Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2C=C)=[C:4]([CH:25]=[CH2:26])[N:3]=1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]2[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH:26]=[CH:25][C:4]=2[N:3]=1
Reactant: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COc1ccc2c(ccc3nc(N)c(Cc4ccccc4)nc32)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 25.4 %

Procedure:
Under an argon atmosphere, to a solution of Hoveyda-Grubbs second generation catalyst (84.5 mg, 135 μmol) in 1,2-dichloroethane (100 mL) was added 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (585 mg, 1.70 mmol) at room temperature. The mixture was then heated to 90° C. and stirred overnight (17 hours). After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1→2/1) to give 3-amino-2-benzyl-8-methoxybenzo[f]quinoxaline (12) as a white solid (136 mg, 431 μmol, 25.3%). TLC Rf=0.64 (n-hexane/ethyl acetate=1/1); NMR (500 MHz, CDCl3) δ 3.98 (s, 3H), 4.39 (s, 2H), 4.63 (s, 2H), 7.21-7.38 (m, 7H), 7.63 (d, 1H, J=9.0 Hz), 7.85 (d, 1H, J=9.0 Hz), 9.00 (d, 1H, J=9.0 Hz); 13C NMR (126 MHz, CDCl3) δ 41.8, 55.4, 107.5, 118.1, 124.9, 125.5, 125.8, 127.2, 128.7 (2C), 129.1 (2C), 130.1, 132.7, 134.6, 136.6, 138.9, 143.1, 151.2, 158.5.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[OH2:5]>>[CH2:1]([OH:5])[CH:2]=[CH:3][CH2:4][CH2:4][CH2:3][CH:2]=[CH2:1].[CH2:1]=[CH:2][CH:3]([OH:5])[CH2:4][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CC=C
Reactant: O
Product: C=CCCCC(O)C=C
Product: C=CCCCC=CCO

Procedure:
In the present invention, a conjugated alkadiene and water are reacted under the above-described reaction conditions to produce an alkadienol. In the reaction solution produced by this reaction (which is called "produced solution" hereinafter), there are contained the catalyst, an alkadienol which is the objective reaction product, the by-products such as alkatrienes, dialkadienyl ethers, organic carboxylic acids and esters, solvent, unreacted conjugated alkadiene and water. In case of using 1,3-butadiene as the starting conjugated alkadiene, the produced alkadienols are octadienlos and octa-2,7-diene-1-ol is produced as the principal reaction product, while octa-1,7-diene-3-ol, octatrienes, dioctadienyl ethers, organic carboxylic acids and esters are yielded as by-products. The yield of the by-products depends on the reaction conditions, but it is usually around a few molar percents based on the conjugated alkadiene. After the reaction, alkadienol can be recovered by known means such as distillation separation or extraction separation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:6][C:7]1[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2].[OH2:38]>CO.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=1)[CH2:6][C:7]1[C:8]([S:18]([CH2:19][CH2:20][CH3:21])=[O:38])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2]
Reactant: CCCSc1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Reactant: O
Solvent: CO
Solvent: ClCCl
Product: CCCS(=O)c1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
(3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester (Example 135) (116 mg, 0.18 mmol) was dissolved in methanol (2 mL) and water (2 mL) followed by the addition of magnesium bis(mono peroxy phthalate hexahydrate) (MMPP) (267.1 mg, 0.54 mmol). The resulting mixture was stirred at room temperature overnight. The sample was diluted with methylene chloride and washed one time with water andone time with brine. The organic phase was dried, filtered and concentrated by rotary evaporation. The resulting sample was dried overnight under vacuum. (Biotage Horizon HPFC chromatography system, SiO2, 70:80 hexanes: ethyl acetate) gave a whit solid (80 mg, 72%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:26])[CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:9].I[CH3:28]>CN(C=O)C.O>[CH3:26][N:4]([CH3:3])[CH2:5][CH2:6][CH2:7][C:8]([N:10]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:28])=[O:9]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCCN(C)C)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(N(C)C(=O)CCCN(C)C)ccc21
Reaction time: 5 h
Yield: 5.9 %

Procedure:
Sodium hydride (8 mg of a 60% suspension in mineral oil, 4 mg, 0.19 mmol, 1.2 equiv) was added to a solution of 4-dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-butyramide (50 mg, 0.15 mmol, 1 equiv) in DMF (0.3 mL). The resultant suspension was stirred at room temperature for 1 hour, and then iodomethane (0.012 mL, 27 mg, 0.19 mmol, 1.25 equiv) was added via syringe. After an additional 5 hours at room temperature, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (1×10 mL) and brine (1×10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by rotary chromatography (CH2Cl2 grading to 2% ammonium hydroxide in 5% MeOH/CH2Cl2) to provide 4-dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-N-methyl-butyramide (3 mg, 5%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH2:22]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
7-Hydroxy-4-methylcoumarin (70.00 g, 0.397 mol), anhydrous K2CO3 (140 g, 1.01 mol), and allyl bromide (100 ml, 1.15 mol) were added to 2.0 L of reagent grade acetone. The milky mixture was refluxed for sixteen hours with overhead stirring, allowed to cool to room temperature, and filtered. Solids were washed once with reagent grade acetone (150 ml.), the filtrate and wash combined, and the resulting combined filtrate concentrated to dryness with a rotary evaporator to obtain 7-allyloxy-4-methylcoumarin (84.2 g, 98% yield). The crude product melted at 100.0°-101.5° C. (lit. 1 101° C.), showed only one spot in TLC, and was used in the next step.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[C:6]1[N:11]=[C:10]([C:12]2[C:20]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[CH3:1][O:2][C:6]1[N:11]=[C:10]([C:12]2[C:20]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 110 °C
Yield: 72.1 %

Procedure:
Add methanol (19 mg, 0.59 mmol) and sodium hydride (14 mg, 60% dispersion, 0.35 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (42 mg, 0.118 mmol) in DMF (0.6 mL) at room temperature. Heat to 110° C. for 3 hours, cool to room temperature, and quench with saturated aqueous ammonium chloride (0.5 mL). Concentrate in vacuo, filter, and purify by flash column chromatography (Silica Gel, 20-40% acetone/hexanes) to provide the title compound 30 mg (73%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([O:37]CC5C=CC=CC=5)=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:18][CH:17]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].Cl>O1CCCC1.O.[Pd].C(#N)C>[C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:20][CH:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1

Procedure:
To a solution of N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine (PP) prepared by the process of Examples 1 and 2 (4.0 g, 6.5 mmol) in tetrahydrofuran (100 mL) and water (16 mL) was added 10% palladium on carbon (800 mg). The reaction was stirred vigorously under one atmosphere of hydrogen for 6.5 h. The solids were filtered off and washed with tetrahydrofuran (4×25 mL) and then 50% methanol/tetrahydrofuran (2×25 mL). The combined filtrates were evaporated to dryness and the crude product was purified by reverse-phase HPLC. Fractions containing pure product were combined and lyophilized. The product from several runs was combined to give 4.68 g which was dissolved in acetonitrile (200 mL) and water (200 mL). 1.0 N HCl (18.7 mL) was added, and the solution was lyophilized. The residue was again dissolved in acetonitrile (125 mL) and water (125 mL). 1.0 N HCl was added and the solution was lyophilized to give an amorphous hydrochloride salt of compound 1 as an off white powder. 1H NMR (300 MHz, DMSO-d6) δ 10.55 (br s, 1H), 9.40 (br s, 1H), 8.80, (br s, 1H), 8.26 (d, 1H), 7.60, (br s, 2H) 7.25–7.45 (m, 5H), 6.92–7.16 (m 10H), 6.55 (d, 1H), 5.45 (d, 1H), 3.69 (s, 3H) 2.80–3.15 (m, 6H); m/z: [M+H+] calcd for C32H31N3O4 522.24; found 522.4.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH2:30][OH:31])[C:25]=2[O:26][CH2:27][O:28][CH3:29])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH:30]=[O:31])[C:25]=2[O:26][CH2:27][O:28][CH3:29])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COCOc1c(CO)csc1-c1ccc(C(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Dimethyl sulfoxide (0.050 mL, 0.70 mmol) in dichloromethane (0.28 mL) was added to oxalyl chloride (0.049 mL, 0.56 mmol) in dichloromethane (2.8 mL) at −78° C., and after 10 minutes of stirring at −78° C., 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-hydroxymethylthiophene (87 mg, 0.28 mmol) in dichloromethane (0.93 mL) was added dropwise. After the addition, the reaction solution was stirred at −78° C. for 20 minutes and at −40 to −50° C. for 1 hour. Triethylamine (0.28 mL, 2.0 mmol) was added dropwise, and the reaction solution was stirred for another 20 minutes under cooling with ice. After addition of saturated aqueous ammonium chloride, the reaction solution was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the desired product as a brown oil (58 mg, yield 68%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][CH:24]=[C:25]([O:27]C)[CH:26]=2)[CH3:10])[C:5]([C:36]#[N:37])=[CH:4][N:3]=1.P(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][CH:24]=[C:25]([OH:27])[CH:26]=2)[CH3:10])[C:5]([C:36]#[N:37])=[CH:4][N:3]=1
Reactant: COc1cncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C#N)n(-c4ccccc4)c(=O)c23)c1
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(-c3cncc(O)c3)c2c(=O)n1-c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (S)-2-amino-4-((1-(8-(5-methoxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile 9 (15 mg, 0.031 mmol) in DCM (5 mL) at −78° C. under argon, PBr3 (77 mg, 0.31 mmol) was added and the resulting mixture was stirred from −78° C. to RT overnight. The reaction mixture was poured into ice-water (10 mL) and then neutralized with saturated aqueous NaHCO3 to adjust the pH value to 8-9. The mixture was extracted with a mixture of methanol in DCM (5%, 5×10 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with 1-3% MeOH/DCM to afford 2-amino-4-((S)-1-(8-(5-hydroxypyridin-3-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethylamino)pyrimidine-5-carbonitrile 13. ESI-MS m/z: 476.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]2[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[C:10]=12)=[O:5].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:29][C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH3:2][O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]([F:19])([F:18])[F:17])[N:9]2[CH2:14][CH2:13][N:12]([C:30](=[O:31])[CH2:29][CH:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH2:33][C:34]3[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=3[F:42])[C@H:11]([CH3:15])[C:10]=12)=[O:5]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1C(C)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(C(F)(F)F)n2c1[C@@H](C)N(C(=O)CC(Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 77.2 %

Procedure:
8-Methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 39c crude product (0.289 g, 0.96 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid if (0.353 g, 1.06 mmol) were dissolved in 10 mL of dichloromethane, followed by addition of triethylamine (0.4 mL, 2.9 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.368 g, 1.45 mmol) under stirring. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 39d (0.43 g, yield 77.2%) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[CH:17][CH:16]=1)=[O:11].[CH2:39]([O:41][P:42]([C:47]([F:59])([F:58])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55](O)=[O:56])=[CH:50][CH:49]=1)([O:44][CH2:45][CH3:46])=[O:43])[CH3:40]>>[CH2:39]([O:41][P:42]([C:47]([C:48]1[CH:49]=[CH:50][C:51]([CH2:54][C:55](=[O:56])[NH:8][C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]3[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]3)=[CH:19][CH:20]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:52][CH:53]=1)([F:59])[F:58])(=[O:43])[O:44][CH2:45][CH3:46])[CH3:40]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)O)cc1
Reactant: NC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@@H](N)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(C3CC(=O)NS3(=O)=O)cc2)C(N)=O)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 10, using 4.23-B of Step 2 and {4-[(diethoxy-phosphoryl)-difluoro-methyl]-phenyl}-acetic acid (Biochemistry, (2003), 42, 12792) as the starting materials. LCMS found for C34H40F2N4O9PS (M+H)+: m/z=749.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[CH2:11][CH2:10][CH2:9]2.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=4)[CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCCc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)CO1
Yield: 42 %

Procedure:
The condensation of (R)-5′,5′-difluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazine]-2′,7-diamine (intermediate A7.1) and 5-chloropicolinic acid yielded the title compound (42% yield) as a white solid. MS (ISP): m/z=407.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:29])[CH2:11][N:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH:13]1[CH2:25][C:26]([NH2:28])=[O:27].[H][H]>[Pd].CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:29])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[CH2:25][C:26]([NH2:28])=[O:27]
Reactant: [H][H]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(Cc2ccccc2)CC1CC(N)=O
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1CC(N)=O
Yield: 97.5 %

Procedure:
A mixture of 12.8 parts of N1 -(2,6-dimethylphenyl)-4-(phenylmethyl)-1,2-piperazinediacetamide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was crystallized from acetonitrile, yielding 7.7 parts (97.5%) of N1 -(2,6-dimethylphenyl)-1,2-piperazinediacetamide; mp. 171.9° C. (intermediate 72).
Reaction SMILES: [CH2:1]([N:3]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:4]1[CH:5]=[C:6]([C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH:7]=[C:8]([C:11](=[O:26])[NH:12][CH2:13][C:14]2[C:15](=[O:25])[NH:16][C:17]([CH3:24])=[C:18]([F:23])[C:19]=2[CH:20]([CH3:22])[CH3:21])[C:9]=1[CH3:10])[CH3:2].Cl.O1CCOCC1>C(O)C>[CH:39]([OH:41])=[O:40].[CH2:1]([N:3]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:4]1[C:9]([CH3:10])=[C:8]([CH:7]=[C:6]([C:27]2[CH:32]=[N:31][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH:5]=1)[C:11]([NH:12][CH2:13][C:14]1[C:15](=[O:25])[NH:16][C:17]([CH3:24])=[C:18]([F:23])[C:19]=1[CH:20]([CH3:22])[CH3:21])=[O:26])[CH3:2]
Reactant: CCN(c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCN(c1cc(-c2ccc(N3CCNCC3)nc2)cc(C(=O)NCc2c(C(C)C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1
Product: O=CO
Reaction time: 2 h
Yield: 15.6 %

Procedure:
To a solution of tert-butyl 4-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate (450 mg, 0.639 mmol) in ethanol (4.3 mL) at room temperature was added 4 M HCl in dioxane (2 mL, 8.00 mmol). LC/MS after 2 h showed both product and remaining starting material. Additional 4 M HCl in 1,4-dioxane (1.5 ml, 6.00 mmol) was added, and LC/MS after total 4 h showed that reaction was completed. The reaction mixture was concentrated to dryness, azeotroped with toluene-methanol to give crude hydrochloride salt (454 mg, 111%). A 125 mg sample of crude hydrochloride salt was purified by reverse phase HPLC/MS (ACN—H2O, 0.1% formic acid) to give 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide formate (65 mg) as a colorless glassy film. 1H-NMR (400 MHz, CD3OD) δ ppm 8.35-8.40 (m, 2H), 7.86 (dd, J=2.4, 8.8 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.54 (s, 2H), 3.92 (m, 2H), 3.84 (m, 4H), 3.54 (m, 1H), 3.30-3.38 (m, 6H), 3.07-3.18 (m, 3H), 2.33 (s, 3H), 2.24 (d, J=2.8 Hz, 3H), 1.73-1.76 (m, 2H), 1.62-1.68 (m, 2H), 1.37 (d, J=6.8 Hz, 6H), 0.89 (t, J=6.8 Hz, 3H); MS (ES)(M+H) 605.6.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:43][OH:44]>>[OH:44][CH2:43][C@@H:38]1[CH2:39][CH2:40][CH2:41][CH2:42][C@H:37]1[NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@H]2CO)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and [(1R,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=480.
Reaction SMILES: [CH2:1]([O:5][C@:6]12[C@@H:19]3[N:20]([CH3:23])[CH2:21][CH2:22][C@:11]41[C:12]1[C:13]([O:25][C@H:10]4[C:9](=[O:26])[CH2:8][CH2:7]2)=[C:14]([OH:24])[CH:15]=[CH:16][C:17]=1[CH2:18]3)[CH2:2][CH2:3][CH3:4].[CH3:27][I:28]>O>[I-:28].[CH2:1]([O:5][C@:6]12[C@@H:19]3[N+:20]([CH3:27])([CH3:23])[CH2:21][CH2:22][C@:11]41[C:12]1[C:13]([O:25][C@H:10]4[C:9](=[O:26])[CH2:8][CH2:7]2)=[C:14]([OH:24])[CH:15]=[CH:16][C:17]=1[CH2:18]3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Reactant: CI
Solvent: O
Product: CCCCO[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CC[N+](C)(C)[C@@H]2C5
Product: [I-]

Procedure:
A solution of 14β-butoxy-4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one (0.53 g, 1.49 mmol) and methyl iodide (1.06 g, 7.44 mmol) in 10 ml of water-free acetonitrile was stirred under N2 at 40° C. (bath temperature) for 2 days and then evaporated down. The evaporation residue (0.70 g of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH 250:4). Yield: 0.31 g (42%) of colourless crystals of the compound 47. Fp. 180-185° C.; MS (CI): 372.2 (M+); IR (KBr): 1726 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): 9.55 (s, OH), 6.68 (s, 2 arom. H), 4.95 (s, CH-5), 3.57 (s, CH3N+, axial), 3.21 (s, CH3N+, equatorial), 0.94 (t, O(CH2)3CH3, J=7.3 Hz).