Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:28]2[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC1CCNCC1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCC(C)CC2)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 4-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 206 mg of 4-(2-butynyloxy)-6-(4-methylpiperidino) pyrimidine (hereinafter, referred to as Compound (18)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:21]2[CH:22]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=2[OH:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Br)cc1I
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2O)CC1
Temperature: 75 °C

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (4.03 g), 4-bromo-2-iodo-phenol (5.00 g), Pd(PPh3)2Cl2 (600 mg), copper iodide (500 mg), and triethylamine (2.35 mL) in N,N-dimethylformamide (30 mL) is heated under an argon atmosphere to 75° C. for 4 h. The reaction mixture is diluted with ice water after cooling to room temperature and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 2): tR=1.32 min; Mass spectrum (ESI+): m/z=402, 404 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (13.19 mmol; 3.21 g) in dry THF (100 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 15.83 mmol; 7.92 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Biphenylmethyl bromide (15.83 mmol; 3.91 g) was added and the resulting solution was stirred at −78° C. for 2 hours, then allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester. MS (ESI) m/z 432.3 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1.[Cl-].[Na+].O>[CH:22]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[O:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccncc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of Example 25A (11.4 g, 64 mmol) in 200 mL THF was cooled to −78° C., treated with 1.6 M nBuLi in hexanes (100 mL, 160 mmol), warmed to 0° C., stirred for 1 hour, treated with a solution of DMF (22 g, 215 mmol) in 100 mL THF, warmed to room temperature, stirred for 1 hour, diluted with brine, and extracted three times with ethyl acetate. The combined extracts were washed with water, washed twice with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (9.1 g, 69%).
Reaction SMILES: [OH:1][CH:2]1[O:10][C@@H:9]([CH3:11])[C@@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].CN(C=O)C.OC1O[C@H](C)[C@H](O)[C@H](O)[C@H]1O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: C[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O

Procedure:
For example, L-fucopyranose was transformed into a 4'-acetyl-2',3'-O-benzyl-L-fucopyranose following a method described in Dale, J. K. et al., J. Chem. Soc. 52:2534 (1930); and Hockett, R. C. et al., J. Am. Chem. Soc. 61:1658 (1939). See Scheme I in FIG. 12 (DMF=dimethylformamide; DMAP=4-(dimethylamino)pyridine; Bn=benzyl; and pyr=pyridine.). Similarly, D-fucopyranose can be converted to 4'-acetyl-2,3-O-benzyl D-fucopyranose.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:23]N(C)C=O.IC>O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][N:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH3:23])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N1CCC(CN(C)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 8.7 part of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine, 1.44 parts of a sodium hydride dispersion 60% and 270 parts of N,N-dimethylformamide was stirred for 1 hour at room temperature. 5.48 Parts of iodomethane were added dropwise slowly. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (98.75:1.25 by volume) as eluent. The second faction was collected and the eluent was evaporated, yielding 7.6 parts (84%) of 1-acetyl-N-(2-benzothiazolyl)-N-methyl-4-piperidinemethanamine as a residue (intermediate 52).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[N:10]=[CH:9]2)=[C:5]([CH3:16])[O:4][N:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[N:10]=[CH:9]2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cnc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1noc(C)c1Cn1cnc(N)c1
Yield: 92.5 %

Procedure:
3,5-dimethyl-4-((4-nitro-1H-imidazol-1-yl)methyl)isoxazole (example 10-40b) (1.0 g, 4.5 mmol) and 10% palladium on charcoal (200 mg) in methanol (40 mL) was shaken on a Parr shaker under a pressure of 2.5 bar hydrogen for 2 hours. Filtration through a plug of celite followed by rotary evaporation afforded 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-amine as a yellowish-red solid (800 mg, 93% yield). MS M+H calculated 193. found 193.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:25][OH:26])=[N:21][CH:22]=[CH:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:25][C:20]2[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1cccnc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccnc1COc1nc(N)nc(-n2cccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[OH:15].[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([I:5])=[C:7]([OH:15])[CH:8]=1
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)c(O)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
5 ml of thionyl chloride was added to 120 ml of MeOH at 0° C. The solution was stirred for 10 min and 20 g of 4-Iodo-3-hydroxy-benzoic acid was added. The reaction was stirred for 16 h at RT then heated to 50° C. for 3 h. The solvents were removed under reduced pressure. The residue was used directly in the next step. Yield 21 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([NH:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]1[C:21]1[N:26]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)NNc2ccc(F)cn2)C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 86a (550 mg, 1.25 mmol), Et3N (0.69 mL, 5 mmol) and Ph3P (657 mg, 2.5 mmol) in THF (20 mL) at 0° C. was added hexachloroethane (590 mg, 2.5 mmol) and the mixture stirred for 10 min. The solution was allowed to warm to RT, stirred for 1 h, then partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give crude 2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester, contaminated with triphenylphosphine oxide, as a pale brown solid (500 mg). The solid (500 mg) was treated with a 4M HCl solution in dioxane (30 mL) and the mixture stirred at RT for 2 h. The suspension was diluted with MeOH, then applied onto an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound as a pale yellow solid (100 mg, 23% over 2 steps). LCMS (Method 4): Rt 0.26, m/z 222 [MH+].
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: BrC1CCCC1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SC2CCCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, cyclopentyl bromide and sodium ethylate in ethanol. EI-MS m/e (%): 296 (M+, 36), 295 ([M—H]+, 100), 228 ([M—C5H8]+, 100).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O.CN(C)C1C=CC=CC=1>ClC(Cl)=C(Cl)Cl>[C:1]1([C@H:7]([CH3:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: C[C@H](C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Into a 10 L four-necked flask, 600 g (4.00 mol) of (S)-(+)-2-phenylpropionic acid, 2.4 L of tetrachloroethylene, 951 g (8.00 mol) of thionyl chloride and a small amount of dimethylaniline were added, followed by stirring at room temperature overnight, and excess of thionyl chloride and tetrachloroethylene were distilled off under reduced pressure to obtain 691 g of (S)-2-phenylpropionic chloride.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[C:24](\[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)/[CH2:25][O:26][CH3:27])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:47]>CO>[CH3:27][O:26][CH2:25]/[C:24](/[C:28]1[CH:29]=[C:30]([C:34]([NH2:35])=[NH:47])[CH:31]=[CH:32][CH:33]=1)=[CH:23]/[C:22](=[O:36])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methoxybut-2-enamide (150 mg, 0.298 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added, and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10 ml) for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-(methoxymethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (34 mg, (25%) as a fluffy off-white powder after lyophilization. ES-MS (M+H+): 465.15
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:44][C:45]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)=[O:46])[CH3:43]>CN(C=O)C>[CH2:42]([O:44][C:45]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)=[O:46])[CH3:43]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester (51 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (5 mg; purity 90%). MS m/z [M+H]+ calc'd for C26H30N4O7, 511.21. found 511.6.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:6](=O)[CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10]>CCOCC.C(Cl)(Cl)Cl>[Br:1][C:9]1[NH:10][C:6]([C:5]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:3]([Cl:2])[CH:4]=2)=[CH:7][C:8]=1[C:11]#[N:12]
Reactant: Br
Reactant: N#CC(C#N)CC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)[nH]c1Br
Temperature: 0 °C
Yield: 24 %

Procedure:
Hydrogen bromide gas is bubbled through a mixture of (3,4-dichlorophenacyl)malononitrile (10.0 g, 0.0395 mol) in ether (150 mL) and chloroform (100 mL) at a moderate rate, keeping the reaction mixture temperature below 35°-40° C. After ten minutes, TLC shows the reaction is complete by UV analysis. The reaction mixture is poured into an ice-water mixture, the layers are separated and the aqueous layer is extracted with ether. The combined organic layer and ether extracts are dried and concentrated in vacuo to give a brown solid. The brown solid is washed with methylene chloride and filtered to obtain the title compound as an off-white solid (3.0 g, 24%, mp >200° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[C:20]=1[Cl:26])=[O:17].O>C1COCC1>[Br:25][C:21]1[C:20]([Cl:26])=[C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[C:30]([F:31])[CH:29]=[CH:28][CH:27]=3)[NH:13][C:2]2=[O:4])[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1c(F)cccc1C(=O)Nc1cccc(Br)c1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cccc2c(=O)n1-c1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Triphosgene (453 mg, 1.53 mmol) was added in one portion to a solution of amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide (350 mg, 1.019 mmol) in THF (10 mL) at 0° C. The mixture was stirred at room temperature for 1 h, then was cooled to 0° C. and treated with water until no more gas evolution was observed. The mixture was concentrated and the residue was dissolved in EtOAc, washed sequentially with saturated aqueous NaHCO3, water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-50%), to provide 3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as a yellow solid (320 mg, 85% yield). Mass spectrum m/z 369, 371 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.54 (br. s., 1H), 7.97 (d, J=8.1 Hz, 1H), 7.77 (dd, J=6.8, 2.6 Hz, 1H), 7.46 (ddd, J=9.8, 8.3, 1.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.24 (td, J=8.0, 4.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[H-].[Na+].[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:29]([NH:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCc1ccccc1
Product: O=c1c(NCc2ccccc2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 mg of 3-amino-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one and 10 mg of sodium hydride were added to 1 ml of toluene, to which 30 mg of benzyl chloride was added dropwise at 70° C. The mixture was stirred for 30 minutes, and heated for 1 hour under reflux. The reaction mixture was left to cool to room temperature, diluted with ethyl acetate, and washed with a water and a saturated saline water. The organic layer was dried by magnesium sulfate, and refined by NH silica gel chromatography (ethyl acetate/hexane-based solvent), to obtain 13 mg of the subject compound.
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42](=O)[C:36]=2[CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[O:38][CH2:39][C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3/[C:42](=[CH:8]/[CH2:7][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)/[C:36]=2[CH:35]=1
Reactant: O=C1c2ccccc2COc2ccc(Br)cc21
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)/C(=C\CN1CCCC1)c1ccccc1CO2

Procedure:
Anhydrous 2-(N-pyrrolidinyl)-ethyltriphenylphosphonium bromide (10 g, 45 mmole), 48 mmole of n-butyl lithium in hexane, and 2-bromo-6,11-dihydrodibenz [b,e1-oxepin-11-one (5 g, 35 mmole) were reacted in 300 mL dry tetrahydrofuran by the procedure in Example 1, Step a. This provided the pure Z-isomer (1.76 g) as a light brown solid, mp 108°-109° C.. pmr (DMSO-d6) δ: 7.28-7.50 (m, 6H, aromatic H); 6.80 (d, J=8.8 Hz, 1H, H4); 5.82 (t, 1H, HC=); 5.20 (s, 2H, ArCH2O); 3.29 (m, 2H, NCH2C=); 2.50 (m, 4H, 2NCH2); 1.70 (m, 4H, 2CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH:32]=[CH:33][C:34]=3[O:35][CH3:36])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 26 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M+H)+.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=[O:28])[O:26]1>C(Cl)(Cl)Cl>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27](=[O:28])[O:26]2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6.3 g of 4-biphenylylacetic acid in 30 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, gives the phthalidyl 4-biphenylylacetate.