Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH2:9][CH3:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCc1cc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(Br)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-Bromo-2-ethylaniline (500 mg, 2.50 mmol) was dissolved in toluene (25 mL), sodium carbonate (397 mg, 3.75 mmol) and benzyl chloroformate (0.428 mL, 3.00 mmol) were added and the mixture stirred under nitrogen at room temperature. After 20 hours water (25 mL) was added, the aqueous phase separated and washed with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. Chromatography (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I38) (708 mg, 85%) as a pink solid; 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.44-7.28 (m, 7H), 6.43 (s, 1H), 5.20 (s, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). LCMS Method C: rt 6.46 min; 258.0 [M-PhCH2O+CH3OH]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C@H:9]([CH2:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[C@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]1=[O:29].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[O:29]=[C:7]1[C@@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([CH2:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[NH:6]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ccccc2=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ccccc1=O)OCc1ccccc1
Temperature: 90 °C
Yield: 77.1 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using Benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-((2-oxopyridin-1(2H)-yl)methyl)azetidin-3-yl)carbamate (361 mg, 0.622 mmol), K2S2O8 (225 mg, 0.833 mmol) and K2HPO4 (135 mg, 0.773 mmol) in ACN:water (2:1, 9.9 mL) while heating for 1.5 h at 90° C. More K2S2O8 (45 mg, 0.17 mmol) and K2HPO4 (26.9 mg, 0.155 mmol) were added and heated for another 30 min, whereupon it was concentrated, redissolved in EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%) to afford the title compound (157 mg, 81%). LCMS: Rt=0.56 min, m/z=328.2 (M+1) Method 2m_acidic.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][O:6][C@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[OH:21].[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O)(=O)C.C([C@@H]1CC=CCO1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:8]([C@@H:5]1[CH2:4][C@@H:3]([OH:21])[C@H:2]([NH:1][CH2:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][CH:23]=[CH:24]3)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Agent: C1=CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Solvent: CC(=O)O
Product: O[C@@H]1C[C@@H](C(c2ccccc2)c2ccccc2)OC[C@H]1NCc1ccc2[nH]ccc2c1

Procedure:
(2S,4R,5R)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 31a (0.03 g, 0.11 mmol) was reacted with 1H-indol-5-carbaldehyde (0.02 g, 0.11 mmol), glacial acetic acid (0.01 g, 0.11 mmol), and NaCNBH3 (0.01 g, 0.21 mmol) (Procedure C) to give (2S,4R,5R)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol, (−)32b, 0.04 g (92%, [α]D=(−)69.90, c=1, Acetone).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17]([O-])([O-])([O:19][CH3:20])[CH3:18]>>[CH3:20][O:19][C:17](=[N:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:18]
Reactant: COC(C)([O-])[O-]
Reactant: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Product: COC(C)=Nc1ccc(C)cc1C(=O)c1ccccc1

Procedure:
2-Amino-5-methylbenzophenone is reacted with methyl orthoacetate, whereby 2-(1-methoxyethylideneamino)-5-methylbenzophenone is obtained. The product is reacted with hydrazine hydrate, whereby 3-amino-3,4-dihydro-2, 6-dimethyl-4-hydroxy-4-phenylquinazoline (colorless peates melting at 192° to 196° C) is obtained. The product is reacted with chloroacetylchloride, followed by the same treatment as Example 1, whereby 3-chloroacetylamino-3, 4-dihydro-2, 6-dimethyl-4-hydroxy-4-phenylquinazoline having 1/2 mole of water of crystallization (colorless powdery crystals melting at 90° to 93° C) is obtained. The product is heated with acetic acid, whereby crystals of 2-(3-chloromethyl-1-methyl-s-triazol-4-yl)-5-methylbenzophenene are obtained. Recrystallization from benzene gives colorless needles melting at 167° to 168° C. Overall yield: 42%.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18]C(O)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>N1C=CC=CC=1>[C:5]([O:4][CH:1]([CH2:18][CH2:17][CH2:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(O)CCCOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OC(C)CCCOCc1ccccc1
Yield: 36 %

Procedure:
Acetic anhydride (1.86 mL) was added to a mixed solution of 5-benzyloxypentan-2-ol (957 mg, 4.93 mmol) in pyridine (1.8 mL) in an ice bath. After completion of the reaction, methanol (1.6 mL) was added to the reaction solution in an ice bath, and the solvent was evaporated. The pH was adjusted to 4 with 2 mol/L hydrochloric acid. After extraction with chloroform-water, the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 420 mg of the title compound (yield: 36%) as a colorless oil.
Reaction SMILES: [C@@H:1]12[C:7](=[O:8])[NH:6][C@@H:5]1[CH2:4][CH2:3][NH:2]2.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:8]=[C:7]1[C@@H:1]2[C@@H:5]([CH2:4][CH2:3][N:2]2[C:16](=[O:17])[NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]1
Reactant: O=C1N[C@@H]2CCN[C@H]12
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1N[C@@H]2CCN(C(=O)Nc3ccccc3)[C@H]12

Procedure:
100 mg (0.89 mmol) of (1S,5R)-2,6-diazabicyclo[3.2.0]heptan-7-one were dissolved in 5 ml of chloroform and heated to boiling under reflux. Phenyl isocyanate (0.1 ml, 0.89 mmol) and 1 drop of triethylamine were added. thereto and the mixture was left to react at the boiling temperature for 1 hour. After concentration the residue was chromatographed over silica gel (0.063-0.2 mm particle size) with ethyl acetate:ethanol=3:2.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:22]([CH3:23])[C:21]3[CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[NH:33][CH2:34][CH3:35])[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]([CH2:39][C:40](Cl)=[O:41])[CH3:38]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:22]([CH3:23])[C:21]3[CH2:20][CH2:19][N:18]([C:40](=[O:41])[CH2:39][N:37]([CH3:38])[CH3:36])[CH2:17][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[NH:33][CH2:34][CH3:35])[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2SC3=C(CCNC3)N2C)C(=O)N1Cc1ccccc1
Reactant: CN(C)CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC3=C(CCN(C(=O)CN(C)C)C3)N2C)C(=O)N1Cc1ccccc1

Procedure:
To the product of Example 183 in CHCl3 was added N,N-dimethylaminoacetyl chloride and TEA. After 4 h the product mixture was concentrated and chromatographed (silica gel, 0-40% EtOAc/Hex) to yield the title compound. 1H-NMR (CDCl3): δ 7.39-7.44 (2H, m), 7.33 (2H, m), 7.23-7.30 (2H m), 7.19 (1H, br s), 6.47 (1H, d), 5.15 (2H, s), 4.61 (1H, br s), 4.51 (1H, br s), 4.27 (1H, m), 3.92 (2H, m), 3.64 (3H, br s), 3.22 (1H, br s), 3.16 (1H, br s), 2.99 (2H, m), 2.63 (1H, br s), 2.56 (1H, br s), 2.31 (3H, s), 2.28 (3H, s), 1.01 (3H, t); MS(ESI): 588 (MH+).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.C(N(CC)CC)C.[NH2:29][C:30]1[C:31]([C:47]([NH:49][NH:50][C:51]([C:53]2[CH:54]=[C:55]3[C:60](=[CH:61][CH:62]=2)[CH2:59][N:58]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:57][CH2:56]3)=[O:52])=O)=[N:32][C:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:44])[CH3:43])[CH:37]=2)=[CH:34][N:35]=1>ClCCl>[NH2:29][C:30]1[C:31]([C:47]2[O:52][C:51]([C:53]3[CH:54]=[C:55]4[C:60](=[CH:61][CH:62]=3)[CH2:59][N:58]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:57][CH2:56]4)=[N:50][N:49]=2)=[N:32][C:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]([C:45]#[N:46])([CH3:43])[CH3:44])[CH:37]=2)=[CH:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)NNC(=O)c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)ccc2C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3nnc(-c4nc(-c5ccnc(C(C)(C)C#N)c5)cnc4N)o3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
PS—PPh3 (145.6 mg, 0.3042 mmol) was suspended in dichloromethane (6.269 mL). Iodine (77.21 mg, 15.66 μL, 0.3042 mmol) was added and the mixture was stirred for 10 minutes before triethyl amine (63.10 mg, 86.91 μL, 0.6236 mmol) was added. After 5 minutes tert-butyl 6-[[[3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazine-2-carbonyl]amino]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (92 mg, 0.1521 mmol) was added as a solution in dichloromethane (3.919 mL) the mixture was stirred at ambient temperature for 1 hour. The resin was filtered off and the filtrate was washed with aqueous saturated sodium bicarbonate. The extracted organic phase was then dried over MgSO4 and concentrated in vacuo. The residue was taken onto the next step as is. (118.7 mg, assumed 100% yield). LC/MS m/z 539.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (58.90 g) in tetrahydrofuran (500 ml) was added aluminum lithium hydride (6.64 g) at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the precipitate was filtered off. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)methanol (45.30 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point: 79–80° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN1CCOCC1.[CH:18]([NH2:21])([CH3:20])[CH3:19].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:18]([NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=1)([CH3:20])[CH3:19]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)c1cccc(O)c1
Reaction time: 16 h

Procedure:
3-Hydroxybenzoic acid (0.966 g, 7.0 mmol), N-methylmorpholine (2.3 mL, 21 mmol), iso-propylamine (1.78 mL, 21 mmol) and CH2Cl2 (30 mL) were dissolved together and hydroxybenzotriazole (1.03 g, 7.7 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.47 g, 7.7 mmol) was added; stirred 16 h, diluted with CH2Cl2 (70 mL) and the organic phase was washed with satd aq NaHCO3, H2O, 0.3 N HCl, H2O, and satd aq NaCl, dried (Na2SO4) and concentrated to afford 443 mg as a white foam. 1H NMR (CDCl3): d 7.23 (m, 3), 6.90 (m, 1), 4.22 (m, 1), 1.25 (d, 6).
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([S:10][CH2:11][CH:12]=[CH2:13])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH3:14][N:15]([CH3:19])[C:16]([N:7]1[C:8]([S:10][CH2:11][CH:12]=[CH2:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]1)=[O:17]
Reactant: C=CCSc1nnc(C(C)(C)C)[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: C=CCSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 87 %

Procedure:
A solution of 56 g (0.284 mol) of 3-tert.butyl-5-allylthio-4H-1,2,4-triazole and 31.2 g (0.29 mol) of dimethylcarbamyl chloride in 300 ml of pyridine was maintained at reflux temperature for 16 hrs. After the pyridine was removed at reduced pressure on the rotary evaporator, water was added followed by chloroform. The organic layer was washed with successive portions of dilute hydrochloric acid, water and brine, then dried over Na2SO4. The solvent was removed in vacuo to give 66.3 g of an oil, nD26 1.5126.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:11]1)(=O)[CH3:8].O>O1CCCC1>[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1

Procedure:
To a suspension of lithium aluminium hydride (0.08 g) in tetrahydrofuran was added a solution of 5-(4-acetyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.34 g) in tetrahydrofuran under ice-cooling, and the resulting mixture was stirred under reflux for 1 hour. the reaction mixture was cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 210°-211° C (oxalate).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:20]Br)=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:20][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[O:19])[CH:8]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-chloropyrimidin-2-one hydrochloride (502 mg), α-bromo-4-methoxyacetophenone (687 mg), triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2 hours, during which the suspension formed a solution from which a solid crystallised out. The solid was crystallised from acetone to give the title pyrimidinone: yield. 449 mg; m.p. 212°-214° C.: λmaxEtOH 222.5 nm (ε 19850), 277 nm (ε 18000), 330 nm (ε 3725).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(C(F)(F)F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-trifluoromethylphenol: SMS m/e: 559.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][N:22]([CH3:30])[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:21][N:22]([CH3:30])[C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:29][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(N(C)C)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-dimethylamino-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1C2C=CC=CC=2N=N1.N>C1COCC1.[Pd]>[OH:1][C:2]1[C:7]2[C:8]3([OH:45])[C:21]([O:25][CH3:26])([CH:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH2:52])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[CH:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: On1nnc2ccccc21
Agent: [Pd]
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COC1[C@@H](NC2=CC(=O)c3c(cc4c(c3O)C(=O)C3(OC)C(O)Cc5cc(C)c(C(N)=O)c(O)c5C3(O)C4=O)C2=O)O[C@@H](C)[C@H](OC)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% Pd/C and the reaction mixture was stirred at room temperature under hydrogen at 1 atmosphere for 4 h. The reaction mixture was filtered without exposure to air into another flask containing polystyrene-carbodiimide (260 mg, 0.29 mmol) and the mixture was stirred for 10 min. A solution of 1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) and ammonia (0.22 mL, 2.0 M solution in THF, 0.16 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford 6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((2S,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (12 mg, 15%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.19 (s, 1H), 12.89 (s, 1H), 8.22 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 5.96 (s, 2H), 5.87 (s, 1H), 4.96 (d, J=6.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.66 (m, 3H), 3.61 (s, 3H), 3.59-3.50 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.13 (t, J=9.5 Hz, 1H), 2.46 (s, 3H), 1.36 (s, 3H); MS (ESI+) m/z 683 (M+H); HPLC 94.3% (AUC), tR 11.64 min.
Reaction SMILES: CCN(CC)CC.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OC([N:26]1[CH2:29][CH2:28][C@H:27]1[CH2:30][O:31][C:32]1[CH:33]=[C:34]([C@H:38]2[CH2:40][C@@H:39]2[CH2:41][CH2:42][OH:43])[CH:35]=[N:36][CH:37]=1)=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:43][CH2:42][CH2:41][C@H:39]2[CH2:40][C@@H:38]2[C:34]2[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH2:30][C@@H:27]3[CH2:28][CH2:29][NH:26]3)[CH:33]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCO)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2C[C@@H]2c2cncc(OC[C@@H]3CCN3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
4-(Dimethylamino)pyridine (DMAP; 14 mg, 0.11 mmol, 0.02 equiv.), Et3N (0.24 mL, 1.7 mmol, 3.0 equiv.), and p-toluenesulfonyl chloride (164 mg, 0.86 mmol, 1.5 equiv.) were added to a stirred solution of 2-[(1R,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 574 μmol) in dry CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (50 mL). The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. 2-[(1R,2S)-2-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethyl p-toluenesulfonate (Rf=0.4, 50% EtOAc in petroleum ether) was obtained by CC (237 mg, 82%) and was directly used for the next reaction.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1[C:47]([CH3:48])=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:49]>C(#N)C>[CH2:49]([N:11]([CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:10][CH2:9][P:4](=[O:8])([OH:5])[OH:3])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CN(CCP(=O)(O)O)Cc1ccccc1)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (15 mg, 0.024 mmol) in acetonitrile (0.5 mL) was treated with TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24 mmol). The solution was stirred at ambient temperature for 1 hour, when it was quenched with methanol. The solvent was removed under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 11 mg of the product (93%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.89 (s, 3H), 2.03-2.15 (m, 2H), 2.14 (s, 3H), 3.30-3.47 (m, 2H), 3.50 (br s, 2H), 3.62 (br s, 2H), 3.79 (s, 3H), 4.28 (s, 2H), 5.23 (s, 2H), 5.76 (br s, 1H), 7.46 (br s, 5H) ppm; 31P (121.4 MHz, CDCl3) δ 20.1 ppm; MS (m/z) 476.3 [M+H]+, 498.3 [M+Na]+.