Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28](O)=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:43]1(OC(N(C)C)=[N+](C)C)[C:47]2N=CC=C[C:46]=2[N:45]=N1.C(CN)O>CN(C=O)C>[NH2:43][CH2:47][CH2:46][NH:45][C:28]([C:27]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:26]=1[CH2:25][NH:24][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:23])=[O:29]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)O)c(OCc1ccccc1)c2=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: NCCO
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)NCCN)c(OCc1ccccc1)c2=O
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A mixture of intermediate 190, 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoic acid, (59 mg, 0.12 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, HATU (76 mg, 0.2 mmol; Aldrich) in DMF (1 mL) was stirred for 20 min. To this mixture was added ethanolamine (20 mg, 0.3 mmol) and the stirring continued overnight. The mixture was concentrated in vacuo, dissolved in CH2Cl2, washed with water then dried (MgSO4), filtered, and concentrated to provide 55 mg (Yield 87%) of the title compound: LC/MS m/z 525 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nn2)CC1
Yield: 42.6 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and oxazolidin-2-one (26 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (52 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].C1COCC1.C([N-]C(C)C)(C)C.[Li+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCC.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccccc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)C(Cc1ccccc1)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A 500 mL round-bottom flask is charged with methyl 2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, 1 eq) and THF (200 mL). The homogeneous mixture is cooled to 0° C. in an ice bath. Lithium diisopropyl amide (23.5 mL of a 2.0 M solution in heptane/THF) is added, maintaining a temperature less than 3° C. The reaction is stirred 45 minutes at this reduced temperature. Benzyl bromide (5.6 mL, 47 mmol, 1 eq) is added dropwise. The reaction is allowed to gradually warm to room temperature and is stirred for 18 hours. The reaction is quenched with 1N HCl and extracted 3 times with equal portions of EtOAc. The combined extracts are washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified over silica to afford 4.433 g (35%) of the desired compound. ESI+ MS 293 (M+Na).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH4+:12].[OH-]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:12])=[O:7]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1cccc(CCl)c1
Yield: 81.4 %

Procedure:
To a solution of 66.50 g (0.352 mol, 1.0 mol-equiv) 3-chloromethylbenzoylchloride in 400 mL CH2Cl2 at 0°-5° C. under argon was added 47.6 mL (0.704, 2.0 mol-equiv) concentrated aqueous NH4OH over 25 min. The resulting slurry was filtered, washed with water and the product was dried overnight at 50° C. under vacuum to provide 48.59 g (81%) of 3-chloromethylbenzamide.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].[CH3:14]N(C)P(=O)(N(C)C)N(C)C>>[O:1]=[C:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Yield: 2 %

Procedure:
Example 9 was repeated except that 6 ml of hexamethylphosphoric triamide was used instead of t-butyl alcohol as the solvent. A mixture of 2-oxo-3-phenylbutanoic acid (46 %) and 2-oxo-3-methyl-3-phenylbutanoic acid (2 %) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]COC)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([B:23]([OH:28])[OH:24])[C:11]([OH:14])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(-c2cccc(F)c2)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2cccc(F)c2)ncc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
100 mg (1.0 eq) of the obtained 2-(3-fluorophenyl)-5-(methoxymethoxy)pyridine was dissolved in 4.3 mL of tetrahydrofuran. After cooling to −78° C., tert-butyllithium 1.7 M solution (0.5 mL, 2.0 eq) was added slowly. The mixture was stirred at the same temperature for 30 minutes. 121 mg (1.5 eq) of B(O-iPr)3 was dissolved in 2.1 mL of tetrahydrofuran, and added to the above mixture. The mixture was stirred at the same temperature for 1 hour, and stirred for 3 hours as warming to room temperature. After quenching by adding distilled water, tetrahydrofuran solution was added, and washed with brine. The reaction solution was dried with magnesium sulfate to remove water, concentrated under reduced pressure, and crystallized with methylchloride to obtain 50 mg of (2-(3-fluorophenyl)-5-hydroxypyridin-4-yl)boronic acid as white solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:40])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)c2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)c1ccccc1
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 82b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]=O>CN(C)C=O.[C].[Pd]>[CH3:14][N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=C(O)c1ccc2c(c1)CCCN2
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1CCCc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinolin-6-carboxylic acid (2 g), 32% aqueous formalin solution (2 ml) and 10% palladium-carbon (400 mg) in N,N-dimethylformamide (10 ml) was stirred under hydrogen atmosphere at room temperature for one hour. After removing the palladium-carbon by filtration, the solvent was removed under reduced pressure and the resulting residue was triturated with diethyl ether to obtain 1-methyl-1,2,3,4-tetrahydroquinolin-6-carboxylic acid (1.98 g) as yellowish powder.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[I:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[CH3:2].CN(C=O)C.[CH2:21](I)[CH3:22]>C(OCC)(=O)C>[CH2:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[C:11]([I:12])=[C:3]1[CH2:1][CH3:2])[CH3:22]
Reactant: CCc1[nH]c2cc([N+](=O)[O-])ccc2c1I
Reactant: CCI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(I)c2ccc([N+](=O)[O-])cc2n1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Add to a solution of 2-ethyl-3-iodo-6-nitro-1H-indole (0.30 g, 00.95 mmol) in anhydrous DMF (5 mL) sodium hexamethyldisilylamide (1.0M in THF, 1.0 mL, 1.00 mmol) dropwise followed by ethyl iodide (0.23 mL, 2.85 mmol) and stir 3 hours at ambient temperature. Quench the reaction with 1N HCl and add ethyl acetate. Wash the organic layer 2×1N HCl, 1× brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate hexane to afford 0.28 g (86%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.[Cl:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[C:22]([O:23][CH2:24][C:25](O)=O)=[C:21]([O:32][CH3:33])[CH:20]=1.B#B.Cl>>[ClH:18].[Cl:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[C:22]([O:23][CH2:24][CH2:25][NH:1][CH2:2][C:3]2[C:12]3[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=3)[CH2:6][CH2:5][CH:4]=2)=[C:21]([O:32][CH3:33])[CH:20]=1
Reactant: COc1cc(Cl)cc(OC)c1OCC(=O)O
Reactant: COc1ccc2c(c1OC)CCCC2(O)CN
Agent: B#B
Agent: Cl
Product: COc1cc(Cl)cc(OC)c1OCCNCC1=CCCc2c1ccc(OC)c2OC

Procedure:
1-aminomethyl-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene is reacted with the acid chloride of 4-chloro-2,6-dimethoxyphenoxy acetic acid. The resulting amide is reduced with diborane and dehydrated with HCl as described in Example 30 to obtain 1-[2(4-chloro-2,6-dimethoxyphenoxy)ethylaminomethyl]-5,6dimethoxy-3,4-dihydronaphthalene HCl.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=2[F:44])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)c(F)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(Oc2ccc(C#N)cc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (3.25 g, 20.24 mmol) and 18-crown-6 (0.535 g, 2.024 mmol) in DMSO (40 ml) was added potassium tert-butoxide (20 wt % in THF) (12.49 g, 22.26 mmol) and the reaction mixture was stirred at rt for 30 minutes. Next, 4-bromo-3-fluorobenzonitrile (4.05 g, 20.24 mmol) was added and the reaction mixture stirred at 135° C. for 3 days. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (4.56 g, 16.30 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (dd, 1H), 7.59 (d, 1H), 7.35-7.43 (m, 1H), 7.30 (t, 1H), 6.89 (t, 1H), 2.24 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:24]([C:23]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Yield: 47.4 %

Procedure:
1,1-Dimethylethyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate 0.6 g, 2 mmol), trimethyl orthovalerate (0.35 g, 2.1 mmol), and toluene (25 mL) were combined and heated at reflux for 2 hours. Additional trimethyl orthovalerate (1 eq.) was added and the reaction mixture was heated at reflux overnight. Xylene was added and the toluene was distilled off. The reaction was heated at reflux for an additional 8 hours. The bulk of the xylene was distilled off leaving a volume of about 5 mL. The reaction mixture was allowed to cool. The resulting precipitate was isolated by filtration, washed with heptane and dried to provide 0.35 g of 1,1-dimethylethyl N-[2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate as an ivory powder, m.p. 198-199° C. Analysis: Calculated for C20H27N5O2: %C, 65.01; %H, 7.36; %N, 18.95. Found: %C, 64.75; %N, 7.57; %N, 19.09.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:38]([OH:40])=O)[CH2:13][C:14]2[N:18]=[CH:17][N:16]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.[NH2:52][C@@H:53]([CH2:62][CH:63]([CH3:65])[CH3:64])[CH:54]([OH:61])[C:55]([O:57]C(C)C)=[O:56].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:61][CH:54]([CH:53]([NH:52][C:38](=[O:40])[CH:12]([NH:11][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])[CH2:13][C:14]1[N:18]=[CH:17][N:16]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=1)[CH2:62][CH:63]([CH3:64])[CH3:65])[C:55]([OH:57])=[O:56]
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
A mixture of 12.4 g (23.4 mmol) of N-[(phenylmethoxy)carbonyl]-1-(triphenylmethyl)-L-histidine, (Jones, J. H., et al, Synthesis, page 1110 (1987)) 3.3 g (24.6 mmol) of 1-hydroxybenzotriazole and 50 ml of dimethylformamide is cooled to <0° C. and treated with a mixture of 5.6 g (23.4 mmol) of (3S)-3-amino-2-hydroxy-5methylhexanoic acid, 1-methylethyl ester, monohydrochloride (mixture of isomers at hydroxy center) (Example B), and 2.5 g (25 mmol) of triethylamine in 30 ml of dimethylformamide at -5° C. The solution is stirred for five minutes, treated with 5.1 g (24.6 mmol) of dicyclohexylcarbodiimide in 30 ml of dimethylformamide and stirred for eight hours at -5 to 0° C., kept at -5° C. overnight, allowed to warm to room temperature under a nitrogen atmosphere and stirred for 24 hours. The mixture is treated with 1 g (10 mmol) of triethylamine, stirred at room temperature for 72 hours, filtered and the dimethylformamide evaporated in vacuo. The residue is dissolved in 200 ml of ethyl acetate, extracted with 200 ml of 1N citric acid solution, filtered, extracted with 200 ml of saturated sodium chloride solution, 200 ml of saturated solution of sodium bicarbonate and 200 ml of saturated solution of sodium chloride. The organic layer is separated, dried (magnesium sulfate) and the solvent evaporated in vacuo to give 14.1 g of the title compound as a tan foam.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH2:5]([C:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])([CH2:10]O)[CH2:8][OH:9])[CH3:6]>CCCCCC>[CH2:2]([CH:1]1[O:9][CH2:8][C:7]([CH2:5][CH3:6])([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][O:4]1)[CH3:3]
Reactant: CCC=O
Reactant: CCC(CO)(CO)OCc1ccccc1F
Solvent: CCCCCC
Product: CCC1OCC(CC)(OCc2ccccc2F)CO1

Procedure:
Using the procedure of Example 51, propionaldehyde and 2-ethyl-2-(2-fluorobenzyloxy)-1,3-propanediol were reacted, using hexane as solvent, to give, after separation by column chromatography, r-2-ethyl-5-ethyl-t-5-(2-fluorobenzyloxy)-1,3-dioxane, b.p. 89°-90°/0.01 mm, nD26 1.4895; and r-2-ethyl-5-ethyl-c-51 -(2-fluorobenzyloxy)-1,3-dioxane, b.p. 93°-95°/0.01 mm, nD26 1.4902. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[O:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(C=O)cc1

Procedure:
A solution containing 3.053 g (25 mmol) of 4-formylphenol, 6.48 ml (3705 mmol) of 1-bromooctane and 6.9 mg (50 mmol) of potassium carbonate in 100 ml of acetone was refluxed overnight. When the reaction was substantially complete, as indicated by thin layer chromatagraphy (TLC), the reaction was quenched by the addition of 100 ml of water. The desired compound was extracted from the reaction mixture using two 100 ml portions of diethyl ether. The resultant solution was dried over magnesium sulfate, filtered and then concentrated in vacuo to provide a liquid which was purified using HPLC (eluent of 10 ethyl acetate in hexane) to provide the desired compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N)C1=O
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.40 g of t-butyl α-[6-amino-5-oxo-2-(2thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 49(g)] was N-alkylated using 0.52 g of butyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][S:18][C:19]2[N:20]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:21]([C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=3)([CH3:26])[CH3:25])=[CH:22][N:23]=2)=[C:12]([Cl:43])[CH:11]=1)(=O)=O.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C=O)C>[N:44]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][S:18][C:19]2[N:20]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[C:21]([C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=3)([CH3:26])[CH3:25])=[CH:22][N:23]=2)=[C:12]([Cl:43])[CH:11]=1)=[N+:45]=[N-:46]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCN=[N+]=[N-])cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a solution of 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propyl methanesulfonate (470 mg, 0.72 mmol) in DMF (3 mL) at 0° C. was added NaN3 (186 mg, 2.87 mmol). After stirring for 16 h, the mixture was partitioned in EtOAc (20 mL) and water (20 mL). The separated organic layer was washed with 1M HCl (10 mL) and water (10 mL) successively, dried over MgSO4, filtered and evaporated. The mixture was purified by column chromatography (EtOAc/Hex=1:3) to provide 2-(4-(3-azidopropoxy)-2-chloro-6-fluorobenzylthio)-5-(2-(4-fluoro-3-methoxyphenyl)-propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (344 mg, 80% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 6.87 (dd, J=10.99, 8.49 Hz, 1H), 6.76 (t, J=8.49 Hz, 2H), 6.67 (s, 1H), 6.58 (dd, J=8.15, 2.15 Hz, 1H), 6.52-6.42 (m, 2H), 6.38-6.29 (m, 2H), 4.16 (t, J=4.34 Hz, 2H), 3.98 (t, J=5.89 Hz, 2H), 3.77 (d, J=5.67 Hz, 3H), 3.50 (t, J=6.51 Hz, 2H), 2.17 (s, 1H), 2.13-1.97 (m, 3H), 1.60 (s, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10](S(C)(=O)=O)=[N:9][C:8]=2[CH2:7]1.[NH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].CCN(CC)CC.Cl>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10]([NH:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[N:9][C:8]=2[CH2:7]1
Reactant: COc1ccc(CN2Cc3nc(S(C)(=O)=O)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CN2Cc3nc(NCCNC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 6-(2,4-dimethoxybenzyl)-2-(methylsulfonyl)-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one (0.07 g, 0.149 mmol), tert-butyl 2-aminoethylcarbamate (0.024 g, 0.149 mmol), and Et3N (0.104 mL, 0.747 mmol) in DMA (2 mL) was heated in a sealed tube at 90° C. for 4 h. The reaction mixture was poured slowly onto ice and its pH adjusted to about 7 through addition of 1 N HCl, resulting in precipitation of a tan solid. The solid was isolated by vacuum filtration, washed with water, and dried under vacuum to give the title compound as a tan brown solid (55 mg, 67%). [M+H] calc'd for C29H36N6O5, 549; found, 549.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2OC)=[O:7])=[CH:4][CH:3]=1.COC1C=C([N+]([O-])=O)C=CC=1N.[Cl:32]C1C=CC=CC=1N[N+]([O-])=O>>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[Cl:32])=[O:7])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])Nc1ccccc1Cl
Reactant: COc1cc(N)ccc1NC(=O)c1ccc(N)cc1
Agent: COc1cc([N+](=O)[O-])ccc1N
Product: Nc1ccc(C(=O)Nc2ccc(N)cc2Cl)cc1

Procedure:
By operating as described under (a) above, but using, instead of 202 parts of 2-methoxy-4-nitro-aniline, 207 parts of 2-chloro-nitro-aniline, high yields of 4,4'-diamino-2'-chloro-benzanilide were obtained (melting point: 194°-197° C.).