Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:34])[S:5]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl.CCOC(C)=O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([N:22]2[C:18]3[CH:19]=[N:20][CH:21]=[C:16]([C:14]([NH:13][CH2:12][C:11]4[CH:10]=[CH:9][C:8]([S:5]([N:4]([CH3:34])[CH2:3][CH2:2][O:1][C:42](=[O:44])[CH3:43])(=[O:6])=[O:7])=[CH:33][CH:32]=4)=[O:15])[C:17]=3[CH:24]=[N:23]2)=[CH:26][CH:27]=1
Reactant: CN(CCO)S(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCCN(C)S(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cc1
Reaction time: 4 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid 4-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-benzylamide (50 mg, 0.1 mmol), Et3N (16 μL, 0.14 mmol) in dichloromethane was added acetyl chloride (0.010 mL, 0.11 mmol). After 4 hours, the mixture was diluted with EtOAc and the organic layer was washed with saturated aqueous sodium bicarbonate, 1 N aqueous HCl, water, brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31]C2C=CC(F)=CC=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:41]=1C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:41]2[C:40]([F:39])=[CH:47][CH:46]=[CH:45][C:44]=2[F:48])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1c(F)cccc1F

Procedure:
In the same manner as in Example 7, 570.3 mg of the title compound was obtained as colorless powder from 600.8 mg of Referential Compound 3 and 220 μL of 2,6-difluorobenzaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH:19]1([CH:24]2[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:19]1([CH:24]2[CH2:25][CH2:26][CH:27]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C@:12]3([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]3)[CH:6]=[CH:5]4)[CH2:28][CH2:29]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OC1CCC(C2CCCC2)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(OC4CCC(C5CCCC5)CC4)ccc3c2)COC(=O)N1
Yield: 27 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one, 4-cyclopentyl-cyclohexanol (1.5 g, 0.0090 mol), triphenylphosphine (2.6 g, 0.0099 mol), tetrahydrofuran (45 mL, 0.55 mol) and diisopropyl azodicarboxylate (2.0 g, 0.0099 mol) to give 895 mg of a 1.6 to 1 diasteromeric ratio of the desired compound as a yellow solid (27%). ESI-MS: 368 (M+H)+. 1H NMR (400 MHz, CDCl3) δ=7.80-7.63 (m, 3 H), 7.39 (dd, J=1.9, 8.7 Hz, 1 H), 7.22-7.08 (m, 2 H), 4.70-4.58 (br. s., 0.63 H), 4.43-4.36 (s, 2 H), 4.34-4.21 (tt, J=4.2, 6.5 Hz, 0.39 H), 2.04 (s, 2 H), 1.87-1.70 (m, 2 H), 1.65-0.77 (m, 17 H)
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:9](=[O:28])[N:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:11]=[CH:12][C:13]=2[N:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)=[CH:3][CH:2]=1.[BH4-].[Na+].ClCCl>CO>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9](=[O:28])[N:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[N:11]=[CH:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)=[CH:5][CH:6]=1
Reactant: O=C1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Oc2ccc(-c3ccccc3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=c1c(Oc2ccc(-c3ccccc3)cc2)c(N2CCC(O)CC2)cnn1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
0.2 g (0.424 mmol) of the compound from Example 14 are dissolved in 7 ml of methanol and, at room temperature, 50 mg (1.3 mmol) of sodium borohydride are added in portions. Stirring for 2 h is followed by dilution with dichloromethane, washing with saturated ammonium chloride solution, drying over sodium sulfate and concentration. The crude product is stirred with 25 ml of boiling methanol and then cooled and filtered off with suction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O-:13])=[O:12])=[C:7]2[CH2:14][CH2:15][CH2:16][OH:17].[C:19]1(O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:31]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:30][CH3:31])=[O:12])=[C:7]2[CH2:14][CH2:15][CH2:16][O:17][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1cccc2ccccc12
Reactant: O=C([O-])c1[nH]c2c(Br)ccc(F)c2c1CCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)ccc(F)c2c1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of EXAMPLE 402C (1.03 g), naphthalen-1-ol (519 mg), and triphenylphosphine (905 mg) in tetrahydrofuran (15 ml) at −10° C. was added di-tert-butyl azodicarboxylate (794 mg) slowly. After one hour, the reaction was allowed to warm to room temperature. Stirring was continued for two hours at room temperature. The reaction mixture was concentrated. The concentrate was purified by column chromatography on silica gel with 0-4% ethyl acetate in hexanes.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:4](N[C@@H](C(OC)=O)CCC(=O)O)=[O:5])[CH3:3].N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@@H](C(OCC1C=CC=CC=1)=O)CC(O[N:37]1[C:42](=[O:43])[CH2:41][CH2:40][C:38]1=[O:39])C(=O)O)=O)C.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=[O:72])=CC=1.CN1CCOCC1>C(Cl)Cl>[NH:1]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@@H:2]([C:4]([O:5][N:37]1[C:42](=[O:43])[CH2:41][CH2:40][C:38]1=[O:39])=[O:72])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CC(ON1C(=O)CCC1=O)C(=O)O)C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](CCC(=O)O)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 155.7 %

Procedure:
To a mixture of Boc-L-Ala-D-Glu(OH)OMe (1) (1.94 g), L-Lys(ε-Z)-GlyOEt (2)(1.67 g) and 1-(4-chlorobenzenesulfonyloxy)-6-chlorobenzotriazole (1.72 g) in methylene chloride (100 ml) was added N-methylmorpholine (1.01 g) and the mixture was stirred for 2 days at room temperature. The reaction mixture was washed sccessively with 5% aqueous sodium bicarbonate, water, 5% hydrochloric acid and water and dried over magnesium sulfate. After evaporation of the solvent, the resulting crystalline mass was filtered and washed with ether, to give Boc-L-Ala-γ-D-Glu(α-OMe)-L-Lys(ε-Z)-GlyOEt (3)(1.34 g).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].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.[CH2:57]([CH:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:58]>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:66][CH:59]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH2:57][CH3:58])=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18]
Reactant: CCC(N)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(F)cc2F)c2ccc(C(=O)O)cc12
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: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(F)cc1F)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a mixture of 1-(2,4-difluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid in DMF was added DIPEA (1.3 equiv) and HATU (1.2 equiv). The mixture was stirred for 5 min, and then α-ethylbenzylamine (1.1 equiv) was added. The reaction mixture was stirred at rt for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the title compound. LC-MS 433 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[C:36]([C:49]([F:52])([F:51])[F:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:62])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:62])=[C:36]([C:49]([F:52])([F:50])[F:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.2 g) was dissolved in dichloromethane (50 ml), and to the solution was added 3-chloroperbenzoic acid (0.69 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) as pale brown oil.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1>C1COCC1>[CH3:1][S:2][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Sodium thiomethoxide (805 mg, 11.5 mmol) was added to a solution of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (Intermediate 182, 3.20 g, 11.5 mmol) and THF (15 ml) at 0° C. The resultant mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was quenched with water (15 ml) and diluted with ethyl acetate (150 ml). The organic phase was separated and washed with brine. The combined aqueous phase was back extracted with ethyl acetate (50 ml). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (hexanes/ethyl acetate, 7:1) to provide the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:17]=[CH:16]3)([OH:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.[OH2:40]>C(Cl)Cl>[Cl:1][C:2]1[S:6](=[O:37])(=[O:40])[C:5]([C:7]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[N:17]=[CH:16]3)([OH:12])[C:8]([F:10])([F:11])[F:9])=[CH:4][CH:3]=1
Reactant: O
Reactant: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1ccc(Cl)s1)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S1(=O)C(Cl)=CC=C1C(O)(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 3 h
Yield: 13 %

Procedure:
To a room temperature solution of 100 mg (0.2 mmol) of 1-(5-chlorothiophen-2-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol in 5 mL of CH2Cl2 was added 100 mg (0.5 mmol) of m-chloroperbenzoic acid. After 3 hours, the reaction was diluted with 5 mL of water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate in hexanes (10-30% gradient) to afford 14 mg (13%) of the title compound. MS m/z 459.82 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[CH:4][C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O)[O:10]2)=[C:6]([OH:8])[CH:7]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:81]I>C1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[C:3]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[CH:4][C:5]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][I:81])[O:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCCCCCO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCCCCCI)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
To a solution of 5-chloro-4-(4-ethoxybenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((5-hydroxypentyloxy)methyl)tetrahydro-2H-pyran-2-yl)phenol (30, 459 mg, 0.58 mmol) in benzene (3 mL) under an atmosphere of nitrogen were added imidazole (448 mg, 1.76 mmol) and triphenylphosphine (467 mg, 1.76 mmol). After 5 min, iodine (448 mg, 1.76 mmol) in benzene (2 mL) was added dropwide to the reaction mixture at room temperature. The reaction solution was stirred for 1 h, diluted with diethyl ether, quenched with saturated sodium hydrogen carbonate, extracted with diethyl ether (2×). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 25% tetrahydrofuran in hexanes gradient) to yield the title compound (31, 485 mg, 0.54 mmol, 93%) as yellow foam.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3c(C(F)(F)F)cccc23)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 5-(5-(8-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 14 (430 mg, 1.02 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (173 μL, 1.21 mmol), methanesulfonyl chloride (95 μL, 1.21 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=95:05. (5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 19 was obtained (188 mg, 37% yield) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([C:9]#[N:10])=[CH:5][CH:6]([CH3:8])[CH3:7].[N+]([CH3:15])([O-])=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:9]#[N:10])[CH2:15][CH:5]1[CH:6]([CH3:8])[CH3:7])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C(C#N)=CC(C)C
Solvent: CC#N
Product: COC(=O)C1(C#N)CC1C(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid methyl ester (10.5 g, 68.3 mmol) in dry acetonitrile (60 mL) was added nitromethane (5.5 mL, 103 mmol) and a portionwise addition of alumina-supported potassium flouride (40% wt, 22 g). The reaction mixture was stirred under reflux for 2 hours and cooled to room temperature. The solid was removed by filtration through a short pad of celite and washed with acetonitrile. Excess of solvent was removed in vacuo and the residue was re-dissolved in ether. The ether layer was washed with water, brine, dried over sodium sulfate (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes/EtOAc (8:2) as an eluent to afford 1-cyano-2-isopropyl-cyclopropanecarboxylic acid methyl ester (7.7 g, 68%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.13 (t, J=7.2 Hz, 6H), 1.39–1.45 (m, 2H), 1.65–1.74 (m, 1H), 1.81 (dd, J=4.4, 8.9 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 19.6, 21.8, 21.9, 25.3, 31.2, 39.3, 53.7, 117.6, 168.7.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]2)=[O:13])=[CH:10][CH:9]=1.C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.CCN(C(C1C=CC=C(C)C=1)=O)CC>CN(C=O)C>[CH:1]1([NH:6][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:28]=[CH:29][CH:30]=[C:15]([NH:14][C:12](=[O:13])[C:11]4[CH:31]=[CH:32][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH:16]=3)[CH2:24][CH2:23]2)=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C(Nc1cccc(CN2CCC(C(=O)O)CC2)c1)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCC3)CC2)c1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1-Cyclopentylamine (10.7 mg, 0.124 mmol) is added to a solution of [3-(4-chloro-benzoylamino)-benzyl]-piperidine-4-carboxylic acid (35.4 mg, 0.095 mmol) in DMF (0.5 mL). The resulting solution is treated with a solution of HOAT (15.5 mg, 0.114 mmol) in DMF (0.5 mL) followed by si-DCC (200 mg, 0.95 mmol/g, 0.19 mmol), and DIPEA (0.033 mL, 0.19 mmol). The mixture is stirred at 50° C. overnight. PI-DETA (7.99 mmol/g, 0.3 mmol, 37 mg) is added to the solution in order to scavenge the acid, PI-NCO (2.24 mmol/g, 0.3 mmol, 130 mg) is added to scavenge the amine in excess and the mixture is stirred for 1 h. The resin is filtered and washed with a mixture of MeOH/DCM 1:1, (4×1 mL). The resulting solution is evaporated under HV. The title compound is obtained by prep. HPLC F as a colourless powder: LC-MS A: tR=1.21 min; [M+H]+=440.1.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(S(C)=O)cc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(S(C)=O)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 61.8 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.8%).
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][Cl:5])=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCc1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.43 mL (5.6 mmol) of methanesulfonic acid chloride is slowly added dropwise at ambient temperature to a solution of 2 g (5.47 mmol) of N-(4′-chlorobiphenyl-4-yl)-3-(4-hydroxymethylphenyl)propionamide and 1.56 mL (11.2 mmol) of triethylamine in 50 mL of dichloromethane and the reaction mixture is stirred for 24 hours at ambient temperature. It is extracted with water and the organic phase is dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether and suction filtered. Yield: 1.45 g (69% of theory); C22H19Cl2NO (M=384.3); calc.: molecular ion peak (M+H)+: 384/86/88 (Cl2) Found: molecular ion peak (M+H)+: 384/86/88 (Cl2); Rf value: 0.45 (silica gel, dichloromethane/ethanol (50:1)).
Reaction SMILES: O1CC1COC1C=CC(NC(=O)C)=CC=1.[Cl:16][C:17]1[N:22]=[C:21]([CH:23]([OH:56])[CH2:24][N:25]([C@H:41]([CH3:55])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH2:51][O:52][CH2:53][CH3:54])=[CH:45][CH:44]=2)CC(O)COC2C=CC(NC(=O)C)=CC=2)[CH:20]=[CH:19][CH:18]=1>CO>[Cl:16][C:17]1[N:22]=[C:21]([CH:23]([CH2:24][NH:25][C@H:41]([CH3:55])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:50][CH2:51][O:52][CH2:53][CH3:54])=[CH:47][CH:48]=2)[OH:56])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOCCOc1ccc(C[C@@H](C)N(CC(O)COc2ccc(NC(C)=O)cc2)CC(O)c2cccc(Cl)n2)cc1
Agent: CC(=O)Nc1ccc(OCC2CO2)cc1
Solvent: CO
Product: CCOCCOc1ccc(C[C@@H](C)NCC(O)c2cccc(Cl)n2)cc1

Procedure:
using 4'-(2,3-epoxypropoxy)acetanilide there were obtained from 1.0 g of (RS)-6-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α -methylphenethyl]amino]methyl]-2-pyridinemethanol (Example 4C) 530 mg of 4'-[(RS)-3-[[(RS)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl][(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]amino]-2-hydroxypropoxy]acetanilide, [α]D20° =-39° (c=0.4 in MeOH),