]
Reactant: CN=C=O
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3O)cc2)C1=O)NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.8 %

Procedure:
A solution of 100 mg (approx. 0.2 mmol) of the crude intermediate obtained in Step G in 5 mL of methylene chloride was treated with 1.0 mL of methyl isocyanate (17 mmol) and 0.1 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes and then evaporated under vacuum to give 146 mg of crude product. 1H NMR (400 MHz, CDCl3): δ 1.32 (s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52 (dd, 1H), 2.57 (m, 2H), 2.59 (s, 3H), 4.38 (dd, 1H), 4.8 (d, 1H), 5.26 (d, 1H), 7.10 (d, 11H), 7.36 (m, l 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C1C=CC2S(=O)(=O)OC(C3C=C(Br)C(O)=C(Br)C=3)(C3C=C(Br)C(O)=C(Br)C=3)C=2C=1.Cl.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41].[OH-].[Na+].N1CCNCC1>O>[CH2:43]([O:42][C:40]([N:6]1[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]1)=[O:41])[CH3:44]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: C1CNCCN1
Agent: Cl
Agent: O=S1(=O)OC(c2cc(Br)c(O)c(Br)c2)(c2cc(Br)c(O)c(Br)c2)c2ccccc21
Solvent: O
Product: CCOC(=O)N1C[C@@H](C)N[C@@H](C)C1

Procedure:
To a solution of 50 grams of cis-2,6-dimethylpiperazine in 130 ml. of water and containing bromphenol blue as indicator is added, with stirring and cooling, a solution of 100 ml. of concentrated hydrochloric acid in 500 ml. of water until the bromphenol blue just turns yellow. Then, 47.7 grams of ethyl chloroformate is introduced in 5 ml. portions of rapid, dropwise addition with stirring. After each 5 ml. addition, aqueous 25% sodium hydroxide solution is added dropwise until the indicator turns green. The addition of reactants is continued until thin layer chromatography shows that all of the piperazine has reacted. The reaction mixture is then made alkaline with aqueous 50% sodium hydroxide solution and then extracted with ethyl ether. The combined ether extracts are dried over anhydrous sodium sulfate and then chromatographed to give 1-ethoxycarbonyl-cis-3,5-dimethylpiperazine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[C:1]([C:3]1[CH:4]=[C:5]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1cccc(C#N)c1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(3-cyanophenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.1 Hz, 3H) 2.67 (s, 6H) 4.00 (q, J=7.1 Hz, 2H) 7.42-7.45 (m, 1H) 7.45-7.50 (m, 1H) 7.53-7.55 (m, 1H) 7.57 (s, 1H) 7.64 (dt, J=7.1, 1.7 Hz, 1H).
Reaction SMILES: ClCCl.[CH:4]([O:7][CH2:8][CH2:9][OH:10])([CH3:6])[CH3:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(OCC)(=O)C.O>[CH3:18][S:19]([O:10][CH2:9][CH2:8][O:7][CH:4]([CH3:6])[CH3:5])(=[O:21])=[O:20]
Reactant: CC(C)OCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)OCCOS(C)(=O)=O

Procedure:
To a dichloromethane (50 mL) mixture of 2-isopropoxyethanol (5.21 g, 50.0 mmol) and triethylamine (7.70 mL, 55.0 mmol), was added methanesulfonyl chloride (4.30 mL, 55.0 mmol) while stirring on ice, and the resulting mixture was stirred for 30 minutes. Water and ethyl acetate were added to the mixture. After the mixture was thoroughly shaken, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was then distilled off under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18](O)[C:17]3[C:12](=[C:13]([CH3:21])[C:14]([OH:20])=[CH:15][CH:16]=3)[O:11][C:10]=2[CH3:22])=[CH:5][CH:4]=1.O.[NH2:24][NH2:25]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:17]3[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([CH3:21])[C:12]=3[OH:11])=[N:24][NH:25][C:10]=2[CH3:22])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C2=C(C)Oc3c(ccc(O)c3C)C2O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(-c3ccc(O)c(C)c3O)n[nH]c2C)cc1

Procedure:
3-(4-Methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol (1 eq) was taken up in a 1:1 solution of EtOH:Hydrazine hydrate and heated under microwave conditions (120° C., 300 sec). The solution was concentrated in vacuo, residue quenched with cold water, extracted with ethyl acetate and purified by flash chromatography (1% MeOH-DCM). The yellow oil was then triturated with ether:hexane to give 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-benzene-1,3-diol as a solid.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].[NH2:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:19]1=[O:36]>>[CH2:1]([O:3][P:4]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:19]1=[O:36])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Reactant: N[C@H]1CCCCN(CC(=O)OCc2ccccc2)C1=O
Product: CCOP(=O)(CCCCc1ccccc1)N[C@H]1CCCCN(CC(=O)OCc2ccccc2)C1=O

Procedure:
Ethoxy(4-phenylbutyl)phosphinyl chloride is reacted with (S)-3-amino-2-oxo-hexahydro-1H-azepine-1-acetic acid, phenylmethyl ester according to the procedure of Example 2(e) to give (S)-hexahydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-2-oxo-1H-azepine-1-acetic acid, phenylmethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].S(Cl)(Cl)=O.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[CH2:21]([NH:24][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])[CH2:22][CH3:23]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: CCCN
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, thionyl chloride and propylamine in a manner as previously described for example 9d. 1H NMR (300 MHz, CDCl3) δ 7.55 (1H, d, J=8.6 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 5.87 (1H, bs), 3.87 (3H, s), 3.63 (3H, s), 3.45 (2H, m), 2.69 (3H, s), 1.67 (2H, m), 1.02 (3H, t, J=7.4 Hz). LCMS (ESI+) [M+H]/z Calc'd 261. found 261.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([N:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:19][CH2:20][CH2:21][CH2:22][C:23]([N:5]1[CH2:6][CH2:7][C@H:8]([N:9]([CH3:10])[CH3:11])[C@H:3]([O:2][CH3:1])[CH2:4]1)=[O:24]
Reactant: O=C(Cl)CCCCl
Reactant: CO[C@@H]1CNCC[C@@H]1N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(C(=O)CCCCl)CC[C@@H]1N(C)C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice/bath) mixture of 7.9 parts of cis-3-methoxy-N,N-dimethyl-4-piperidinamine, 7 parts of N,N-diethylethanamine, 195 parts of dichloromethane were added dropwise 6.16 parts of 4-chlorobutanoyl chloride (temperature <5° C.). Upon completion, stirring was continued for 30 minutes. The organic layer was washed twice with a saturated sodium chloride solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.7 parts (100%) of cis-1-(4-chloro-1- oxobutyl)-3-methoxy-N,N-dimethyl-4-piperidinamine (int. 29).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[F:11][B-](F)(F)F.F[B-](F)(F)F.F[N+]12CC[N+](O)(CC1)CC2>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:9][F:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: F[B-](F)(F)F
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CO
Product: O=C(CF)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(6-Bromopyridin-2-yl)ethanone (2 g, 10.0 mmol) and 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (9.65 g, 15.0 mmol) were combined in MeOH (100 mL) and heated to reflux for 3 days. After cooling to room temperature, the white solid (alumina) was removed by filtration and filtrate was concentrated in vacuo. The residue was taken up in EtOAc and water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was stirred in a combination of 6 N HCl and Et2O overnight. The organic phase was separated and the aqueous phase extracted with Et2O. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-20% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:16][C@@H:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[CH2:18][OH:19].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:16][C@@H:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=3)[CH2:18][OH:19])=[O:13])=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Reactant: N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(C2CC2)cc1)N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}-2-methylpropane-2-sulfinamide (3.84 g, 11.3 mmol) and methanol (50 ml) was added 2.0N HCl in ether (45.1 ml, 90 mmol). The reaction was stirred for an hour and concentrated to give (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride as a white foam (3.49 g, 100%). MS (Electrospray): m/z 237.1 (M+H). To a 100 ml round bottom flask equipped with a magnetic stir bar were added 4-cyclopropylphenylacetic acid (1.79 g, 10.2 mmol), (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride (3.14 g, 10.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.34 g, 12.2 mmol), 1-hydroxy-7-azabenzotriazole (1.66 g, 12.2 mmol) and triethylamine (4.25 ml, 30.5 mmol) into 68 ml of dimethylformamide. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was washed with brine (3×50 ml) and extracted with ethyl acetate (3×70 ml). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give an oil. Purification by flash chromatography (SiO2, 50-100% EtOAc/Hexanes, gradient) gave 2-(4-cyclopropylphenyl)-N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a light yellow solid (3.00 g, 75%); 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=2.4 Hz, 1H), 7.42 (dd, J=2.4 Hz and 6.8 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 2H), 7.01 (d, J=6.4 Hz, 2H), 5.07-4.99 (m, 1H), 4.63 (q, J=6.4 Hz, 2H), 3.82-3.79 (m, 2H), 3.54 (s, 2H), 1.89-1.84 (m, 1H), 0.92 (m, 2H), 0.64 (m, 2H); MS (Electrospray): m/z 395.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([OH:13])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:3]2[O:14][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:13][C:4]=2[C:5]([Cl:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(Br)c(O)c(O)c1Cl
Product: COC(=O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2

Procedure:
A mixture of 1.0 g (3.5 mmol) of methyl 5-bromo-2-chloro-3,4-dihydroxybenzoate and 7.5 ml of dichlorodiphenylmethane is held at 150° C. under argon for 21/2 minutes. After rapid cooling the product is crystallized from n-pentane. There are obtained 1.3 g of methyl 7-bromo-4-chloro-2,2-diphenyl-1,3-benzodioxol-5-carboxylate as white crystals of melting point 137°-138° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])=O.[CH3:24][NH:25][CH3:26]>C(O)C.[Pd]>[CH3:24][N:25]([CH2:1][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:26]
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reactant: CNC
Agent: [Pd]
Solvent: CCO
Product: CN(C)Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
2-[3-[3-(Formyl)phenoxy]propyl]-1H-isoindole-1,3(2H) dione (132 g) and 33% ethanolic dimethylamine (300 ml) were hydrogenated at room temperature and atmospheric pressure in ethanol over 10% palladium on charcoal. The catalyst was filtered off and the filtrate evaporated to give the title compound as a yellow oil (142 g). TLC silica (ethyl acetate) Rf 0.35, m.p. (oxalate salt) 204°-207°.
Reaction SMILES: C([C:4]1[C:12]([S:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6](C(C)C)[C:5]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([P:30]([O:36][CH:37]([CH3:39])[CH3:38])([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=1)(C)C.[NH2:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O>C(Cl)Cl.CN(C=O)C>[CH:33]([O:32][P:30]([C:27]1[CH:28]=[CH:29][C:24]([O:23][C:5]2[CH:6]=[C:7]([C:8](=[O:10])[NH:40][C:41]3[S:42][CH:43]=[CH:44][N:45]=3)[CH:11]=[C:12]([S:13][C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[CH:4]=2)=[CH:25][CH:26]=1)(=[O:31])[O:36][CH:37]([CH3:39])[CH3:38])([CH3:35])[CH3:34]
Reactant: Nc1nccs1
Reactant: CC(C)OP(=O)(OC(C)C)c1ccc(Oc2c(C(C)C)c(Sc3nccn3C)cc(C(=O)O)c2C(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)OP(=O)(OC(C)C)c1ccc(Oc2cc(Sc3nccn3C)cc(C(=O)Nc3nccs3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
A mixture of diisopropyl 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid (68 mg, 0.139 mmol), 2-aminothiazole (28 mg, 0.277 mmol), HATU (66 mg, 0.174 mmol), DMA (0.058 mL, 0.35 mmol) and 0.7 mL of DMF were stirred for 16 h at rt, diluted with CH2Cl2, washed with water, brine, dried and evaporated. The residue was adsorbed to SiO2 and subjected to MPLC on a 12 g column of SiO2 eluting with % MeOH in CH2Cl2 (time): 1% (5 min), 2.5% (10 min), 5% (10 min) which provided 50 mg (63%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 1.20 (d, 6H, J=6 Hz). 1.28 (d, 6H, J=6 Hz), 3.66 (s, 3H). 4.56 (m, 2H), 6.95 (t, 1H, J=2 Hz), 7.13 (d, 1H, J=1 Hz), 7.15 (dd, 2H, J=8, 3 Hz), 7.30 (br s, 1H), 7.50 (d, 1H, J=1 Hz), 7.55 (d, 1H, J=3 Hz). 7.60 (br s, 1H), 7.67 (br s, 1H), 7.73 (dd, 2H, J=12, 8 Hz); LCMS (m/z): 573.7 [C26H29N4O5PS2+H]+.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:29])=[CH:26][C:25]=1[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[N:33]1([CH2:32][CH2:31][NH:30][C:28]([C:27]2[CH:38]=[CH:39][C:24]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:6][CH:7]=3)=[C:25]([CH3:40])[CH:26]=2)=[O:29])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)ccc1Br
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: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)ccc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 4-bromo-3-methyl-N-(2-pyrrolidin-1-yl-ethyl)benzamide (0.31 g, Example 63a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium(0) (0.012 g) in ethanol(5 ml) with heating at reflux for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil. (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[OH-].[Na+].Cl.[CH3:17][C:18]([CH3:20])=[O:19]>O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:17][C:18](=[O:19])[CH3:20]
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1C=CC(C)=O
Temperature: 65 °C
Yield: 100 %

Procedure:
To a mixture of 2-methoxy-4-nitrobenzaldehyde (10.0 g; 55.2 mmol) in 11 mL of water and 11 mL of acetone at 65° C. was added a 1% solution of NaOH (13.8 mL) over 30 minutes. The mixture was heated at 65° C. for 2 h, cooled in an ice bath and neutralized with 10% HCl. A solid precipitated which was filtered, washed with water and dried under vacuum to afford 12.2 g (100%) of the title compound as a reddish-brown solid. HPLC (Method #1) 2.48 min retention time, (80%); MS (ES): m/z 222 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:31])[CH3:30]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:24]3[O:26][N:31]=[C:29]([CH3:30])[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 21.9 mg (0.269 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 41.6 mg (32% of theory).
Reaction SMILES: O1CCCCC1OC[C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[B:24]1[O:28]C(C)(C)[C:26](C)(C)[O:25]1)[O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.Cl.C([O-])(O)=O.[Na+]>CCO>[OH:28][B:24]1[C:23]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH:17]=[O:18])=[CH:19][CH:20]=3)=[CH:21][C:22]=2[CH2:26][O:25]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C=O)cc3)cc2COC2CCCCO2)OC1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=Cc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 4-[3-(tetrahydro-pyran-2-yloxymethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-benzaldehyde (1.4 g, 3.2 mmol, 1.0 eq.) in EtOH (15 mL) at 0° C. was added HCl (15 mL, 3N). The mixture was stirred at 0° C. for 20 minutes and allowed to warm to room temperature in another 1 h. The mixture was then treated with sat. NaHCO3 drop wise until PH reaching 7. The precipitate was collected by filtration, washed with H2O to give 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzaldehyde as a white solid. LCMS (m/z) 255 (M+H); 1H NMR (DMSO-d6) δ: 9.92 (s, 1H), 9.19 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.92 (q, J=4.6 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.7 Hz, 2H), 7.12-7.19 (m, 1H), 7.09 (dd, J=8.0, 2.1 Hz, 1H), 4.95 (s, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[N:13](C(OCC2C=CC=CC=2)=O)[CH:12]=[CH:11][N:10]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.[Pd]>[CH2:1]([C@@H:8]1[NH:13][CH:12]=[CH:11][N:10]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1C=CN(C(=O)OCc2ccccc2)[C@@H](Cc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN1C=CN[C@@H](Cc2ccccc2)C1=O
Reaction time: 2 h
Yield: 167.1 %

Procedure:
A solution of the compound of Example 29 (1 g, 2.4 mmol) in absolute ethanol (10 mL) was treated with 5%Pd/C (200 mg) and concentrated HCl (2 mL). The mixture was hydrogenated at 40 p.s.i. for 2 hours. The mixture was filtered through Celite to remove the catalyst and the filtrate was evaporated under reduced pressure to give the title compound (1.1 g, 81% yield).