Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl>[F:65][C:66]1[CH:72]=[CH:71][C:69]([NH:70][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:68][CH:67]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(F)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 4-fluoro-aniline (Aldrich, 38 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 67 mg.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:10][N:11]1[C@@H:28]2[CH2:29][C:16]3[CH:17]=[CH:18][C:19]([O:31][CH3:32])=[C:20]4[O:21][C@H:22]5[C:23]([CH2:25][CH2:26][C@:27]2([OH:30])[C@:14]5([C:15]=34)[CH2:13][CH2:12]1)=[O:24].CN(C)C=O.CN1CCOCC1.[N:45]1(C(OC(C)(C)C)=O)[CH2:66][CH2:65][CH2:64][C@H:46]1[C:47]([N:49]1[CH2:63][CH2:62][CH2:61][C@H:50]1[C:51](ON1C(=O)CCC1=O)=[O:52])=[O:48]>>[NH:45]1[CH2:66][CH2:65][CH2:64][C@H:46]1[C:47]([N:49]1[CH2:63][CH2:62][CH2:61][C@H:50]1[C:51]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:52])=[O:48].[CH3:10][N:11]1[C@@H:28]2[CH2:29][C:16]3[CH:17]=[CH:18][C:19]([O:31][CH3:32])=[C:20]4[O:21][C@H:22]5[C:23]([CH2:25][CH2:26][C@:27]2([OH:30])[C@:14]5([C:15]=34)[CH2:13][CH2:12]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of Leu-Oxycodone (1.0 eq) in dimethylformamide (10 ml/0.1 mmol) was added 4-methylmorpholine (10 eq) and Boc-Pro-Pro-OSu (2 eq). The reaction was stirred at ambient temperatures for 18 hours, quenched with water, and solvents removed. Crude protected product was purified using reverse phase HPLC. Deprotection occurred using 4N HCl in dioxane (20 ml/mmol) to obtain Pro-Pro-Leu-Oxycodone.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([F:30])=[C:13]([CH:29]=1)[CH:14]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:35][C@H:36]1[CH2:41][NH:40][C@H:39]([CH3:42])[CH2:38][NH:37]1.CO>ClCCl>[CH3:35][C@H:36]1[CH2:41][NH:40][C@H:39]([CH3:42])[CH2:38][N:37]1[CH:14]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:13]1[CH:29]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=[CH:11][C:12]=1[F:30]
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)N2C[C@@H](C)NC[C@@H]2C)cc1
Yield: 20 %

Procedure:
The benzhydrol from above (1.77 g, 4.1 mmol) was treated with thionyl chloride (0.45 mL, 6.2 mmol) by the method in Example 1. The crude product (approximately 4.1 mmol) was treated with trans-2,5-dimethylpiperazine (1.64 9, 14.3 mmol) as in Example 1. Chromatography on silica gel with 1-7% methanol in dichloromethane gave 0.44 g (20% from benzhydryl chloride) of (±)-4-(α-(trans-2,5-dimethyl-1-piperazinyl)-5-(tert-butyldimethylsilyloxy)-2-fluorobenzyl)-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(C(O)=O)CC[CH2:31]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:31][CH2:30]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCC1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Product: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCCCC1

Procedure:
Cyclohexane carboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-amide (compound of Formula II where R1=cyclohexyl and Q1=Ph-(3-OBn)) was prepared according to the procedures described for the synthesis of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]amide (compound of Formula III where R1=cyclobutyl and Q1=Ph-(3-OBn)) above except for the substitution of cyclohexane carboxylic acid for cyclobutanecarboxylic acid; MS (ES) 436.2 (M+1), 438.2 (M+3).
Reaction SMILES: [Na+].[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1Br)NC(=O)CN2
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A solution of N-(4′-bromo-5′-methyl-2′-nitrophenyl)glycine sodium salt (0.200 g, 0.692 mmol, as prepared above) and tin (II) chloride dihydrate (0.468 g, 2.07 mmol, Aldrich, used as received) in ethanol (2.0 mL) was refluxed for 30 min. It was then cooled to room temperature. The precipitated solid was filtered and dried under vacuum to yield 0.064 g (38%) of the title compound as a yellow powder; 1NMR (DMSO-d6): δ 2.130 (s, 3H), 3.674 (s, 21), 6.120 (s, 1H), 6.583 (s, 1H), 6.868 (s, 1H), 10.284 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH3:16][NH:17][C:18](=[S:26])[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:26][C:18](=[N:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]2[CH3:16])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)Nc1ccccc1
Solvent: CC(C)=O
Product: Br
Product: CN1C(=Nc2ccccc2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
A solution of 3.13 g (0.01 mole) of 2-bromo-4'-chloro-3'-sulfamoylacetophenone in 50 ml of acetone is added to a solution of 1.66 g (0.01 mole) of 3-methyl-1-phenylthiourea in 100 ml of acetone, whilst stirring with a magnetic stirrer; during this addition the reaction temperature should not rise above 30° C. After stirring for 5 hours at room temperature, the crystals are filtered off. Melting point 164° C. (with decomposition).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[NH:25]1[C:21]([C:17]2[CH:16]=[C:15]([NH:14][S:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)(=[O:12])=[O:11])[CH:20]=[CH:19][CH:18]=2)=[N:22][N:23]=[N:24]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc2ccccc2o1
Yield: 45.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 1-benzofuran-2-sulfonyl chloride (11.9 mg, 0.055 mmol) and 5-(3-amino-phenyl)-tetrazole (8 mg, 0.05 mmol) affording 7.8 mg (46%) of the title compound. MS (ESI+) calcd for C15H11N5O3S 341.058260, found 341.058160.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](Cl)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[N:32]([CH2:39][C@:40]([OH:44])([CH3:43])[CH2:41][OH:42])[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:42][CH2:41][C@@:40]([OH:44])([CH3:43])[CH2:39][N:32]3[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=[C:31]3[Cl:30])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@](O)(COC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 8.5 h
Yield: 90.7 %

Procedure:
4-(4-Trifluoromethoxyphenyl)piperazine-1-carbonylchloride (1.25 g, 4.2 mmol), N,N-diisopropylethylamine (0.96 ml, 5.6 mmol) and 4-dimethylaminopyridine (67 mg, 0.56 mmol) were added to a suspension of (R)-2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (0.65 g, 2.8 mmol) in toluene (13 ml) followed by stirring at 100° C. for 8.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=19/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate (1.29 g, yield 92%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19]C)=O)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH3:21]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:21])=[O:19])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(N)cc3)nc12
Product: NC(=O)c1cccc2[nH]c(-c3ccc(N)cc3)nc12

Procedure:
Following standard procedure C, the acetate salt of methyl 2-(4′-aminophenyl)-1-H-benzimidazole-4-carboxylate (113 mg, 0.346 mmol) was treated with liquid ammonia under pressure for 24 hours. The pure title compound was isolated with column chromatography of the crude material using dichloromethane/methanol 90:10 (21.4 mg, 25%) mp 237-240° C.; δH 5.90 (2H, s, NH2), 6.79-6.83 (2H, d, J=8.3), 7.31-7.39 (1H, t), 7.71-7.75 (1H, d), 7.84 (1H, s, NH), 7.88-7.92 (1H, d), 8.00-8.04 (2H, d, J=8.3), 9.5-9.6 (1H, br s, NH), 13.0 (1H, br s, NH).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Br:15][C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.O>[Br:15][C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:14][CH:12]([OH:13])[CH2:11][CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(Br)nc2)c(Cl)n1
Temperature: 83.5 °C
Reaction time: 28 h
Yield: 36.9 %

Procedure:
A mixture of epoxide 129 (see Example 2AA) (1.004 g, 4.61 mmol), 6-bromo-3-pyridinol (4.015 g, 23.1 mmol) and powdered K2CO3 (3.319 g, 24.0 mmol) in anhydrous 2-butanone (10 mL) under N2 was stirred at 82-85° C. for 28 h. The resulting cooled mixture was diluted with water (100 mL) and extracted with 25% EtOAc/CH2Cl2 (3×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-40% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 40% EtOAc/petroleum ether gave 1-[(6-bromo-3-pyridinyl)oxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-butanol (137) (667 mg, 37%) as a cream solid: mp (MeOH/CH2Cl2/pentane) 112-114° C.; 1H NMR [(CD3)2SO] δ 8.56 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8, 3.2 Hz, 1H), 5.28 (br d, J=4.5 Hz, 1H), 4.24 (dd, J=14.0, 5.8 Hz, 1H), 4.18 (dd, J=14.2, 7.3 Hz, 1H), 3.99 (dd, J=10.0, 4.9 Hz, 1H), 3.96 (dd, J=10.0, 5.5 Hz, 1H), 3.82 (m, 1H), 2.06 (dtd, J=13.9, 7.7, 3.4 Hz, 1H), 1.90 (ddt, J=13.7, 9.2, 6.7 Hz, 1H); HRESIMS calcd for C12H13BrClN4O4 m/z [M+H]+ 394.9754, 392.9782, 390.9803. found 394.9753, 392.9777, 390.9797.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:6].[NH2:10][CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.CC[O:21]CC>>[ClH:6].[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[CH:11]([NH:10][C:5](=[O:21])[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)[CH2:12]2
Reactant: Fc1cccc(CCl)c1
Reactant: CCOCC
Reactant: NC1CN2CCC1CC2
Product: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a closed system, a solution of 3-fluorobenzyl chloride (7.93 g, 0.050 mole) in 30 ml ether was added dropwise to a stirred solution of 3-aminoquinuclidine (6.3 g, 0.050 mole) in 100 ml ether. After the addition was completed, the mixture was stirred at ambient temperature for 16 hr. The solid hydrochloride salt was collected under a nitrogen atmosphere and vacuum dried for 2 hr, to yield 13.11 g (92.1%). The salt was recrystallized from absolute ethanol-isopropyl ether to give 8.87 g of a white solid. The material was recrystallized from ethanol, and vacuum dried for 12 hr at 70° C., m.p. 257°-258° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17]>[OH-].[Na+]>[C:1]([NH:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nn[nH]c1N
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nn[nH]c1NC(=O)c1ccccc1

Procedure:
Benzoyl chloride (3.26 ml.) and 4N aqueous sodium hydroxide solution (8 ml.) were added alternately, in portions over 25 minutes, to a vigorously shaken, ice-cooled solution of 5-amino-4-carbamoyl-1H-1,2,3-triazole (1.27 g; prepared by the method of J. R. E. Hoover and A. R. Day, J. Amer. Chem. Soc., 1956, 78,5832) in 4N aqueous sodium hydroxide solution (15 ml.). The reaction mixture was extracted with diethyl ether, the aqueous layer cooled and acidified with concentrated hydrochloric acid, and the white precipitate filtered off and washed well with water. The crude solid was stirred in diethyl ether and then purified by dissolving in dilute aqueous sodium hydroxide solution, and reprecipitation by the addition of concentrated hydrochloric acid. The solid was filtered off, washed with water, and dried to give 5-benzamido-4-carbamoyl-1H-1,2,3-triazole (0.085 g.), m.p. 299° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[CH:17]=[CH:18][CH:19]=1.Cl>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(3-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.17 (s, br, 1H), 7.75–6.88 (m, 11H), 5.26–5.14 (m, 1H), 3.68–3.56 (m, br, 2H), 3.05–2.90 (br, 2H), 2.90–2.60 (m, br, 4H), 2.56–2.36 (m, br, 2H), 2.18–1.84 (m, br, 6H), 1.70–1.44 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C33H38Cl2F4N2O2.0.9EtOAc: C, 60.98; H, 6.32; N, 3.89; Found: C, 60.99; H, 6.17; N, 3.81. ESMS m/e: 605.2 (M+H)+.
Reaction SMILES: I(O)(=O)(=O)=O.CC1(C)[O:11][C@H:10]([C@H:12]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:14](=[O:24])[C@H:13]2[NH:25][C:26](=[O:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)CO1>O1CCCC1.O>[CH:10]([C@H:12]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:14](=[O:24])[C@H:13]1[NH:25][C:26](=[O:34])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:11]
Reactant: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)cc1
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2C=O)cc1

Procedure:
Periodic acid (18.7 g, 45.6 mmol) was added to a suspension of (3S,4S)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(4-methoxyphenyl)-3-phenylacetamidoazetidin-2-one (15.1 g, 36.8mmol) in tetrahydrofuran (210 ml) and water (210 ml). The reaction mixture was heated under reflux for 1.5 h and then cooled in ice. The precipitated product was collected by filtration, washed with water and dried over phosphorus pentoxide to yield the title compound as a mixture of aldehyde and the corresponding hydrate (10.18 g, 82%); νmax (KBr) 1713, 1638, 1552 and 1514 cm-1 ; aldehyde δH (d6 -DMSO) 3.43 and 3.50 (2H, ABq, J 14.4 Hz), 3.73 (3H, s), 4.95 (1H, dd, J 6.1, 1.2 Hz), 5.19 (1H, m), 6.95 (2H, d, J 9.0 Hz), 7.18-7.35 (7H, m), 9.09 (1H, d, J 7.3 Hz) and 9.52 (1H, d, J 1.2 Hz); hydrate δH (d6 -DMSO) 3.50 (2H, s), 3.72 (3H, s), 4.16 (1H, t, J 5.6 Hz), 5.07 (1H, q, J 5.8 Hz), 5.29 (1H, dd, J 9.4, 5.6 Hz), 6.28 (2H, t, J 6.7 Hz, exch.), 6.9 (2H, d, J 9.1 Hz), 7.19-7.35 (5H, m), 7.52 (2H, J 9.1 Hz) and 8.52 (1H, d, J 9.4 Hz); m/z (EI) 338 (10); (CI, +ve ion, ammonia) 339 (MH+), 356 (MNH4+).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 (0.3 g, 0.9 mmol) in DMF (10 mL) was added K2CO3 (0.2 g, 1.3 mmol), and phthalimide (0.1 g, 0.9 mmol). The resulting solution stirred 20 h at room temperature. The reaction was concentrated in vacuo and diluted with water (10 mL). The heterogeneous mixture was filtered to afford 2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isoindoline-1,3-dione 31 (0.3 g, 75%). MS (Q1) 415 (M)+
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]=1[C:7]([O:9]CCC)=[O:8])[CH2:2][CH3:3].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]=1[C:7]([OH:9])=[O:8])[CH2:2][CH3:3]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)OCCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)O
Temperature: 70 °C
Yield: 8.1 %

Procedure:
To a stirred solution of Propyl 2-propoxy-6-pentadecylbenzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Propoxy-6-pentadecylbenzoic Acid (7.6 g, 80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([CH:16]=[CH2:17])[N:3]=[C:4]([CH3:15])[N:5]=2)[N:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Temperature: 110 °C

Procedure:
To a solution of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-2) (5.2 g, 23.2 mmol) in degassed toluene (200 mL) under nitrogen was added tetrakis(triphenylphosphine)palladium(O) (1.3 g, 1.16 mmol) followed by tributyl(vinyl)tin (8.8 mL, 30.2 mmol) and the reaction was heated at 110° C. for 3 h. The solvent was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (0-50% EtOAc/hexanes) to afford 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 6.76 (dd, 1H, J=17.3, 10.6 Hz), 6.52 (br d, 1H, J=17.3 Hz), 5.72 (br d, 1H, J=10.6 Hz), 2.91 (s, 3H), 2.72 (s, 3H), 2.42 (s, 3H). MS m/z=216 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O.CC(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
To a solution of D-valine (6.40 g, 54.6 mmol) in H2O (62 mL) and acetone (25 mL) was added triethylamine (16.2 mL, 117 mmol). The solution was cooled to zero degrees C. in an ice/H2O bath and a solution of 4-fluorobenzenesulfonyl chloride (10.0 g, 51.4 mmol) in acetone (25 mL) was added dropwise. After stirring at room temperature for 20 hours, the resulting yellow solution was concentrated in vacuo to remove the acetone. The aqueous residue was extracted with toluene (2×50 mL) and acidified to pH=1 with 12 M HCl. The solution was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed successively with 1M KHSO4 (50 mL), H2O (50 mL), and sat'd NaCl (50 mL), then dried over MgSO4. Concentration in vacuo and trituration with hexane afforded N-[(4-fluorophenyl)-sulfonyl]-D-valine as a white solid (12.56 g, 89%): MS MH+ calcd. for Anal. Calc'd for C11H14NO4SF: C, H, N. Found: C, H, N. HR mass calculated for C11H14NO4S: 276.0706. Found: 276.0710.