Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH:16]1([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]2=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.089 mmol), β-alanine (795 mg, 8.9 mmol) and NaOMe solution (13 mL, 6.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound as a light yellow solid. MS: (+) m/z 450.30 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN([C@H]2CCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 49 %

Procedure:
The titled compound (133 mg) was prepared in 49% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 4-bromomethyl-benzonitrile according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.84 (d, 2 H, J=8.0 Hz), 7.73 (d, 2 H, J=8.0 Hz), 7.66 (d, 2 H,J=8.0 Hz), 7.48 (d, 2 H,J=8.0 Hz), 7.29 (s, 1 H), 6.60 (s, 1 H), 4.63 (AB2,2 H,Δv=16,Jab=76 Hz), 3.84 (m, 1 H), 2.79 (m, 1 H), 2.41 (m, 1 H), 1.64 (m, 2 H), 1.27 (m, 3 H), 0.85 (m, 1 H); MS m/e 454.02 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=[O:6].Cl(O)(=O)(=O)=O.O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
240 mg (0.46 mmol) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid was dissolved in 5 mL of glacial acetic acid. 500 μL of 70% perchloric acid was added and the mixture stirred at ambient temperature for 24 h. 50 mL of water was added and the resulting precipitate filtered off and dried by suction to afford 117 mg (0.29 mmol, 64%) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, 1H), 8.34 (d, 1H), 8.14 (d, 1H), 8.07 (d, 1H), 7.66 (dd, 1H), 7.47 (ddd, 1H), 7.22 (d(d), 1H), 7.10 (ddd, 1H), 3.84 (s, 3H), MS: m/z 394.0 (M−H+).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[NH2-].[Na+].[OH:26][C:27]1[CH:44]=[CH:43][C:42]2[C@:41]3([CH:45]=O)[C@H:32]([C@H:33]4[C@@:37]([CH2:39][CH2:40]3)([CH3:38])[CH2:36][C@H:35]([OH:47])[CH2:34]4)[CH2:31][CH2:30][C:29]=2[CH:28]=1.CS(C)=O.O>C(OCC)(=O)C>[CH:45]([C@:41]12[CH2:40][CH2:39][C@@:37]3([CH3:38])[C@@H:33]([CH2:34][C@@H:35]([OH:47])[CH2:36]3)[C@@H:32]1[CH2:31][CH2:30][C:29]1[CH:28]=[C:27]([OH:26])[CH:44]=[CH:43][C:42]2=1)=[CH:2][CH2:3][CH3:4]
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC=C[C@]12CC[C@]3(C)C[C@H](O)C[C@H]3[C@@H]1CCc1cc(O)ccc12

Procedure:
8.68 g (20 mmol) of propyltriphenyl-phosphonium bromide+sodium amide (1 g contains 2.3 mmol of propyltriphenyl-phosphonium bromide), 0.2 g (0.67 mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde and 30 ml of DMSO are introduced into a reaction flask that was rendered inert. The reaction mixture is treated for about 2 hours in an ultrasound bath at 60° C. After the reaction is completed, water is added to the reaction solution. The crude product is isolated by extraction with ethyl acetate, washing of the organic phase with water, and concentration by evaporation until a dry state is reached.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]3[CH:26]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:8]4[C:7]([CH:6]3[O:13][C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:25](=[O:32])[C:24]=2[C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)OCCO2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC1c2ccccc2C(OC(C)=O)C2C(=O)C3=C(CC(OC(C)=O)(C(C)=O)CC34OCCO4)C(=O)C12
Yield: 42 %

Procedure:
A solution of 110 mg (0.5 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 112 mg (0.35 mmol) o rac-3-acetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene in 10 ml of toluene was stirred and heated under reflux for 3 hours under an atmosphere of nitrogen. The solution was evaporated and the resulting yellow gum was crystallised from diethyl ether to yield 80 mg (42%) of rac-3,6,11-triacetoxy-3-acetyl-1,1-ethylenedioxy-1,2,3,4,5,5a,6,11,11a,12-decahydro-5,12-dioxonaphthacene in the form of a pale yellow solid of melting point 133°-143° C.
Reaction SMILES: C(OC([N:8]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[CH:26][C:25]([C:35]([F:38])([F:37])[F:36])=[N:24]2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:9][C:10](OC)=[O:11])=O)(C)(C)C.[BH4-].[Na+]>CO>[OH:11][CH2:10][CH2:9][NH:8][S:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[CH:26][C:25]([C:35]([F:36])([F:38])[F:37])=[N:24]2)=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-N-({4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}sulfonyl)glycinate (1.18 g, 2.13 mmol) in 50 ml anhydrous methanol (50 mL) was added NaBH4 (0.8 g, 21.1 mmol) and the mixture was stirred at room temperature. At 30 minutes, additional MeOH (50 mL) was added and then NaBH4 (3.6 g, 95.1 mmol) was added in portions over 5.5 hours and the mixture was stirred at room temperature for an additional 18 hours. The solvent was removed under vacuum and ethyl acetate (100 mL) was added. The mixture was then poured into sat. NaHCO3 (200 mL) and the layers were separated. The aqueous layer was then extracted with ethyl acetate (100 mL). The organic layers were combined, washed with sat. NaHCO3 (100 mL), dried over MgSO4, filtered and concentrated under vacuum. The resulting pale yellow glass was dissolved in TFA (100 mL) and the mixture was allowed to stand at room temperature for 2 hours. The TFA was removed under vacuum, and remaining traces of TFA were removed by addition and removal under vacuum of CH2Cl2 (several portions) to give a yellow oil. The crude product was purified by flash chromatography (silica gel, 1:1 hexanes:ethyl acetate) to afford 0.365 g (40% yield) of the product as a white powder: mp, 57.8° C.; 1H NMR (dmso-d6/300 MHz) δ 7.86-7.83 (m, 2H), 7.76 (exchangeable with D2O, t, 1H), J=5.9 Hz), 7.56-7.53 (m, 2H), 7.22-7.17 (m, 5H), 4.70 (exchangeable with D2O, t, 1H, J=5.6 Hz), 3.37-3.32 (m, 2H), 2.84-2.79 (m, 2H), 2.30 (s 3H); HRMS (M+H)+ calcd. for C19H19F3N3O3S: 426.1099; found 426.1071.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=O)=[CH:5][CH:4]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH2:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CN)cc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A mixture of 4-ethylbenzoic acid (0.50 g, 3.33 mmol) in SOCl2 (1 mL) and DMF(1 drop) was refluxed for 2 h. The reaction mixture was concentrated and then stripped with toluene (2×10 mL) to yield 4-ethylbenzoyl chloride (0.59 g, >100%) as a colorless oil. The crude acid chloride (0.59 g, 3.5 mmol) in toluene (minimum amount) was added dropwise to conc. aq. NH4OH (1.4 mL). After stirring for 1 h, the reaction mixture was concentrated, the residue was dissolved in water and extracted with EtOAc (3×25 mL). The combined organic layers were washed with 1 N aq. NaOH (10 mL) and brine and dried over Na2SO4 prior to removal of the volatiles to yield 4-ethylbenzamide (460 mg, 88%) as a white solid. A suspension of this crude amide (430 mg, 2.87 mmol) and LiAlH4 (180 mg, 4.7 mmol) in dry THF (5 mL) was refluxed at 65° C. for 4.5 h. More LiAlH4 (60 mg, 1.58 mmol) was added, and the reaction mixture was heated at 65° C. for 2 h. The reaction mixture was cooled, and 1 N aq. NaOH (0.4 mL) was added. After stirring for 4 h, the mixture was filtered, and the filtrate was concentrated to give 4-ethylbenzylamine (350 mg, 90w) as a pale yellow oil.
Reaction SMILES: [CH2:1](Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].OC(CCC=C(CCC=C(C)C)C)(C=C)C.[CH3:33][O:34][CH:35]([O:43][CH3:44])[C:36](=[O:42])[CH2:37]C(OC)=O>>[CH3:33][O:34][CH:35]([O:43][CH3:44])[C:36](=[O:42])[CH2:37][CH2:1]/[CH:2]=[C:3](/[CH3:4])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: COC(=O)CC(=O)C(OC)OC
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Product: COC(OC)C(=O)CC/C=C(/C)CC/C=C(\C)CCC=C(C)C

Procedure:
Following the procedure stated in Referential example 1, reaction of farnesyl bromide which had been prepared from 22 g of nerolidol with 19 g of methyl 4,4-dimethoxyacetoacetate was carried out and the reaction mixture was purified by the silica gel (200 g) column chromatography to yield 12.8 g of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH:10]([OH:20])[CH2:11][C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1>C(O)C.CO.[Pt]=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1
Reactant: OC(CC#Cc1cccnc1)CC#Cc1cccnc1
Agent: O=[Pt]
Solvent: CO
Solvent: CCO
Product: OC(CCCc1cccnc1)CCCc1cccnc1
Yield: 98.9 %

Procedure:
A suspension of platinum oxide (280 mg) in absolute ethanol (1 mL) was diluted with absolute methanol (10 mL) followed by the addition of compound 1 (2.81 g, 10.73 mmol). The suspension was placed under 40 psi ofhydrogen gas. After hydrogen consumption ceased, the hydrogen was replaced with nitrogen and the reaction was filtered and concentrated to provide 2.87 g of compound 2 as a viscous oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([CH:20]([O:25][C:26]2[C:27]([CH3:33])=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:16]1)=O)(C)(C)C>COC1C=CC=CC=1.ClCCl>[Cl:32][C:29]1[N:28]=[C:27]([CH3:33])[C:26]([O:25][CH:20]([C@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)[CH2:21][CH:22]2[CH2:23][CH2:24]2)=[CH:31][CH:30]=1
Reactant: Cc1nc(Cl)ccc1OC(CC1CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Cl)ccc1OC(CC1CC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Add trifluoroacetic acid (1.51 g, 1.0 mL, 13.2 mmol) to a solution of (3S)-3-[1-(6-chloro-2-methyl-3-pyridyloxy)-2-cyclopropyl-ethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (S-1) (99.0 mg, 0.260 mmol) in methoxybenzene (1.0 mL) and dichloromethane (2.0 mL). Stir under nitrogen at room temperature for 1 h. Load the mixture directly onto a pre-packed SCX column and rinse with CH2Cl2 followed by CH3OH. Elute with 2M NH3 in methanol and concentrate under reduced pressure to give 58 mg (79%) of (3S)-3-[1-(6-chloro-2-methyl-3-pyridyloxy)-2-cyclopropyl-ethyl]-pyrrolidine (S-1). MS (m/z)=281.2 [M+1]
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=3)[CH2:22][CH2:21][N:20]2[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:15][CH:14]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[F:35][C:32]([F:33])([F:34])[C:31]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH:19]1[C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)=[O:36]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(N1CCc2cc(O)ccc2C1c1ccc(O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 9.9 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (6.0 ml, 6.0 mmol) was added slowly to a solution of 1-[1-(4-benzyloxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone (1.054 g, 2.4 mmol) in anhydrous CH2Cl2 (100 ml) at 0° C. under N2. The reaction mixture was warmed to rt and stirred at rt for 17 hr. MeOH (50 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a red oil. This was dissolved in MeOH (20 ml) and 1M HCl (20 ml), and the resulting solution was stirred at rt for 4 hr, then neutralized with saturated NaHCO3 solution (60 ml). The resulting suspension was concentrated in vacuo and the remaining material was extracted with EtOAc (4×30 ml). The combined extracts were dried over MgSO4 and evaporated in vacuo to give 0.775 g of crude brown solid. Purification by flash chromatography, eluting with hexane:EtOAc (1:1) gave 0.080 g (10% yield) of white solid.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][O:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(Cl)(Cl)Cl>[CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCOCC(CO)OCCCCCCCCCC
Yield: 63 %

Procedure:
Detritylation of 3-dodecyloxy-2-decyloxy-1 -triphenylmethoxypropane was accomplished using p-toluenesulfonic acid (0.9 g) in CHCl3 :MeOH (72 mL:36 mL) (stirred at room temperature for 48 h, added 10% sodium bicarbonate, extracted with CHCl3, dried over magnesium sulfate, and concentrated). The residue was purified by column chromatography using a gradient of hexanes:ethyl acetate (20:1 to 5:1) to give 3.5 g (63%) of pure 3-dodecyloxy-2-decyloxy-1-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([OH:16])=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1.[C:26]1([C:32]2[CH:33]=[CH:34][C:35]([CH2:38]Cl)=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:37][N:36]=4)=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1
Reactant: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(O)c(c23)S1
Reactant: ClCc1ccc(-c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(OCc4ccc(-c5ccccc5)cn4)c(c23)S1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of product from Step 5 (150 mg, 0.39 mmol), 5-phenyl-2-picolyl chloride (95 mg, 0.47 mmol) and Cs2CO3 (152 mg, 0.47 mmol) in CH3CN (5 mL) was stirred at r.t. for 20 hours, then at 60° C. for 1.5 hours. The mixture was diluted with EtOAc (25 mL), washed 3× with H2O, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as an oil which solidified.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11]C2C=CC=CC=2)CO)[CH2:3][CH2:2]1.[H-].[Na+]>CN(C=O)C>[CH:1]1([CH2:4][C@H:5]2[CH2:11][O:10][C:9](=[O:18])[NH:8]2)[CH2:2][CH2:3]1
Reactant: O=C(N[C@H](CO)CC1CC1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N[C@@H](CC2CC2)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a stirred solution of (S)-benzyl 1-cyclopropyl-3-hydroxypropan-2-ylcarbamate (0.734 g, 2.94 mmol) in DMF (15 mL) was added sodium hydride (0.177 g, 4.42 mmol) at 0° C. The mixture was then stirred at ambient temperature for 30 minutes. The solvent was concentrated and the residue distributed between water and EtOAc. The combined organic extracts were dried (phase separator silicone treated filter paper), concentrated to provide (S)-4-(cyclopropylmethyl)oxazolidin-2-one (0.318 g, 76% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:28])[C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:29])[C:3]=1[CH2:30][OH:31].C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40].C(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:28])[C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:29])[C:3]=1[CH2:30][O:31][S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: CN(C)C(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COS(C)(=O)=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(dimethylcarbamoyl)cinnamoylglycyl]amino]benzene (300 mg) and triethylamine (78.5 mg) in dichloromethane (3 ml) was dropwise added mesyl chloride (81.4 mg) under ice-cooling, and the mixture was stirred for 10 minutes at the same temperature and for 30 minutes at ambient temperature. Chloroform was added thereto, and the mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo to give 2,6-dichloro-1-methanesulfonyloxymethyl-3-[N-methyl-N-[4-(dimethylcarbamoyl)cinnamoylglycyl]amino]benzene (330 mg) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:36]([F:46])[C:35]=1[Cl:47]>ClCCl.CN(C=O)C.C(#N)C>[Cl:47][C:35]1[C:36]([F:46])=[C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:38]=[CH:39][C:34]=1[NH:33][C:4]([C:3]1[CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1F
Reactant: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)c(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A solution of 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoic acid (200 mg, 0.67 mmol) in dichloromethane (3 ml) was treated with oxalyl chloride (90 ul, 1.0 mmol) and DMF (1 drop). Effervescence was observed and the mixture was stirred at room temperature for 30 minutes. The solvent was then evaporated in vacuo and azeotroped with toluene. The resulting solid was dissolved in dichloromethane (3 ml) and treated with triethylamine (140 ul, 1.0 mmol) and a solution of ethyl (4-amino-3-chloro-2-fluorophenyl)acetate (230 mg, 1.0 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with acetonitrile and purified by SCX cartridge eluting with acetonitrile. Fractions combined and evaporated, residue purified by MDAP to give the title compound as a white solid (110 mg). MS (ES+) m/z 510 [M+H]+ (C24H1935Cl3FNO4). 1H-NMR (400 MHz, d6-DMSO) δ 1.20 (3H, t, J 7.2), 3.81 (2H, s), 4.12 (2H, q, J 7.2), 5.20 (2H, s), 7.16-7.55 (9H, m).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4C#N)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12d and 3-bromoanisole.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-methylpiperidine (180 mg, 1.813 mmol) was added to the 3-(chlorosulfonyl)benzoic acid (200 mg, 0.906 mmol) in presence of Potassiumcarbonate (251 mg, 1.813 mmol) in THF (Volume: 5 ml) at room temperature and the reaction mixture was stirred for 12 h at room temperature. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography (3% CH3OH/CH2Cl2) afforded the title compound as a solid. 1H NMR (CD3OD, 400 MHz): δ 8.32 (m, 1H), 8.27 (m, 1H), 7.96 (m, 1H), 7.72 (t, 1H, J=8.0 Hz), 3.72 (m, 2H), 2.27 (m, 2H), 1.68 (m, 2H), 1.29 (m, 1H), 1.21 (m, 2H), 0.88 (d, 3H, J=6.4 Hz). ESI-MS: 284.1 [M+H]+