Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:7]2=[O:30])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:38][C:39]([NH2:41])=[O:40])=[CH:26][C:20]=4[S:19](=[O:28])(=[O:29])[N:18]=3)[C:7]2=[O:30])[CH2:2][CH2:3][CH2:4]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NC1CCC1
Reactant: NC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 165 °C
Yield: 37.6 %

Procedure:
The product of Example 304I (0.048 g, 0.11 mmol) in N,N-dimethylformamide (2 mL) was reacted with cesium carbonate (0.15 g, 0.45 mmol), bromoacetamide (0.026 mL, 0.18 mmol), and a catalytic amount of tetrabutylammonium iodide at 25° C. for 3 hours. The reaction was concentrated under a stream of nitrogen stream of nitrogen warmed through a manifold heated to 165° C. and the resulting residue was triturated with water, filtered and dried. The resulting solid was triturated in hot ethyl acetate, filtered, and dried to give the title compound (0.020 g, 37%). MS (ESI−) m/z 482 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59 (m, 2 H) 1.99 (m, 4 H) 3.60 (m, 1 H) 4.49 (s, 2 H) 6.08 (d, J=6.62 Hz, 1 H) 7.05 (t, J=7.17 Hz, 1 H) 7.20 (m, 3 H) 7.40 (s, 1 H) 7.50 (m, 1 H) 7.65 (m, 2 H) 8.05 (d, J=7.72 Hz, 1 H) 16.25 (s, 1 H). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59 (m, 1 H) 1.99 (m, 4 H) 3.61 (m, 2 H) 4.49 (s, 2 H) 6.08 (d, J=6.62 Hz, 1 H) 7.05 (m, 1 H) 7.21 (m, 2 H) 7.40 (s, 2 H) 7.50 (m, 1 H) 7.64 (m, 2 H) 8.06 (dd, J=7.91, 1.29 Hz, 1 H) 8.32 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:6]=[CH:5][C:4]=1[OH:13])#[N:2].[ClH:14]>CO.[Pd]>[ClH:14].[ClH:14].[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([CH3:11])([CH3:10])[CH3:12])[N:6]=[CH:5][C:4]=1[OH:13]
Reactant: CC(C)(C)c1cc(C#N)c(O)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(CN)c(O)cn1

Procedure:
A solution of 4-cyano-6-(1,1-dimethylethyl)-3-pyridinol (5.7 g., 0.032 mole) in methanol -- 12N hydrochloric acid (30:1; v:v; 310 ml.) is hydrogenated in the presence of 10% palladium on charcoal (1 g.) in a Parr apparatus at 25° C. and 40-45 p.s.i. pressure until the theoretical quantity of hydrogen has been consumed. Then the hydrogenation mixture is filtered and the collected catalyst, washed with ethanol. Evaporation (in vacuo) of the combined filtrate and washings leaves the 4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol dihydrochloride as a residual solid (7.9 g., 98%), m.p. 304°-306° C. with dec. Recrystallization of the solid from ethanol-ether-water (100:100:4; v:v:v) affords an analytical sample of 4-aminomethyl-6-(1,1-dimethylethyl)-3-pyridinol dihydrochloride as colorless crystals, m.p. 304°-306° C. with dec.
Reaction SMILES: N.[Na].[NH2-].[Na+].[CH3:5][C:6]([CH3:11])=[CH:7][C:8](=[O:10])[CH3:9].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCOCC>[CH2:13]([CH:7]([C:6]([CH3:11])=[CH2:5])[C:8](=[O:10])[CH3:9])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)C=C(C)C
Reactant: CCCCCBr
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: C=C(C)C(CCCCC)C(C)=O
Reaction time: 1 h
Yield: 897.6 %

Procedure:
100 ml of liquid ammonia was condensed into a 2-neck flask fitted with a dropping funnel, inlet tube, and dry-ice condenser. A few crystals of ferric chloride were added, followed by the addition of 2.3 g (0.1 mole) of sodium. When the sodium was converted to sodium amide, the deep blue color changed to gray. A solution of 10 g (0.1 mole) of 4-methyl-3-pentene-2-one in 10 ml of ether was added dropwise, resulting in a green-blue solution. After 15 minutes a solution of 1.5 g (1 equivalent) of bromopentane in 5 ml of ether was added, changing the color to light brown. After 1 hour of stirring, the ammonia was allowed to evaporate and ether and water were added. The organic layer was separated, washed with water, washed with two 10 ml portions of 5% HCl, and dried over MgSO4. Evaporation of the ether yielded 15 g (88% yield) of 3-pentyl-4-methyl-4-pentene-2-one: ##STR15##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.O[CH2:21]N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>CCO.CN(C=O)C>[CH3:21][NH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reactant: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 70 °C

Procedure:
A mixture of (S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (154 mg, 0.613 mmol, described in Intermediate 3) and 1-(hydroxymethyl)benzotriazole (93 mg, 0.625 mmol) in EtOH (2 mL) and DMF (0.2 mL) was heated at reflux for 4 h, then concentrated to dryness under reduced pressure. The residue was resuspended in THF (3 mL) and sodium borohydride (40 mg, 1.05 mmol) was added. The resulting mixture was heated to 70° C. for 6 h then quenched with H2O (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=266 (M+1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.ClCCl>[CH2:34]([O:33][C:31]([N:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)[CH2:18][CH2:19]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)C1CCC(c2ccccc2N2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 87.7 %

Procedure:
A mixture of the 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (92 mg, 0.306 mmol) produced in Example (10a), triethylamine (0.085 mL, 0.612 mmol) and dichloromethane (2 mL) was cooled in an ice bath and stirred. Ethyl chloroformate (0.032 mL, 0.337 mmol) was added to the mixture, followed by stirring for 2 hours under the same conditions. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 100 mg of the title compound as a colorless oil, as a mixture of diastereomers at the position of t-butylcyclohexyl.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>CO.C1(C)C=CC=CC=1>[OH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:1])=[O:17])[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
(Trimethylsilyl)diazomethane (21 mL, 12.4 mmol) was added dropwise into a solution of 2-(hydroxymethyl)-2′-methylbiphenyl-4-carboxylic acid (2.0 g, 8.3 mmol) in MeOH (20 mL) and toluene (20 mL) at 0° C. After 10 minutes at 0° C., the resulting mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under vacuum to give the title compound (2.1 g, quantitative), used without further purification in the next step. HPLC (Method A) Rt 3.95 min (purity 95.5%). 1H NMR (CDCl3, 300 MHz) δ 8.23 (d, J=1.3 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.28-7.18 (m, 4H), 7.08 (d, J=7.3 Hz, 1H), 4.42 (d, J=5.7 Hz, 2H), 3.92 (s, 3H), 2.01 (s, 3H), 1.61 (t, J=5.7 Hz, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a suspension of K2CO3 (0.654 g, 4.74 mmol) in DMF (6 mL) is added 2-benzyloxy-4-fluoro-1-nitrobenzene (0.90 g, 3.64 mmol), followed by phenol (0.343 g, 3.64 mmol). The mixture is stirred at 100° C. for 48 h. The mixture is allowed to cool to ambient temperature, then poured into water and extracted into EtOAc. The organic phase is washed with water (2×), saturated NaCl (1×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford 2-benzyloxy-4-phenoxy-1-nitrobenzene as a pale-yellow solid: mp=96-98° C.; 1H NMR (CDCl3) δ 7.87 (d, J=9.09 Hz, 1H), 7.36-7.23 (m, 7H), 7.20-7.15 (m, 1H), 6.95 (dd, J=8.59, 1.01 Hz, 1H), 6.58 (d, J=2.27 Hz, 1H), 6.46-6.43 (m, 1H), 5.08 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]#[C:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:8][CH:6]([CH2:5][C:4]#[C:3][C:2]([CH3:1])([OH:20])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:7])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CCCC(C)CCCC(C)(O)C#CCC(C)O
Solvent: c1ccncc1
Product: CC(=O)OC(C)CC#CC(C)(O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 230 mg (0.814 mmole) of 6,10,14-trimethyl-4-pentadecyne-2,6-diol (produced in accordance with Example XVI) and 0.25 mL (2.65 mmoles) of acetic anhydride in 0.25 mL of pyridine (A.C.S. reagent-grade, purchased from Aldrich Chemical Co., Milwaukee, Wis.) was stirred, while being maintained under a nitrogen atmosphere, at room temperature for 8 hours. After destroying excess acetic anhydride by addition of 10 mL of ice-cold 1M aqueous sodium hydroxide, the mixture was diluted with 20 mL of hexane and 25 mL of 10% aqueous sodium chloride. The layers were then separated, and the organic layer washed in successive order with 1:1 (v/v) 1M aqueous sodium hydroxide: 10% aqueous sodium chloride (1×10 mL), 1:1 (v/v) 2M aqueous hydrochloric acid: saturated brine (2×20 mL), saturated aqueous sodium bicarbonate (1×10 mL), and saturated brine (1×10 mL). The washed organic layer was subsequently dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic material by evaporation at reduced pressure afforded 249 mg (94% yield) of 2-acetoxy-6,10,14-trimethyl-4-pentadecyn-6-ol (i.e., the product derived by selective acetylation of the 2° alcohol functionality in the starting alkynediol).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[O:17]1[CH2:16][CH2:15][N:14]([C@@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 39A (2.43 g) in dichloromethane (15 ml) was added trifluoroacetic acid (5 ml) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated and the crude product was used without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:28])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>C(N(CC)CC)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][N:25]([CH2:26][C@@H:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28])[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:11])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(CCNC[C@H](C)c2ccccc2)cc1OC
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C[C@H](C)c2ccccc2)C(=O)c2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.5 %

Procedure:
A stirring solution of benzo[1,3]dioxole-5-carbonyl chloride (151 mg, 0.82 mmol) in MDC (5 ml) was treated with a pre-mixed solution of (R)-[2-(3,4-dimethoxy-phenyl)-ethyl]-(2-phenyl-propyl)-amine (D12, 245 mg, 0.75 mmol) and triethylamine (0.17 ml) in MDC (2 ml). After stirring under argon at room temperature for 72 h the solvent was removed in vacuo and the residue was chromatographed (silica gel, 0–40% EtOAc-pentane) to afford the title compound as a colourless gum (250 mg, 68%).
Reaction SMILES: P(=O)(O)(O)O.OO.Cl[CH2:9][CH2:10][S:11]([CH2:14][C:15]([CH2:30][S:31]([CH2:34][CH2:35]Cl)(=[O:33])=[O:32])([CH2:23][S:24]([CH2:27][CH2:28]Cl)(=[O:26])=[O:25])[CH2:16][S:17]([CH2:20][CH2:21]Cl)(=[O:19])=[O:18])(=[O:13])=[O:12]>>[CH:34]([S:31]([CH2:30][C:15]([CH2:16][S:17]([CH:20]=[CH2:21])(=[O:18])=[O:19])([CH2:14][S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])[CH2:23][S:24]([CH:27]=[CH2:28])(=[O:26])=[O:25])(=[O:32])=[O:33])=[CH2:35]
Reactant: O=S(=O)(CCCl)CC(CS(=O)(=O)CCCl)(CS(=O)(=O)CCCl)CS(=O)(=O)CCCl
Agent: O=P(O)(O)O
Agent: OO
Product: C=CS(=O)(=O)CC(CS(=O)(=O)C=C)(CS(=O)(=O)C=C)CS(=O)(=O)C=C
Temperature: 25 °C

Procedure:
To 400 parts of ethanol were successively added 9.2 parts of metallic sodium, 31.2 parts of 2-mercaptoethanol amd 38.8 parts of pentaerythritol tetrabromide, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium bromide was removed, and the ethanol was removed by distillation to obtain tetrakis(2-hydroxyethylthiomethyl)methane. This compound was added to 80 parts of chloroform, and 60 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the ether by distillation to obtain tetrakis(2-chloroethylthiomethyl)methane. To this compound were successively added 0.4 part of phosphoric acid and 80 parts of 30% aqueous hydrogen peroxide, and the resulting mixture was heated under reflux and then cooled to deposit tetrakis(2-chloroethylsulfonylmethyl)methane. The deposited compound was recovered by filtration and dissolved in 200 parts of acetone, and the resulting solution was incorporated with 40 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and the acetone was removed by distillation to deposit solids. The deposited solids were recrystallized from acetone-ethanol to obtain tetrakis(vinylsulfonylmethyl)methane.
Reaction SMILES: [OH:1][C:2]([CH:4]=[CH2:5])=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)[CH3:26].CCOCC.O>CS(C)=O.O1CCCC1>[C:28]1([C:25]([CH3:26])=[CH:5][CH2:4][C:2]([OH:1])=[O:3])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=CC(=O)O
Reactant: CC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(=CCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (1.70 g., 57% in oil dispersion) is washed free of oil using hexane under nitrogen, and then 7.4 g (20 mmole) of triphenylphosphine hydroxycarbonylethylene and 2.4 g (20 mmole) of acetophenone in 25 ml of dimethylsulfoxide (DMSO) and 20 ml tetrahydrofuran (THF) are added. The reaction is stirred overnight at RT and then poured into ether and water. The aqueous phase is washed (2×) with ether and then acidified with 2 N sulfuric acid followed by extraction into ether. The organic phase is washed with water, dried over calcium sulfate and solvent removed to give 4-phenyl-3-pentenoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](N)[CH:3]=1.N([O-])=[O:13].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([OH:13])[CH:3]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(O)ncc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
Dissolve 4-methyl-5-nitro-pyridin-2-ylamine (3.0 mmol, 0.5 g) in 0.5 mL of sulfuric acid. Add 7.6 mL of water and cool the solution down to 0° C. Add sodium nitrite (4.5 mmol, 0.3 g) and stir the mixture for two hours, allowing to reach room temperature. Dilute with water and add aq. sodium hydroxide solution 10% until basic pH. Extract in ethyl acetate and wash combined organic layers with saturated aq. sodium chloride solution. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 4-methyl-5-nitro-pyridin-2-ol. MS(ES): m/z=155 [M+H].
Reaction SMILES: [O:1]=[C:2]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][CH2:4][CH2:3][C:2]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:1]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Tert-butyl 3-oxo-3-(phenylsulfonamido)propylcarbamate (3.6 g, 15.1 mmol) was dissolved in dichloromethane (60 mL). Then CF3COOH (1.1 mL, 0.3 mmol, 20 equiv) was added to the mixture at 0° C. and stirred for 2 h at 0° C. The reaction mixture was concentrated and purified by flash chromatography to give 3-amino-N-(phenylsulfonyl)propanamide as a white solid (1.4 g, 40%). EDI-MS: 229.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 7.79˜7.71 (m, 2H), 7.70˜7.43 (brs, 3H), 7.42˜7.34 (m, 3H), 2.83 (t, 2H), 2.24 (t, 2H).
Reaction SMILES: C1CO[C:3]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11]C3CCCCO3)[CH2:9][C:8](=[O:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[O:2]1.C(O)(=O)C.C1COCC1>O>[OH:11][C@@H:10]1[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C@H:6]1[CH2:5][CH2:4][C:3](=[O:2])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCC1(CC[C@H]2[C@H](OC3CCCCO3)CC(=O)[C@@H]2C/C=C\CCCCCC(=O)OC(C)C)OCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OC(C)C
Temperature: 50 °C
Yield: 64.4 %

Procedure:
The compound (5-a)(0.311 g) was dissolved in the solvent mixture (acetic acid:THF:water=2:1:1)(5 ml) and the solution was maintained at 50° C. for 3 hours. The crude product obtained by the conventional treatment of the reaction mixture was purified on silica gel column to give the titled compound (6-a)[yield:0.156 g (66%)].
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].C[O:10][C:11]([C:13]1[O:14][C:15]([CH2:18]Cl)=[CH:16][CH:17]=1)=[O:12]>CN(C=O)C.CCOC(C)=O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:18][C:15]1[O:14][C:13]([C:11]([OH:12])=[O:10])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(COCC(F)(F)F)o1
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 60 mg, 1.50 mmol) was added to 2,2,2-trifluoroethanol (99 μL, 1.38 mmol) in anhydrous DMF (1 mL) and the mixture was stirred under nitrogen for 20 min. 5-Chloromethylfuran-2-carboxylic acid methyl ester (200 mg, 1.15 mmol) was then added and the mixture was stirred at room temperature for 18 h, then at 60 C for 3 h, then at 100 C for 3 h. Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added under nitrogen and the reaction mixture was stirred at room temperature for 18 h. Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (30 mL) then washed with saturated aq. sodium bicarbonate (4×6 mL), saturated aq. ammonium chloride (2×6 mL) and then brine (6 mL). The aqueous extractions were combined and brought to pH 1 by the addition of 2M HCl and then extracted with DCM (5 mL). The combined organic extractions were washed with water (3×6 mL), then brine (6 mL) and then dried over sodium sulfate and evaporated under vacuum to afford the title compound (123 mg, 48%), which was used without further purification. Method C HPLC-MS: (MH+) requires m/z=225. Found: m/z=252, Rt=1.15 min (97%).
Reaction SMILES: Cl.[CH2:2]1[O:16][C:15]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH2:13])[O:8][C:7]=3[CH:14]=2)[O:3]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:32])[O:29]2)=[CH:24][CH:23]=1.[I-].[Na+]>CN(C=O)C>[CH2:2]1[O:16][C:15]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]5[CH:26]=[CH:27][C:28](=[O:32])[O:29][C:30]=5[CH:31]=4)[O:8][C:7]=3[CH:14]=2)[O:3]1
Reactant: NC[C@H]1COc2cc3c(cc2O1)OCO3
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc5c(cc4O3)OCO5)cc2o1
Temperature: 80 °C
Yield: 16.3 %

Procedure:
(S)-2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine hydrochloride (5.50 g, 22.4 mmole), 7-(3-chloropropoxy)coumarin (5.49 g, 23.0 mmole) diisopropylethylamine (39.0 ml, 224 mmol) and sodium iodide (3.45 g, 23.0 mmole) were combined in 200 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with chloroform. The mixture was treated with an equal volume of saturated aqueous sodium bicarbonate and the aqueous phase was then back-extracted with 3:1 chloroform-isopropanol. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on a silica gel column using dichloromethane as eluant. The product-containing fractions (Rf=0.59 on silica gel tlc with 1:5:95 ammonium hydroxide-methanol-chloroform) were combined and concentrated in vacuum, and the residue redissolved in methanol and acidified with 4N HCl/isopropanol to pH<3 in an ice bath to precipitate a white solid. This was recrystallized from methanol and triturated with a small amount of isopropanol to give 1.50 g of the title compound as an off-white crystalline, solid, monohydrochloride, m.p. 244°-245° C.