Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1[C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)C(=O)CC1.C(C(C)CC1CC(CC2C=C[C:28]([O:31]C)=[CH:27]C=2)CCC1=O)#N.[Br-].COC1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(C1OC1)Cl>C1(C)C=CC=CC=1>[O:12]1[C:9]2([CH2:8][CH2:7][CH2:6][CH2:11][CH2:10]2)[O:31][CH2:28][CH2:27]1
Reactant: COc1ccc(CC2CCC(=O)C(CC(C)C#N)C2)cc1
Reactant: O=C1CCC2(CC1)C(=O)CCC2=O
Agent: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: ClCC1CO1
Solvent: Cc1ccccc1
Product: C1CCC2(CC1)OCCO2
Yield: 136.4 %

Procedure:
2-(2-Cyanopropyl)-4-(4-methoxybenzyl)cyclohexanone 1,4-Dioxospiro[4,5]decan-8-one (45.6 g) was added to a mixture of 4-methoxybenzyl triphenylphosphonium bromide (127.3 g) and epichlorohydrin (100 ml) in toluene (1500 ml) and heated at reflux under a nitrogen atmosphere for 36 hours. The solvent was evaporated under reduced pressure and the residue was extracted into hexane. The hexane solution was evaporated under reduced pressure and the residue distilled at 24° C./1 mmHg to give 8-(4-methoxybenzylidine)- 1,4-dioxaspiro[4,5]-decane, (19 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)(Cl)Cl.N1C=CC=CC=1.[F:17][C:18]1[CH:19]=[C:20]([C@H:26]2[NH:31][C@@H:30]([C:32]([OH:35])([CH3:34])[CH3:33])[CH2:29][O:28][CH2:27]2)[CH:21]=[C:22]([F:25])[C:23]=1[F:24]>O>[CH3:34][C:32]1([CH3:33])[C@H:30]2[CH2:29][O:28][CH2:27][C@@H:26]([C:20]3[CH:19]=[C:18]([F:17])[C:23]([F:24])=[C:22]([F:25])[CH:21]=3)[N:31]2[C:2](=[O:3])[C:1](=[O:5])[O:35]1
Reactant: CC(C)(O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)C(=O)N2[C@H](c3cc(F)c(F)c(F)c3)COC[C@@H]21
Reaction time: 1 h

Procedure:
Under ice-cooling, oxalyl chloride (205 μL) was added dropwise into a chloroform (10 mL) solution of pyridine (2 mL) and 2-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]propane-2-ol (330 mg). The reaction solution was stirred for 1 hour at the same temperature, and the resultant was stirred a further 2 hours at room temperature. Water was added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum. The residue was purified by silica gel column chromatography (heptane/ethyl acetate), and the title compound (260 mg) was obtained. The physical property values are as follows.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[NH2:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:42][C:37]([CH3:36])=[CH:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CN)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 105.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.81 min, m/z=472.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([NH2:22])[CH3:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([NH:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH3:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cc(Cl)cc(Cl)c1
Yield: 11 %

Procedure:
A mixture of 2,4-difluoro-nitrobenzene (3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (3.13 mmol) and N,N-diisopropylethylamine (6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (11% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:17]=[C:18]([Si:21]([CH3:24])([CH3:23])[CH3:22])[O:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1.CCCCCC>C(OCC)C.CCCCCC>[C:25]([O:1][CH:2]([C:16]1[CH:17]=[C:18]([Si:21]([CH3:22])([CH3:23])[CH3:24])[O:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=[O:27])[CH3:26]
Reactant: C[Si](C)(C)c1cc(C(O)CCCCCCCCc2cccs2)co1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)OC(CCCCCCCCc1cccs1)c1coc([Si](C)(C)C)c1

Procedure:
A solution of 4-(1-hydroxy-9-thiophen-2-ylnonyl)-2-trimethylsilylfuran (0.034 g, 0.093 mmol), acetic anhydride (1 ml) and pyridine (0.25 ml) was stirred at room temperature until no starting material was visible by TLC. The reaction mixture was concentrated and the residue taken up in ethyl ether, washed with 10% hydrochloric acid, saturated sodium chloride, aqueous 5% cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale oil. Purificatioon by flash chromatography (silica, 100% hexane to 5% ethyl ether/hexane) gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([CH2:13][Br:14])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(F)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(F)c1CBr
Yield: 82.5 %

Procedure:
To a solution of 11 g of ethyl 3-fluoro-2-methylbenzoate in 300 ml of carbon tetrachloride is added 12 g of N-bromosuccinimide and the mixture is refluxed with heating for 12 hours. After cooling, the mixture is washed with water and a saturated saline solution and dried over magnesium sulfate and the solvent is distilled off under reduced pressure to give 13 g of ethyl 3-fluoro-2-bromomethylbenzoate. Mass spectrum m/z: 262, 260(M+).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH3:13][NH:14][C@H:15](C(O)=O)[CH3:16]>C1(C)C=CC=CC=1>[CH3:13][N:14]1[CH:15]([CH3:16])[CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: CN[C@@H](C)C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC(C)N(C)C2C1

Procedure:
17.2 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 10.5 g (0.1 mol) of N-methylalanine in 300 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@H:26]4[CH3:35])=[CH:21][N:20]=3)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=2)=[CH:10][C:9]([F:38])=[CH:8][C:7]=1[N:39]1[CH2:50][CH2:49][N:48]2[C:41](=[CH:42][C:43]3[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=32)[C:40]1=[O:53])(=O)C.[OH-].[Li+].C1COCC1.C(O)(C)C>O>[F:38][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@H:26]4[CH3:35])=[CH:21][N:20]=3)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=2)[C:6]([CH2:5][OH:4])=[C:7]([N:39]2[CH2:50][CH2:49][N:48]3[C:47]4[CH2:46][C:45]([CH3:52])([CH3:51])[CH2:44][C:43]=4[CH:42]=[C:41]3[C:40]2=[O:53])[CH:8]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
A mixture of 124a (59 mg, 0.080 mmol), lithium hydroxide (19 mg, 0.80 mmol), THF (10 mL), i-propanol (8 mL), and water (10 mL) was stirred at room temperature for 1.5 h. It was then concentrated under reduced pressure and the residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 124 (43 mg, 79%). MS: [M+H]+ 682.3. 1H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (m, 1H), 8.41 (s, 1H), 7.84 (d, J=3.0 Hz, 1H), 7.37-7.31 (m, 3H), 7.22 (d, J=9.5 Hz, 1H), 7.19-7.16 (m, 1H), 6.50 (s, 1H), 4.87 (d, J=2.0 Hz, 1H), 4.57-4.53 (m, 2H), 4.46 (t, J=6.0 Hz, 1H), 4.41 (t, J=6.0 Hz, 1H), 4.31 (d, J=3.0 Hz, 2H), 4.21-4.18 (m, 2H), 4.15-4.10 (m, 1H), 3.88-3.85 (m, 1H), 3.67 (d, J=2.0 Hz, 1H), 3.58 (s, 3H), 3.41-3.37 (m, 2H), 3.10-3.07 (m, 1H), 2.95-2.91 (m, 1H), 2.56 (d, J=1.5 Hz, 2H), 2.41 (s, 2H), 2.32-2.28 (m, 2H), 2.17-2.15 (m, 1H), 1.21 (s, 6H), 0.91 (d, J=6.5 Hz, 3H)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C([Li])(C)(C)C.[CH:16](=[O:18])[CH3:17]>C1COCC1.CCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:16]([OH:18])[CH3:17]
Reactant: CC=O
Reactant: COCOc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCOc1cnccc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A solution of 3-(methoxymethoxy)pyridine (9.8 g, 70 mmol) and THF (40 mL) was added to a stirring mixture of tert-butyllithium (91 mL of a 1.7 M solution with pentane, 160 mmol) and THF (100 mL) at −78° C. After 1 h, acetaldehyde (9.9 mL, 180 mmol) was added, and the reaction mixture was stirred for 3 h and then warmed to RT. After 21 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, the layers were separated, the organic material was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (1:1 hexane-ethyl acetate) to afford 4.6 g (36%) of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol as a colorless solid.
Reaction SMILES: 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.[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40]([OH:42])=O)[CH:36]=1.[NH2:43][C@H:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([C:53]([O:55][CH3:56])=[O:54])[CH:51]=2)[CH2:46][CH2:45]1>ClCCl>[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40]([NH:43][C@H:44]2[C:52]3[C:47](=[CH:48][CH:49]=[C:50]([C:53]([O:55][CH3:56])=[O:54])[CH:51]=3)[CH2:46][CH2:45]2)=[O:42])[CH:36]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
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: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cc(C)on1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
HATU (4.4 g, 11.7 mmol, 1.5 eq) and DIPEA (3.0 ml, 15.6 mmol, 2 eq) were added to an ice-cooled solution of 5-methylisoxazole-3-carboxylic acid (990 mg, 7.8 mmol, 1 eq) in dichloromethane (80 ml), and stirring was carried out for 30 min. (R)-Methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (7.8 mmol, 1 eq) was dissolved in dichloromethane (20 ml) and added dropwise to the reaction solution, and stirring was carried out for 16 h at RT. The reaction solution was diluted with dichloromethane (250 ml), washed with sat. sodium hydrogen carbonate solution (50 ml), sat. ammonium chloride solution (50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 2% MeOH in dichloro-methane), the desired product was obtained in the form of a yellowish solid. Yield: 68% (1.6 g, 5.3 mmol).
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][C@@H:11]([C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](OC=O)(=[O:41])C>C1COCC1>[CH2:1]([O:8][N:9]([CH2:10][C@@H:11]([C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:39]=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(C(=O)[C@H](CNOCc3ccccc3)CC(C)C)CC2)cc1
Reactant: CC(=O)OC=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(C=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
To a solution of (2S)—N-(benzyloxy)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentan-1-amine (122 mg; 0.29 mmol; 1.0 eq.) and triethylamine (123 μL; 0.86 mmol; 3.0 eq.) in THF (2 mL) was added formic acetic anhydride (63 mg, 0.72 mmol, 2.5 eq., prepared as described in Krimen et al., in Organic Syntheses Coll. Vol 6, p8. The solution was stirred for 4.5 h at room temperature. The solvents were evaporated and the residue purified by column chromatography (Silicagel, 1/1 EtOAc/c-Hex) to give the title product as a colorless oil (105 mg, 81%). HPLC, Rt: 3.17 min (purity: 100%). M+(LC-MS (ESI)): 454.4.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]([C:18]([NH:20][CH3:21])=[O:19])[C:15](Cl)=[O:16]>ClCCl>[CH3:13][N:14]([C:18]([NH:20][CH3:21])=[O:19])[C:15]([N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:16]
Reactant: CNC(=O)N(C)C(=O)Cl
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: CNC(=O)N(C)C(=O)N1CCN(c2ccccc2)CC1
Yield: 72.6 %

Procedure:
Into 40 ml of dichloromethane, was dissolved 6.5 g of 1-phenylpiperazine. To the solution, while being stirred and cooled in ice, was added dropwise 3.0 g of 2,4-dimethylallophanoyl chloride. After 0.5 hour of reaction at room temperature, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a mixture of ethanol and petroleum ether to obtain 4.0 g (72% yield) of 1-(2,4-dimethyl-allophanoyl)-4-phenylpiperazine having a melting point of 79°-80° C.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:17]([O-:20])(=[O:19])C.[K+]>CN(C)C=O.O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:17]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 95 °C
Reaction time: 22 h

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (0.36 g; 1.25 mmol), potassium acetate (0.15 g; 1.5 mmol) and N,N-dimethylformamide:water (6:4 v/v) (3.5 ml) is heated at 95° C. under stirring for 22 h. Usual work up gives 2-(4-methoxyphenyl)-propionic acid. 2-(1-Bromoethyl)-2-(4-methoxyphenyl)-1,3-dioxolane (0.36 g; 1.25 mmol) and 2-chloro-1,1-dimethoxy-1-(4-methoxyphenyl)-propane (0.30 g; 1.25 mmol), when reacted, separately, under the reaction conditions above described give similar results.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:38])[CH:8]([N:15]2[C:19]3[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=3[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]2=[O:37])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[CH3:39][N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1>C1COCC1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([N:17]2[C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=3[N:15]([CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][CH:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)[CH2:3]3)=[O:38])[C:16]2=[O:37])(=[O:27])=[O:28])=[CH:34][CH:33]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@H](N)C3)c3ccccc3)c3cc(C#N)ccc32)cc1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@H](NC4CCN(C)CC4)C3)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
To a solution of 3-[2-((S)-3-amino-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (Example 171, 200 mg, 0.38 mmol) and 1-methyl-4-piperidone (0.087 mL, 0.75 mmol) in THF (5 mL) MP-(OAc)3BH resin (Argonaut; 2.55 mmol/g; 369 mg, 0.94 mmol) was added. The reaction mixture was agitated at room temperature for 24 hours, then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 15% methanol in CH2Cl2 to afford 1-(4-methoxy-benzenesulfonyl)-3-{2-[(S)-3-(1-methyl-piperidin-4-ylamino)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (167 mg, 71%) as a white solid.
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.Br[C:39]1[C:43]2[N:44]([CH3:51])[C:45](=[O:50])[N:46]([CH3:49])[C:47](=[O:48])[C:42]=2[N:41]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[Cl:59])[C:40]=1[N:60]1[CH2:65][CH2:64][CH2:63][C@@H:62]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH2:61]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[CH2:52][N:41]1[C:42]2[C:47](=[O:48])[N:46]([CH3:49])[C:45](=[O:50])[N:44]([CH3:51])[C:43]=2[C:39]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[C:40]1[N:60]1[CH2:65][CH2:64][CH2:63][C@@H:62]([NH:66][C:67](=[O:73])[O:68][C:69]([CH3:71])([CH3:72])[CH3:70])[CH2:61]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cn1c(=O)c2c(c(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(-c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c3c(=O)n(C)c(=O)n(C)c23)cc1
Temperature: 50 °C
Yield: 10.6 %

Procedure:
Bis(dibenzylideneacetone)palladium (18 mg), tri-tert-butylphosphonium tetrafluoroborate (22 mg), potassium phosphate (329 mg) and 4-methoxyphenylboronic acid (236 mg) were added to a solution of tert-butyl {(3R)-1-[7-bromo-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (90 mg) in dioxane (4 ml), and the resulting mixture was stirred with heating at 50° C. for 15 hours. The reaction solution was filtered through Celite and washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. A 10% aqueous potassium carbonate solution was added to the residue, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (10 mg).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([CH2:9][C:10]1[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C(OC)=O>O>[CH2:18]([CH:17]([O:16][C:15]1[CH:14]=[C:13]([CH3:22])[N:12]=[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[C:10]=1[CH2:9][CH2:4][C:3]([OH:33])=[O:2])[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Solvent: O
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CCC(=O)O

Procedure:
Hydrolysis of 2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester with phosphoic/water at reflux to give the title compound as a white foam. Anal. For C23H32N2O3. ¾H2O calc.: C, 69.40; H, 8.48; N, 7.04; found: C, 69.17; H, 8.62; N, 6.90.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([OH:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCC>Cl>[ClH:1].[ClH:1].[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([OH:16])[CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCC(O)CCCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(OCC(O)CCN2CCN(c3ccccc3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of Example 97. A mixture of 12.3 g (0.05 mole) of 4-chloro-1-(4-nitrophenoxy)-2-butanol, 8.1 g (0.05 mole) of 1-phenylpiperazine, and 26.0 g (0.25 mole) of anhydrous sodium carbonate in a total volume of 250 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized thrice from methanol-water to give 1.1 g (5%) of white solid, m.p. 195°-200° C.
Reaction SMILES: [Cl:1]C1C=CC([C@H]2[C@H](O)[C@@H](O)[C@H](O)C(OC)O2)=CC=1CC1C=CC(OCC)=CC=1.C(Cl)(C)=O.C([Si](C)(C)[O:38][C@H:39]1[C@H:46]2[C@H:42]([O:43][C:44](C)(C)[O:45]2)[O:41][C@H:40]1[C@H:49]([C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH3:67])=[CH:61][CH:60]=2)[CH:52]=1)[OH:50])(C)(C)C>CO>[ClH:1].[Cl:57][C:54]1[CH:55]=[CH:56][C:51]([C@H:49]2[C@H:40]([OH:41])[C@@H:39]([OH:38])[C@H:46]([OH:45])[CH:42]([O:43][CH3:44])[O:50]2)=[CH:52][C:53]=1[CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:65][CH2:66][CH3:67])=[CH:63][CH:64]=1
Reactant: CCOc1ccc(Cc2cc([C@H](O)[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@@H]3O[Si](C)(C)C(C)(C)C)ccc2Cl)cc1
Agent: CCOc1ccc(Cc2cc([C@@H]3OC(OC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: CC(=O)Cl
Solvent: CO
Product: Cl
Temperature: 25 °C

Procedure:
Preparation of (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol. A solution of 0.35 M HCl in MeOH was prepared by adding AcCl (0.25 ml, 3.5 mmol) to MeOH (10 ml) and stirring for 15 minutes The alcohol from step D (0.84 g, 1.5 mmol) was treated with this solution for 16 hours at room temperature and 2 hours at 80° C. in a sealed vial. The reaction was cooled to room temperature, quenched with K2CO3 until basic, diluted with CH2Cl2, filtered, and concentrated under vacuum. The product was purified by flash chromatography (40 g SiO2, 0-10% MeOH: CH2Cl2, 60 minutes, 35 ml/min), suspended in H2O, and lyophilized to give (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol (0.46 g, 1.1 mmol, 75%) as a white solid. NMR revealed a 1.2:1 ratio of α and β anomers.