Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH3:27]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: COc1ccccc1-c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (1 g) in toluene (6 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.09 g) was added saturated aqueous sodium hydrogen carbonate solution (7 ml) and a solution of 2-methoxypbenylboronic acid (1.7 g) in ethanol (3 ml). The mixture was heated under reflux for 2.5 hours, cooled and then poured into ether (60 m) and water (50 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (60 ml). The combined organic layers were washed with water (2×45 ml). brine (40 ml) and then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (60 g) eluted with ether:hexane (3:2). After combination and evaporation of suitable fractions the residue was further purified by HPLC. Combination and processing of suitable fractions gave the title compound as a white crystalline solid, m.p. 193° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:30]=2[CH3:31])=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].[CH3:41]I.O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([CH3:41])[C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:30]=2[CH3:31])=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2]
Reactant: CI
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)N(C)c2ccc(N3CCC(O)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
N-[3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (1.5 g) and sodium hydride (60% content, 0.2 g) were reacted in dimethylformamide (10 ml) under ice-cooling for 1 h. Dimethylformamide solution (1 ml) containing methyl iodide (0.6 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to room temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Tetrabutylammonium fluoride (1.4 g), tetrahydrofuran (10 ml) and acetonitrile (10 ml) were added to the residue, and the mixture was stirred at 80° C. for 2 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of ethyl acetate-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound (0.8 g), melting point: 211–212° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](Cl)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[C:16]([O:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C(c1ccccc1)N(CCO)CCO
Product: CCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCC)C(=O)c1ccccc1

Procedure:
N,N-bis(2-lauroyloxyethyl)-benzamide was prepared by the procedure of example 1 from 19.5 gms. (0.1 mole) of N,N-bis(2-hydroxyethyl)benzamide and 44 gms. (0.2 mole) of lauroyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:6]([C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7].[C:38](=O)([O:49]C1C=CC([N+]([O-])=O)=CC=1)[O:39][CH:40]1[CH:48]2[CH:43]([O:44][CH2:45][CH2:46][CH2:47]2)[O:42][CH2:41]1.C(N(C(C)C)CC)(C)C.C(#N)C>ClCCl.CO>[O:13]1[C:12]2[CH:16]=[CH:17][C:9]([S:6]([N:5]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:4][C@@H:3]([OH:22])[C@@H:2]([NH:1][C:38](=[O:49])[O:39][CH:40]3[CH:48]4[CH:43]([O:44][CH2:45][CH2:46][CH2:47]4)[O:42][CH2:41]3)[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:29]=3)(=[O:7])=[O:8])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCCC12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC1COC2OCCCC12)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
N-{(2R,3S)-3-Amino-4-[4-(benzyloxy)phenyl]-2-hydroxybutyl}-N-isobutyl-1,3-benzodioxole-5-sulfonamide was treated with hexahydro-4H-furo[2,3-b]pyran-3-yl 4-nitrophenyl carbonate/diisopropylethylamine/acetonitrile as previously described to afford after silica gel chromatography (dichloromethane/methanol, 49:1) the title diastereomers as a solid foams. Diastereomer A: 1H NMR (DMSO-d6): δ 0.76 (3H, d), 0.80 (3H, d), 1.2 (1H, br s) 1.6 (2H, br s), 1.9 (1H, br s), 2.1 (1H, br s), 2.4 (1H, br s), 2.75 (1H, dd), 2.8-3.0 (3H, m), 3.2-3.3 (3H, m), 3.4-3.6 (3H, m), 3.7 (1H, d), 4.0 (1H, m), 4.8-4.9 (2H, m), 5.0 (3H, br s), 6.15 (2H, s), 6.8 (2H, d), 7.0-7.2 (4H, m), 7.21-7.42 (7H, m); MS: 719 (M+23) Diastereomer B: 1H NMR (DMSO-d6): δ 0.76 (3H, d), 0.82 (3H, d), 1.0 (1H, br s), 1.3 (1H, br s), 1.5 (1H, br s), 1.95 (2H, br s), 2.4 (1H, t), 2.7 (2H, td), 2.9 (1H, d), 2.97 (1H, dd), 3.2-3.3 (3H, m), 3.5 (1H, br s), 3.55 (1H, br s), 3.64 (2H, br s), 4.0 (1H, dd), 4.9 (1H, s), 4.95-5.05 (4H, m), 6.15 (2H, s), 6.8 (2H, d), 7.0-7.2 (4H, m), 7.22, (1H, s), 7.25-7.40 (6H, m); MS: 719 (M+23)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@H:11]([C@@H:25]([OH:27])[CH3:26])[C:12]([NH:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@@H:11]([C:12]2[O:24][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[N:15][N:14]=2)[C@@H:25]([OH:27])[CH3:26])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(F)c2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(F)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3-fluorobenzohydrazide (1 g, 2.47 mmol) in anhydrous THF (15 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (3 mmol base/g) (3.37 g, 7.41 mmol) followed by para-toluene sulfonyl chloride (p-TSCl) (471 mg, 2.47 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction, the residue then washed with acetone (300 mL) followed by methanol (300 mL) and then concentrated to furnish a yellow oil (0.968 g). Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white crystalline solid (101 mg, 10%). 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.86-7.83 (m, 1H), 7.75-7.71 (m, 1H), 7.67-7.61 (m, 2H), 7.49 (d, J=9 Hz, 1H), 7.43-7.37 (m, 1H), 6.87 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 5.13 (m, 1H), 4.82 (br s, 1H), 4.67-4.59 (m, 1H), 2.41 (s, 3H) and 1.41 (d, J=6.5 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:19][S:16]([CH2:15][CH2:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1)(=[O:17])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CC[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans [4-(2-methanesulfonyl-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (900 mg, 2.95 mmol) was dissolved in DCM (7 mL) and trifluoroacetic acid (7 mL) was added. The mixture was stirred at room temperature for 1 h, then concentrated. The residue was taken up in methanol and purified by Isolute® SCX-2 column (gradient: methanol to 2 M NH3 in methanol) to give 594 mg (98%) of trans 4-(2-methanesulfonyl-ethyl)-cyclohexylamine. LCMS (method Q, ESI): RT=0.48 min, m+H=206.1; NMR (400 MHz, DMSO) δ: 3.09 (m, 2H), 2.93 (s, 3H), 2.48-2.41 (m, 1H), 1.78-1.64 (m, 4H), 1.58-1.51 (m, 2H), 1.30-1.18 (m, 1H), 1.03-0.82 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH2:20][CH:19]1[CH2:21]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[O:18]1[CH2:20][CH:19]1[CH2:21][N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Product: c1ccc(-c2nsc(N3CCN(CC4CO4)CC3)n2)cc1
Yield: 60 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-(3-phenyl-1,2,4-thiadiazol-5-yl)-piperazine and 3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after Biotage chromatography the title compound as a white powder in a 60% yield.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:24]=[N+:25]=[N-:26])=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)c1nnc(Cl)cc1Nc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1nnc(N=[N+]=[N-])cc1Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-(4-bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid tert-butyl ester (300 mg, 0.74 mmol) in DMF (5 ml) under argon at room temperature is added sodium azide (96 mg, 1.48 mmol) with stirring. The reaction mixture is stirred at 50° C. for 6 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and washed with water, saturated NaHCO3 (20 ml×3) and saturated NaCl (30 ml×3). The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography to provide the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc3ccc(O)cc3oc2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1oc2cc(O)ccc2cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.00 g (14.9 mmol) of 7-hydroxy-3-(4-methoxyphenyl)chromen-2-one are initially introduced in 190 ml of dichloromethane, and a solution of 2.5 ml (26.3 mmol) of boron tribromide in 10 ml of dichloromethane is added with ice-cooling. The cooling is removed, and the batch is stirred overnight at room temp. The solution is added to ice-water, acidified using 2 N hydrochloric acid and extracted three times with ethyl acetate. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is recrystallised from toluene/ethyl acetate (2:1), giving 7-hydroxy-3-(4-hydroxyphenyl)chromen-2-one as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[C:6]([NH:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:7])([O-])=O.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[C:6]([NH:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([N:15]([CH3:16])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:14])=[CH:11][CH:10]=1)=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2N)cc1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A solution of 4-(2-nitrobenzoyl)amino-N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]-N-methylbenzamide (800 mg), 20% palladium hydroxide (200 mg) in ethanol (20 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 2 hours, the reaction mixture was filtered through a bed of Celite, and the solvent was removed by rotary evaporation and the crude product was purified by silica gel column chromatography (SiO2 30 g, ethyl acetate/hexane=3/1) to give 4-(2-aminobenzoyl)amino-N-methyl-N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]benzamide (700 mg).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH2:9]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCc1ccccc1
Reactant: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCCc1ccccc1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 34.9 %

Procedure:
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 1.2 g (0.01 mol) of 2-phenylethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 1.5 g of the subject compound as white crystals.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C1C=CC(C=CC=O)=CC=1.[NH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][N:59]=[C:60]([O:62][CH2:63][CH3:64])[CH3:61]>CN(C)C=O.C(O)C.CO.C(Cl)(Cl)Cl>[C:2]([NH:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][N:59]=[C:60]([O:62][CH2:63][CH3:64])[CH3:61])(=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1
Reactant: CCOC(C)=NOCCCCN
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccc(C=CC=O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(C)=NOCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.1 %

Procedure:
Biotin (1.0 g, 4.1. mmol) was placed in a 100 mL round-bottom flask and dissolved in 25 mL of anhydrous dimethyl formamide (DMF) (dried by storing over heat activated (120° C. overnight) molecular sieves 4A, 8-12 mesh for 48 hours). To this solution was added N-hydroxy succinimide (0.71 g, 6.2 mmol) and dicyclohexyl carbodiimide (1.0 g, 4.9 mmol). The reaction mixture was stirred at room temperature for 48 hours under nitrogen. Analytical TLC (85:15 chloroform:methanol) of the reaction showed nearly complete conversion of biotin to a less polar biotin derivative (detection of biotin and biotin derivatives on TLC plates was carried out using a spray reagent consisting of 0.2% (w/w) 4-dimethylaminocinnamaldehyde in acidified ethanol available from Sigma Chemical Company, Product No. D-3588) with Rf =0.68, presumed to be the N-hydroxy succinimidyl ester of biotin. A solution of ethyl N-[(4-aminobutyl)oxy]acetimidate (3) (1.08 g, 6.2 immol) in 15 mL of dry DMF was added and the reaction was stirred under nitrogen at room temperature for 24 hours. Analytical TLC (85:15 chloroform:methanol) showed two main products containing biotin, Rf =0.60 and Rf =0.56. The solvent was removed on a rotary evaporator and absolute ethanol (50 mL) was added to the residue. Not all of the material dissolved, and the solution was filtered from a white solid, dicyclohexyl urea, which was discarded. The ethanolic solution was diluted with 50 mL of deionized water and the resulting white precipitate was dissolved by heating the solution briefly. Upon cooling to room temperature, white crystals formed and the solution was filtered. The crystals were discarded and the filtrate was evaporated to about half the original volume on a rotary evaporator and filtered again. The solid was discarded and the filtrate was further reduced to one fourth of the original volume and filtered again. Finally, the remaining solvent was evaporated to yield ethyl N-[(4-biotinamidobutyl)oxy]acetimidate (4) (0.431 g, 1.07 mmol, 26%). Single spot on TLC, Rf =0.56. 1H NMR (DMSO-d6): δ7.7 (m, 1H), 6.5 (s, 1H), 6.4 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.9 (q, 2H), 3.7 (m, 2H), 3.1 (m, 4H), 2.7 (dd, 2H), 2.5 (d, 2H), 2.1 (t, 2H), 1.7 (s, 3H), 1.3-1.5 (m, 8H), 1.2 (t, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH:26]([CH3:28])[CH3:27])[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:47]=[CH:46][C:33]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:47][CH:46]=3)=[CH:42][CH:41]=2)[C:3]=1[N:22]1[CH2:25][CH:24]([CH:26]([CH3:28])[CH3:27])[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
The Pd(Ph3P)4 (38.1 mg, 0.033 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.33 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (94 mg, 0.36 mmol), and sodium carbonate (209 mg, 1.98 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-75% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate 152 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.31-7.30 (m, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.82-6.80 (m, 1H), 5.18 (s, 1H), 5.03-4.98 (m, 1H), 4.21 (t, J=6.6 Hz, 2H), 3.43-3.25 (series m, 4H), 3.05 (t, J=6.6 Hz, 2H), 2.27 (s, 3H), 2.01 (s, 3H), 2.01-1.98 (m, 1H), 1.48-1.44 (m, 1H), 1.21-1.19 (m, 6H), 1.10 (s, 9H), 0.68 (d, J=6.6 Hz, 3H), 0.63 (d, J=6.6 Hz, 3H). UPLC (M+H)=591.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CS(O[CH2:31][CH2:32][CH:33]1[CH2:35][C:34]1([F:37])[F:36])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:36][C:34]1([F:37])[CH2:35][CH:33]1[CH2:32][CH2:31][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)=[CH:3][C:2]=1[F:1]
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC4CC4(F)F)c(F)c3)nc2cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide (100 mg), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (232 mg), potassium carbonate (160 mg) and DMF (1 mL) was stirred overnight at 70° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethyl acetate) to give the title compound (107 mg).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1ccc(OCCCBr)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)cc3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.758 g of 1-(3-bromopropoxy)-4-fluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.13 (1:2 EtOAc-heptane); Rt=5.12.