Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH2:20][OH:21])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:32]2[C:33]([CH:38]=O)=[N:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH3:30])=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)[O:41]C(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:41])=[CH:14][C:13]=2[CH2:20][OH:21])[CH2:38][C:33]2[C:32]([C:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)([CH3:31])[CH3:30])=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CNCc2ccc(C#N)cc2CO)c(C)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ccc(C(N)=O)cc2CO)Cc2ncccc2C(C)(C)c2ccc(F)cc2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-3-hydroxymethyl-benzonitrile in CH2Cl2 with 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 4-[((3,5-dimethyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-methyl]-3-hydroxymethyl-benzamide as a white foam. 1H NMR (CDCl3) δ 1.62 (s, 6H), 2.24 (s, 3H), 2.26 (s, 3H), 3.05 (s, 2H), 3.21 (s, 2H), 3.47 (s, 1H), 3.59 (s, 2H), 4.18 (s, 2H), 5.75 (br s, 1H), 6.29 (br s, 1H), 6.89 (t, 1H, J=9.0 Hz), 7.02 (m, 3H), 7.21 (dd, 1H, J=7.5, 3.0 Hz), 7.26 (s, 1H), 7.61 (d, 1H, J=7.5 Hz), 7.66 (s, 1H), 7.87 (d, 1H, J=7.5 Hz), 8.15 (s, 1H), 8.45 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.3, 18.5, 31.3, 42.3, 51.1, 57.78, 58.4, 58.9, 63.1, 115.6, 115.8, 122.2, 127.1, 127.6, 127.7, 130.3, 131.8, 132.5, 133.5, 133.6, 134.3, 139.5, 141.7, 142.4, 143.5, 145.5, 146.8, 146.9, 152.7, 156.7, 159.9, 163.1, 169.5. HPLC: 98%. ES-MS m/z 527 [M+H]+, 549 [M+Na]+. Anal. Calcd. for C32H35N4O2F 0.4 CH2Cl2: C, 69.41; H, 6.44; N, 9.99. Found: C, 69.15; H, 6.35; N, 9.97.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:7])=[O:6]
Reactant: OCc1ccccc1
Reactant: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COC(C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 38.4 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (14) (0.50 g, 1.2 mmol) dissolved in 5 mL of anhydrous dichloromethane (DCM) was reacted with 0.14 mL (0.2 g, 1.5 mmol) of oxalyl chloride. After completion of the reaction, a solution of 0.34 mL of benzyl alcohol (0.25 mL, 0.26 g, 2.4 mmol) and 0.26 mL of pyridine (0.15 g, 1.9 mmol) in dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.23 g (38% yield) of the title compound (32a) as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (31a).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].C([O:27][C:28](=[O:30])[CH3:29])(=O)C.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17](=[CH:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])[CH:16]=[C:15]([OH:20])[CH2:14][CH2:13]4)[CH3:2].[CH3:32][C:31]([CH2:29][C:28]([OH:27])=[O:30])=[O:33]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC=C4C=C(O)CC[C@@H]4[C@H]3CC[C@@]21CC
Product: CC(=O)CC(=O)O

Procedure:
Reflux dl-13-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one (1.0 g) for 11/2 hours with acetic anhydride (16 cc), acetyl chloride (8.0 cc) and pyridine (0.8 cc). Remove the liquids under reduced pressure and partition the dry crystalline residue between benzene-ether and water. Wash the organic solvents under reduced pressure and triturate the residue with ice-cold ether to provide dl-13-ethyl-17α-ethynyl-3,17-dihydroxygona-3,5-diene, diacetate (0.725 g), m.p. 144°-150°C; λmax. KBr 3.09, 5.67, 5.77μ; λmax. EtOH 236 mμ (ε19,300).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[CH:17][CH:18]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Reactant: NCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccc(C(=O)NCc2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.36 g of 4-diethoxyphosphinylmethylbenzoic acid and 0.54 g of benzylamine in 15 ml of dry DMF was added dropwise a solution of 1.00 g of diethyl phosphorocyanidate in 2 ml of dry DMF under ice-cooling with stirring. Then, a solution of 0.56 g of triethylamine in 3 ml of dry DMF was added dropwise thereto requiring 5 minutes. The mixture was stirred for 30 minutes under ice-cooling and one hour at room temperature. After adding 30 ml of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water two times. After drying over anhydrous sodium sulfate, the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=1:1), and 4-diethoxyphosphinylmethyl-N-benzylbenzamide was obtained. It was recrystallized from benzene-n-hexane to give 1.60 g of colorless needles.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([O:6][CH3:7])=[O:5].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C=O)C>[CH3:22][O:1]/[CH:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)/[C:4]([O:6][CH3:7])=[O:5].[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(=CO)c1ccccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Product: COC(=O)Cc1ccccc1OCc1ccccc1

Procedure:
The crude methyl 3-hydroxy-2-(2'-benzyloxyphenyl)propenoate was dissolved in dry DMF (100 ml) and potassium carbonate (29.0 g) was added in one portion. Dimethyl sulphate (16.00 g) in dry DMF (10 ml) was then added dropwise with stirring. After ninety minutes, water (300 ml) was added and the solution was extracted with ether (2 x 300 ml). After washing with water (3 x 150 ml) and brine, the extracts were dried and concentrated under reduced pressure, and the resulting yellow oil solidified on trituration with ether/petrol. Recrystallization from dry methanol afforded E-methyl 3-methoxy-2-(2'-benzyloxyphenyl)propenoate as a white, crystalline solid (5.44g, 17% yield from methyl 2-benzyloxyphenylacetate), M.P. 76-77° C.; infrared maxima (nujol mull): 1710, 1640 cm-1 ; 1H nmr (CDCl3, 90MHz): delta 3.63 (3H,s), 3.75 (3H,s), 5.05 (2H,s), 6.80-7.40 (9H,m), 7.50 (1H,s)ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2C[C@H:9]2[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1.[CH3:16][C@@H:17]1[C@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20][C:19](=[O:28])[NH:18]1.CCN(CC)CC>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:11]([N:18]2[C@@H:17]([CH3:16])[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:20][C:19]2=[O:28])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-bromo-phenyl)-1-imidazol-1-yl-propenone (1.05 eq) from Step 1, (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.0 eq) or (−)-isomer and Et3N (1.2 eq) in CH3CN (0.2M) was refluxed overnight. The resulting mixture was cooled to rt, filtered on a pad of silica gel and concentrated. Crystallization in hexane:Et2O afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-:22].[Na+].OO.Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH2:21])=[O:22])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1OC
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1OC
Yield: 84 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-1H-indazole-5-carbonitrile (200 mg, 0.72 mmol) in ethanol (3.5 mL) was added 6 N NaOH (0.5 mL) followed by H2O2 (2.0 mL of a 30% solution). The solution was heated to 45° C. for 1 hour when water (80 mL) was added and the pH adjusted to <1 with 3 N HCl. The reaction was then filtered and the product dried to give the title compound (180 mg, 61 mmol, 84% yield). 1H NMR (DMSO-d6) δ 13.3 (s, 1H), 8.59 (s, 1H), 8.12 (br s, 1H), 7.92 (d, 1H), 7.6–7.5 (m, 2H), 7.52 (s, 1H), 7.3 (br s, 1H), 7.13 (d, 1H), 3.87 (s, 3H), 3.84 (s, 3H); ES-MS (m/z) 298 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7]O)[S:5][CH:6]=1.FC(F)(F)S(Cl)(=O)=O.CCN(CC)CC.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.O>[N:24]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[N:3]=1)=[N+:25]=[N-:26]
Reactant: OCc1nc(Br)cs1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(Cl)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc(Br)cs1
Reaction time: 8 h

Procedure:
(4-Bromo-thiazol-2-yl)-methanol (1.1 g, 5.7 mmol) in DMF (15 ml) is treated at room temperature under nitrogen atmosphere with trifluoromethanesulfonyl chloride (0.61 ml, 1 equivalent), and Et3N (0.8 ml, 1 equivalent). The reaction mixture is stirred for 3 hours at room temperature before the addition of sodium azide (1.11 g, 3 equivalents), followed by overnight stirring at the same temperature. The reaction mixture is diluted with water and extracted with DCM and diethyl ether. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to afford the crude product, which is used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]1.[Cl:24][C:25]1[C:38]([N:39]=[C:40]=S)=[C:37]([Cl:42])[CH:36]=[CH:35][C:26]=1[CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].[CH3:43]C(C)N=C=NC(C)C>C1COCC1>[CH2:1]([O:2][C:3]([C:4]1[C:5]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([F:21])([F:20])[F:22])[CH2:17][CH2:18]2)=[CH:6][C:7]2[N:11]([CH3:12])[C:40]([NH:39][C:38]3[C:37]([Cl:42])=[CH:36][CH:35]=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]=3[Cl:24])=[N:10][C:8]=2[CH:9]=1)=[O:23])[CH3:43]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CC(C)N=C=NC(C)C
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)OC)cc1N
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1

Procedure:
The title compound is prepared in analogy to 6c from methyl-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoate (349 mg, 1.01 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (336 mg, 1.06 mmol), DIC (0.19 mL, 1.2 mmol) and THF (20 mL).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](Cl)([Cl:13])=[O:12]>>[Cl:13][C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:12]
Reactant: CCCCCCCCCO
Reactant: O=C(Cl)Cl
Product: CCCCCCCCCOC(=O)Cl

Procedure:
396 Parts of nonyl alcohol are reacted with phosgene to give 558 parts of nonyl chloroformate as a colourless liquid b.p. 70°-72° C/1 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH2:10][C:11]2[NH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.[OH2:28].C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH2:10][C:11]2[NH:12][C:13](=[O:16])[NH:14][N:15]=2)(=[O:25])=[O:28])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: O=c1[nH]nc(CSCc2ccc(Br)cc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]nc(CS(=O)(=O)Cc2ccc(Br)cc2)[nH]1
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 5-({[(4-bromophenyl)methyl]thio}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one obtained in Reference Example 108 (0.500 g, 1.67 mmol) in DMF (5 mL) was added m-chloroperbenzoic acid (0.903 g, 3.67 mmol) at room temperature, and the mixture was stirred for 12 hr. Water and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was washed with water and diethyl ether to give the title compound as a white powder (0.508 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4](Cl)[N:3]=1.C(O)C.O1CCCC1>[Pd].C(N(CC)CC)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)c2ncn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c2n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ncc2ncn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c2n1
Reaction time: 24 h

Procedure:
A mixture of 3.393 g (7.04 mM) of 2-amino-9-[(2-benzoyloxy-1-(benzoyloxymethyl)ethoxy)methyl]-6-chloro-9H-purine, 100 ml ethanol, 100 ml tetrahydrofuran, 1.9 ml triethylamine was added to 0.6 g Pd-C catalyst in a Parr bottle. The mixture was shaken under 50 P.S.I. of H2 for 24 hours. The Pd-C was filtered through a Celite pad and 0.65 g fresh Pd-C was added to the reaction mixture and the hydrogenation was continued for 4 days. Column chromatography using 100% CH2Cl2, 4:1 CH2Cl2 /acetone, and 100% acetone produced the title compound, mpt. 132°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]1[O:14][C:13](=[O:15])[NH:12][CH2:11][CH2:10]1.[CH3:16]C([O-])(C)C.[K+].Br[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O-:50])=[O:49])=[CH:44][C:43]=2[CH3:51])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]>CN(C=O)C>[CH3:41][O:40][C:39]1[CH:38]=[CH:37][C:36]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:16])=[O:49])=[CH:44][C:43]=2[CH3:51])=[CH:35][C:34]=1[C:25]1[CH:26]=[CH:27][C:28]([C:30]([F:32])([F:33])[F:31])=[CH:29][C:24]=1[CH2:23][N:12]1[CH2:11][CH2:10][C@@H:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:14][C:13]1=[O:15]
Reactant: COc1ccc(-c2ccc(C(=O)[O-])cc2C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: COc1ccccc1[C@@H]1CCNC(=O)O1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3CC[C@@H](c4ccccc4OC)OC3=O)c2)c(C)c1
Reaction time: 0.25 h

Procedure:
To a solution of (6S)-6-(2-methoxyphenyl)-1,3-oxazinan-2-one (31.6 mg, 0.152 mmol) in DMF (1.5 mL) was added t-BuOK (16.5 mg, 0.144 mmol). The reaction was stirred for 15 minutes, then a solution of 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (75 mg, 0.152 mmol) in DMF (15 mL) was added via cannula. The reaction was stirred at room temperature for 1 hour, and then quenched with saturated NH4Cl solution (10 mL), diluted with EtOAc (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10 to 50% EtOAc/hexanes) to afford methyl 4′-methoxy-2″-{[(6S)-6-(2-methoxyphenyl)-2-oxo-1,3-oxazinan-3-yl]methyl}-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate LCMS=619.8 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.78-7.94 (m, 2H), 7.68 (s, 1H), 7.60 (t, J=9.0 Hz, 1H), 7.25-7.44 (m, 5H), 6.79-7.15 (m, 4H), 5.58 (dd, J=9.2, 2.5 Hz), 5.32 (dd, J=9.2, 2.5 Hz), 4.76 (d, J=15.3 Hz, 1H), 4.57 (d, J=15.3 Hz), 4.48 (d, J=15.6 Hz), 3.92 (s, 3H), 3.86 (s), 3.84 (s), 3.80 (s), 3.65 (s), 2.88-3.16 (m, 2H), 2.35 (s), 2.32 (s), 1.85-2.20 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.CN(C)C=O>O>[Cl:18][C:6]1[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc(OC)c2nccc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2nccc(Cl)c2c1

Procedure:
A solution of 6.5 g (31.6 mmol) of 6,8-dimethoxyquinolin-4-ol, 29 mL (316 mmol) of phosphorous oxychloride and 2.6 mL of N,N-dimethylformamide was stirred at room temperature for seven hours. The reaction solution was poured into a stirred mixture of ice and water. The aqueous mixture was washed three times with 300 mL portions of ethyl acetate, and then adjusted to pH 6 by the addition of solid sodium carbonate. 4-Chloro-6,8-dimethoxyquinoline was thus obtained as a colorless solid: yield 5.73 g (81%). The product was recrystallized from hot water for analysis: m.p. 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH2:20][O:21][C@H:22]([CH3:31])[C:23](N3CCOCC3)=[O:24])=[CH:14][CH:13]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=[O:33].C1C[O:44]CC1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[CH2:20][O:21][C@H:22]([CH3:31])[C:23]([OH:44])=[O:24])=[CH:16][CH:17]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:32](=[O:33])[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)c2c(C)n(Cc3ccc(/C=C/CO[C@H](C)C(=O)N4CCOCC4)cc3)c3ncccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)n(Cc3ccc(/C=C/CO[C@H](C)C(=O)O)cc3)c3ncccc23)cc1
Yield: 96 %

Procedure:
The compound of Example 74-1 (33 mg, 0.06 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide solution (1 ml), followed by stirring under reflux for 8 hours. The mixture was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (28 mg, 96%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:62]=[CH:61][C:30]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[CH:35][CH:34]=2)=[O:32])=[CH:29][CH:28]=1)=[N+]=[N-].O>CCOCC.C1COCC1>[NH2:20][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:62]=[CH:61][C:30]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])=[CH:35][CH:34]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN=[N+]=[N-])cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCN)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
Triphenylphosphine (2.62 g, 10.0 mmol) was added to a solution of tert-butyl 1-((4-(4-(3-azidopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate (5.0 g 8.32 mmol) in Ether:THF (1:1, 50 mL) at 0° C. followed by of water (500 mg, 27.8 mmol). The reaction was stirred at r.t. overnight. Upon completion, the reaction was concentrated and purified by silica gel chromatography (EtOAc to EtOAc:MeOH gradient with 1% TEA) to provide 3.24 g (5.63 mmo 68.7% yield) of tert-butyl 1-((4-(4-(3-aminopropoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as yellow oil.
Reaction SMILES: [C:1](Cl)(C)(C)[CH3:2].NCC(O)=O.CCC1OC2C=CC(N)=CC=2C(=O)N1.[CH2:25](Cl)[CH3:26].NCC(O)=O.Cl[C:34]1[CH:62]=[CH:61][C:37]([O:38][C:39]2N=[CH:43][C:42]([CH2:45][N:46]3[CH2:51][CH2:50][C:49]([OH:52])=[C:48]([C:53]([NH:55][CH2:56][C:57]([OH:59])=[O:58])=[O:54])[C:47]3=[O:60])=[CH:41][CH:40]=2)=CC=1>>[CH:61]1([CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45][N:46]3[CH2:51][CH2:50][C:49]([OH:52])=[C:48]([C:53]([NH:55][CH2:56][C:57]([O:59][CH2:1][CH3:2])=[O:58])=[O:54])[C:47]3=[O:60])=[CH:43][C:25]=2[CH3:26])[CH2:62][CH2:34]1
Reactant: CC(C)(C)Cl
Reactant: O=C(O)CNC(=O)C1=C(O)CCN(Cc2ccc(Oc3ccc(Cl)cc3)nc2)C1=O
Reactant: CCCl
Agent: CCC1NC(=O)c2cc(N)ccc2O1
Agent: NCC(=O)O
Product: CCOC(=O)CNC(=O)C1=C(O)CCN(Cc2ccc(OCC3CC3)c(C)c2)C1=O

Procedure:
Instead of the compound obtained in Reference Example A-1 and glycine tert-butyl hydrochloride, the compound (2.10 g) obtained in Reference Example A-302 and glycine ethyl hydrochloride (956 mg) were respectively used and treated by the same techniques as in Example 1-1(1) to (3) to give ethyl N-({1-[4-(cyclopropylmethoxy)-3-methylbenzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a yellow oil (2.01 g).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][OH:13])[O:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[C:18]1(C)[C:19]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.[CH2:29](Cl)Cl>CN(C1C=CN=CC=1)C>[CH3:29][C:22]1[CH:23]=[CH:18][C:19]([S:24]([O:13][CH2:12][CH:8]2[O:7][C:6]3[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)(=[O:25])=[O:26])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CO)CO2
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1

Procedure:
A solution of [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.4 g, 1.7 mmol), toluenesulfonyl chloride (0.5 g, 2.6 mmol), TEA (0.4 ml, 2.6 mmol) and 4-DMAP (0.2 g, 1.7 mmol) in DCM (10 ml) was stirred at rt for 1 h. DCM was added and the resulting mixture was washed with HCl (1 N) and brine. The organic phase was dried (Na2SO4) and evaporated to dryness to give the title compound (0.7 g). MS m/z (rel. intensity, 70 eV) 416 (M+, 31), 244 (bp), 243 (26), 231 (19), 91 (70).