Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:27])([F:26])[CH2:24]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:24][C:23]([F:27])([F:26])[F:22]
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 60 °C
Yield: 78.7 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (6.5 g, 22 mmol), in DMF (100 mL), K2CO3 (7.67 g, 55.6 mmol) was added. Trifluoroethyl iodide (13.16 mL, 133 mmol) was added in a drop wise manner to the reaction mixture at RT. The mixture was then heated at 60° C. for 4 h. After completion of reaction, the mixture was poured into water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to give compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)acetate (6.5 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO.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>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Nc1cnc(Br)cn1
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: C1COCCO1
Solvent: CO
Product: Nc1cnc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C

Procedure:
50 mL of 2N sodium carbonate solution and 1.16 g (1.00 mmol) of Pd(PPh3)4 were added to a solution of 8.70 g (174 mmol) of 5-bromopyrazin-2-ylamine and 7.98 g (156 mmol) of 4-chlorophenylboric acid in 150 mL of 1,4-dioxane and 50 mL of MeOH and the mixture was heated to 110° C. for 2.5 hours. The reaction mixture was evaporated down in vacuo and diluted with EtOAc. The organic phase was washed with water, dried over sodium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, DCM→DCM/MeOH 20:1). Yield: 8.30 g (81% of theoretical); C10H8ClN3 (M=205.643); calc.: molpeak (M+H)+:206/208 (Cl); found: molpeak (M+H)+:206/208 (Cl); HPLC-MS: 7.15 minutes (method G).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)=[CH:5][CH:4]=1.[Cl:32]CCl>>[ClH:32].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)=[CH:30][CH:31]=1
Reactant: ClCCl
Agent: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)cc1
Product: Cl

Procedure:
A hydrogen chloride ether saturated solution was added to a solution of 12.0. g (23.2 mmols) of (S)-(−)-5,11-dihydro-5-(1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine in 50 ml of dichloromethane, and the mixture was stirred for 5 minutes. Then, the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of acetone and diethyl ether to give 9.5 g of (S)-(−)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine hydrochloride as a colorless prism crystal in a yield of 73%.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6](=O)([O:12]C(C)(C)C)[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5]
Reactant: C[C@H](N)CO
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-aminopropan-1-ol (1 eq) in THF (0.3 M) at room temperature was added di-tert-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2×), 1:1 saturated aqueous NH4Cl, water and brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was carried onto the next step without further purification.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.O>C1C=CC=CC=1>[CH2:1]([O:8][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([Cl:11])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Clc1cncc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
7.6 g of benzylalcohol was dissolved in 65 ml of benzene, and 2.8 g of 60% sodium hydride was added little by little to the solution under stirring not so as to foam too much at room temperature. After the addition, stirring was continued for 10 min. at room temperature, followed by reflux for 1 hour. Subsequently, the solution was cooled to 50° to 60° C., and added dropwise with a solution of 10 g of 2,6-dichloropyrazine in 65 ml of benzene for 10 min. Then, after reflux for 4 hours, the reaction was finished. After cooling below 10° C., about 100 ml of water was added, and the separated benzene layer was collected. The residue obtained by distilling off the solvent was purified by silica-gel column chromatography (developing solvent: n-hexane and ethyl acetate) to obtain 12.8 g of 2-benzyloxy-6-chloropyrazine as a colourless oil (yield: 86.5%)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25].[Cl-].[NH4+]>C1COCC1.CC(OC)(C)C>[CH2:13]([C:15]([CH2:24][OH:25])([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14]
Reactant: CCCCC(CC)C(=O)OC
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
47 ml (0.334 mol) of diisopropylamine are added dropwise at −20° C. to a solution of 118 ml (0.319 mol) of n-butyllithium (2.7 M in heptane) in 118 ml of THF, and the mixture is stirred at −20° C. for 30 min. Within approx. 15 min, 48 g (0.304 mol) of methyl 2-ethylhexanoate are added dropwise at −20° C., and the mixture is stirred at −20° C. for a further 30 min and subsequently admixed with 18 g (0.60 mol) of paraformaldehyde. After 30 min at −20° C., the mixture is stirred at 0° C. for 2 h. After addition of 100 ml of MTBE and 100 ml of saturated aqueous solution of ammonium chloride, the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1×with 100 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The crude product (97% conversion based on methyl 2-ethylhexanoate) can be purified by distillation to obtain methyl 2-ethyl-2-hydroxymethylhexanoate (b.p.: 100° C., 6 mbar) in 91% yield with a purity of >99%.
Reaction SMILES: [OH-].[Na+].CC(C)=O.Cl.[OH:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ncccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: OCc1ncccc1OCc1ccccc1
Yield: 104.9 %

Procedure:
Sodium hydroxide (31.5 grams, 0.78 mole) was dissolved in 100 ml water and 100 ml of acetone was added followed by 3-hydroxy-2(hydroxymethyl)pyridine hydrochloride (63.8 grams; 0.39 mole). 250 ml of acetone was added followed by benzyl bromide (74.1 grams; 51.5 ml; 0.43 mole). The mixture was refluxed for a period of 4.5 hours and the acetone evaporated in vacuo. The aqueous layer was extracted with CH2Cl2 (three times 150 ml) and the extracts dried (anhydrous Na2SO4) and concentrated to yield 88.1 grams of a brown liquid. The brown liquid (88.1 grams) was dissolved in ether and ether-HCl added to form the hydrochloride salt. The HCl salt was filtered and the filter cake dissolved in water. The aqueous solution was basified to afford a brown pasty precipate which on trituration with ether afforded 58.7 grams of material. Recrystallization from ethanol yielded 31.6 grams of a tan solid, m.p. 79°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 1e (1.81 g, 9.18 mmol), triphenylphosphine (4.83 g, 18.4 mmol), and triethylamine (5.12 mL, 36.7 mmol) in THF (25 mL) at 0° C., hexachloroethane (4.36 g, 18.4 mmol) was added in 2 portions at a 1 min intervals. The resulting pale brown solution was allowed to warm to RT then stirred for 2 h. The resulting yellow suspension was filtered, washing with THF (2×25 mL). The combined organics were purified using SCX-2 cartridge (washed with DCM-MeOH (1:1, 100 mL) and MeOH (50 mL), and then the product was eluted with 2M NH3 in MeOH) to give a pale yellow solid (1.60 g, 97%, contaminated with ˜2.5% Ph3P═O). 1H NMR (400 MHz, CDCl3): 1.53 (6H, d), 3.32 (1H, sept), 7.15 (1H, ddd), 7.75 (1H, ddd), 7.84 (1H, m).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[CH:12]=[C:11](O)[N:10]=[C:9]([NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:3])[N:10]=[C:9]([NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(Nc2nc(N)cc(O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(Nc2nc(N)cc(Cl)n2)cc1
Temperature: 97 °C

Procedure:
1500 ml of phosphorus oxychloride and 300 g of 4-(4-Amino-6-hydroxypyrimidin-2-ylamino)benzonitrile at 27±3° C. were added to the reaction vessel and heated to 97±3° C.; and maintained at same temperature for 7 hrs. After completion of the reaction, ˜50% of phosphorous oxychloride was distilled off under vacuum at 83±2° C. and the reaction mixture was cooled to 30±5° C. In a clean RB flask were added 1000 g of ice and 1000 mL of water and such was slowly added the above obtained reaction mass. The pH of the reaction mass was adjusted to 9.0±0.5 with 50% potassium carbonate solution in water at 5±5° C. The reaction mixture was stirred, filtered and the obtained solid was washed with 600 ml of water and suck dried. The wet solid was charged into a RB flask at 27±3° C. to which was added 600 ml of water. The resulting wet solid was taken into a RB flask and 600 ml of water was added, stirred, and filtered. The obtained solid was washed with water and suck dried. 3000 ml of ethyl acetate was charged into a RB flask and to this was added the obtained solid and heated to 43±3° C. The reaction mass was stirred for 20 mins and filtered hot. The residue was washed with ethyl acetate and filtrate (1) collected at 27±3° C. The obtained solid was again taken in RB flask to which was added 1500 ml of ethyl acetate and heated to 43±3° C., stirred and the hot reaction mass filtered and the filtrate (2) collected. Both filtrates (1) and (2) were taken and distilled off solvent at 47±3° C. To the residue was added 900 ml of heptane and cooled to 27±3° C. and was again added 1100 ml of heptane, stirred, the solid filtered and suck dried, and the solid was washed with heptane. The obtained solid was dried under vacuum. To the obtained 190 g of crude was added 380 ml of dimethyl formamide and 20.4 ml of 1,8-diazabicycloundec-7-ene under stirring at 27±3° C. and the reaction mass heated to 47±3° C. To the obtained clear solution was added 760 ml of water and stirred for 1 hr. The reaction mass was cooled and filtered. The solid was washed with 760 mL of water twice and suck dried. The solid was washed with 48 ml of chilled methanol and the solid suck dried. The obtained solid was further dried under vacuum to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:7]=1.[OH-].[Na+]>O.CCO.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:19][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:9][C:8]2=[O:18]
Reactant: O=C(C=Cc1cccc(Cl)c1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC(c2cccc(Cl)c2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 82 %

Procedure:
1-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl) prop-2-en-1-one (23 g, 68 mmol) was dissolved in H2O (513 mL) and EtOH (171 mL). Then NaOH (2.74 g, 68 mmol) was added. The mixture was stirred overnight and filtered to give a solid cake. The cake was dissolved in EtOAc and washed with H2O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-2-(3-chlorophenyl)chroman-4-one (18.82 g, 82%). 1H-NMR (CDCl3): 2.87 (m, 1H), 3.02 (m, 1H), 5.44 (m, 1H), 6.96 (d, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.58 (m, 1H), 8.02 (d, 1H).
Reaction SMILES: [H-].[Na+].C1COCC1.Cl[CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O)(=O)C.[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)COCc1ccccc1
Temperature: 10 °C
Reaction time: 20 h

Procedure:
80 g of 60% NaH are added in portions to 800 ml of anhydrous THF. The medium is cooled to 10° C. and maintained at this temperature. 500 ml of benzyl alcohol are then introduced dropwise. A solution of 65.8 g of ethyl 4-chloroacetoacetate in 200 ml of benzyl alcohol is then added. The mixture is stirred at room temperature for 20 h. It is neutralized by the slow addition of acetic acid (120 ml) while being cooled with an ice bath. The whole is then poured into a mixture of water and ice and extracted with ether. The organic phase is washed with a solution of sodium bicarbonate, dried over MgSO4 and then concentrated to give an orange oil. The product is purified by two successive distillations to give a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:21]=[CH:20][C:10]3[N:11]=[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C.O>[CH3:33][S:34]([CH:14]([C:12]1[S:13][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:21]=[CH:20][C:10]=2[N:11]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1nc2ccc(-c3ccccc3)cc2s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a solution of ethyl 2-(6-phenylbenzo[d]thiazol-2-yl)acetate (390 mg, 1.3 mmol) (described in WO 2011/074560) in DMF (4 mL) at 0° C. was added DBU (0.49 mL, 3.3 mmol) and the reaction mixture was stirred at rt for 10 min. Methanesulfonyl chloride (0.12 mL, 1.6 mmol) was added dropwise and the mixture stirred for 0.5 h. Additional methanesulfonyl chloride (0.030 mL, 0.40 mmol) was added and the reaction mixture stirred for 10 min. The reaction mixture was diluted with H2O then extracted with EtOAc (3×), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc/hexane to give Compound 89a (360 mg, 73% yield) as yellow powder. RT=2.06 min using analytical method (Q), 376.9 (M+H). 1H NMR (500 MHz, CDCl3) δ 7.88-7.75 (m, 1H), 7.68-7.53 (m, 3H), 7.53-7.34 (m, 5H), 4.42 (qd, J=7.2, 3.0 Hz, 2H), 3.39-3.21 (m, 3H).
Reaction SMILES: O.[OH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a water cooled (25° C.) solution of 10.0 g of (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester in 250 ml of dry methylene chloride is added in one portion 16.0 g of pyridinium chlorochromate, 36.0 g of dried, crushed 4 Å molecular sieves and 4.5 ml of glacial acetic acid. The resulting mixture is stirred at 25° C. for one hour. Twenty-five grams of diatomaceous earth and 500 ml of diethyl ether is added, the suspension is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in diethyl ether and is passed through a short column of silica gel using diethyl ether as the eluant. The first two 500 ml fractions contain the desired aldehyde. The solvent is concentrated in vacuo to give 10.1 g of desired product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH:11]#[C:12][CH3:13]>CN(C)C=O.CN(C)C(N(C)C)=N.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:11]=[C:12]([CH3:13])[O:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(I)c(O)c1
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(C)oc2c1
Temperature: -78 °C
Yield: 69.2 %

Procedure:
A solution of 2-iodo-5-methoxy-phenol (39 g, 156 mmol) in dimethylformamide (300 mL) and N,N,N′,N′-tetramethylguanidine (150 mL) is treated with copper(I) Iodide (1.89 g, 9.82 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.9 g; 2.71 mmol; 1.900 g). The mixture is cooled to −78° C., and propyne (100 g; 2.50 moles) is bubbled through the mixture for 1 hour. The reaction mixture is stirred and allowed to warm to room temperature gradually over 6 hours. After stirred for 2 days, the reaction mixture is quenched with water (800 mL) and extracted with EtOAc (500 mL). The organic layers is dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (eluted with 10% EtOAc/Hexanes) and the appropriate fractions are concentrated. The material is dried in vacuo to afford 6-methoxy-2-methyl-benzofuran (17.5 g, 69%). 1H NMR (400 MHz, CDCl3): δ 7.31-7.29 (d, 1H), 6.95 (s, 1H), 6.81-6.79 (d, 1H), 6.26 (s, 1H), 3.81 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(Cl)(Cl)(Cl)Cl.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][Br:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)c(Br)c1

Procedure:
Methyl 3-bromo-4-methylbenzoate (6.56 g, 28.64 mmol), carbon tetrachloride (100 mL), NBS (6.07 g, 34.10 mmol) and AIBN (150 mg, 0.91 mmol) were heated at reflux for 18 h. The reaction mixture was cooled and diluted with DCM (200 mL) and water (100 ml) and washed with 5% NaHCO3 saturated solution (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure (rotary evaporator) affording an oily residue.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[B:9](OC(C)C)([O:14]C(C)C)[O:10]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[B:9]([OH:14])[OH:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccncc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccncc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a stirring solution of 3-bromo-4-methylpyridine (5.9 g, 34.3 mmol) in toluene (30 mL) and THF (7.5 mL) was added triisopropyl borate (10.3 mL, 44.6 mmol). The resulting mixture was cooled to −78° C. under a nitrogen atmosphere followed by the addition of n-butyllithium (17.83 mL, 44.6 mmol, 2.5 M in hexanes) over a period of 1 hour. The reaction mixture was allowed to stir for an additional 30 min and then the dry ice bath was removed. The reaction mixture was quenched by the addition of 2N HCl (60 mL). Upon reaching room temperature, the resulting yellow solution was transferred to a 500 mL separatory funnel and the layers were separated. The aqueous layer was neutralized to pH 7.0 with sodium hydroxide and then extracted with THF (3×60 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid material was vigorously stirred with acetonitrile and filtered to yield Intermediate 1A (2.2 g, 16.06 mmol, 48.8% yield) as an off-white solid. MS (ES): m/z=138.0 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 8.45 (1 H, s), 8.33 (1 H, d, J=5.77 Hz), 7.50 (1 H, d, J=5.27 Hz), 2.62 (3 H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC(=O)NC)COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCCCCCCCCCCC.C(SCC(OC)CNS(CCC[I:111])(=O)=O)CCCCCCCCCCCCCCC>>[I:111][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC
Agent: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)OC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-2-methylcarbamoyloxy-1-octadecylcarbamoyloxypropane III c2 is allowed to react and worked up by the same procedure as described in (5). m.p. 97°-99° C. The summary of the experimental condition and the physical data of the product are listed in the Table 8.