Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[S:24]1(=[O:33])(=[O:32])[CH2:30][CH2:29][NH:28][C:27](=[O:31])[CH2:26][NH:25]1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na][Na]>N1C=CC=CC=1.[Cu-]=O.C(Cl)(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:25]3[CH2:26][C:27](=[O:31])[NH:28][CH2:29][CH2:30][S:24]3(=[O:33])=[O:32])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C1CNS(=O)(=O)CCN1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Agent: O=[Cu-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na][Na]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)(=O)CCN1
Temperature: 115 °C

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-7-carboxamide (0.99 g, 2.66 mmol), 1,2,5-thiadiazepan-4-one 1,1-dioxide from step 2 (0.41 g, 2.5 mmol) and copper (I) oxide (0.18 g, 1.25 mmol) in pyridine (13 mL) was heated in an oil bath at 115° C. overnight. The resultant mixture was treated with a mixture of chloroform (200 mL) and a saturated aqueous solution of ethylenediamine tetraacetic acid, disodium salt (200 mL) and stirred vigorously at room temp overnight in the presence of air. The slurry was filtered through a pad of Celite. The organic extract was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[CH3:13][O:14][C:15](=[O:19])[CH:16](Br)[CH3:17]>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([C:8]([CH:16]([CH3:17])[C:15]([O:14][CH3:13])=[O:19])=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)Br
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)C(C)C1=CCc2cc(OC)ccc21
Temperature: 25 °C
Yield: 44.8 %

Procedure:
In an oven dried 3-neck 5.0 L flask fitted with a condenser, a thermometer, and an addition funnel was charged under argon, 5-methoxy-1-indanone (86.73 g, 0.52 mol) and THF (2.13 L). The mixture was stirred at rt and became an orange-colored solution. To this were added zinc granules (59.96 g, 0.92 mol, 30 mesh). The mixture was heated to ˜50° C. with simultaneous addition of a solution of methyl-2-bromopropionate (88.80 g, 0.79 mol) in THF (393 mL). The reaction mixture was heated for a period of 20 h, after which heating was stopped and the reaction mixture cooled to rt followed by cooling on an ice bath. The mixture was then slowly quenched with HCl (3.3 L, 1 N aqueous solution) maintaining the internal temperature at ˜18° C. The aqueous layer was extracted with EtOAc (3×500 mL). The organic layer was then washed with water (4×500 mL, a pH of ˜4.5 achieved), brine (500 mL), and dried over Na2SO4. The solvent was removed under vacuum to give a dark brown colored oil. The crude product was purified by silica gel chromatography (1-8% EtOAc/hexane gradient) to give 54.09 g (52%) of the title compound as a dark brown oil. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (1H, d), 7.09 (1H, s), 6.87 (1H, dd), 6.24 (1H, s), 3.82 (1H, q), 3.75 (3H, s), 3.58 (3H, s), 3.30 (2H, s), 1.21 (3H, d); LC-MS: RT=3.00 min, (M+H)+:233.0.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7].[C:17]1([NH:23][OH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:26]Cl>>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[C:6]([NH:9][C:10](=[O:11])[N:23]([O:24][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(N=C=O)c1cccc(C(F)(F)F)c1
Reactant: ONc1ccccc1
Reactant: ClCCl
Product: CON(C(=O)NC(C)(C)c1cccc(C(F)(F)F)c1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2.2 g of m-trifluoromethyl-α,α-dimethylbenzyl isocyanate in 10 ml of dichloromethane was added dropwise to a solution of 1.1 g of N-phenylhydroxylamine in 10 ml of dichloromethane over a period of 10 minutes. After completion of the addition, the mixture was stirred for 30 minutes and the solvent was removed by distillation. The resulting white crystals were dried well and dissolved in 10 ml of a methanolic solution of 600 mg of sodium methoxide. 2.0 g of methyl iodide was added to the solution and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated and extracted with water and benzene. The benzene layer was washed successively with 2N aqueous sodium hydroxide and water and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the resulting crystals were then recrystallized from a mixture of benzene and hexane to obtain 2.4 g of the title compound.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.CN(C)C=O.[NH2-].[Na+].[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>O>[N+:17]([C:13]1[CH:12]=[C:11]([N:10]2[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3](=[O:20])[N:31]([CH2:28][CH2:29][CH3:30])[C:32]2=[O:33])[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: CCCN=C=O
Reactant: COC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 2.9 g of 2-(m-nitroanilino)benzoic acid methyl ester and 20ml of dry dimethylformamide was added 0.43 g of sodium amide, and the whole was stirred for 30 minutes. To this was added dropwise under cooling 2.6 g of propyl isocyanate. This mixture was allowed to stand for one hour at room temperature and for additional one hour at 60° C, and then reacted for 4 hours at 120° C. The solvent was distilled off from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to produce 2.4 g of 1-(m-nitrophenyl)-3-propylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#N)[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1.[OH-:16].[Na+].C[OH:19]>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([OH:19])=[O:16])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1cc(Cl)cc2cn(C3CC3)nc12
Reactant: CO
Agent: [Na+]
Product: O=C(O)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 110 °C

Procedure:
A microwave tube was charged 5-chloro-2-cyclopropyl-2H-indazole-7-carbonitrile (0.54 g, 2.5 mmol), methanol (8.0 mL) and a 4 N sodium hydroxide solution (5 mL, 20 mmol). The tube was sealed and heated at 110° C. for 3 h via microwave. After cooling to room temperature, the mixture was concentrated in vacuo to remove most of the methanol. The residue was poured into water/ethyl acetate. The product was extracted with water (2×) and the organics discarded. The aqueous layers were pooled together and acidified to pH 2.0 with 1 N hydrochloric acid. The resulting precipitate was filtered and dried in vacuo for several hours to afford 0.47 g (80%) as a white powder. 1H-NMR (CD3OD, 300 MHz) δ 8.40 (s, 1H), 7.94-7.95 (m, 2H), 4.08-4.14 (m, 1H), 1.37-1.42 (m, 2H), 1.21-1.23 (m, 2H). Mass spec.: 237.16 (MH)+.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH:9]1([CH2:12][O:13][C:14]2[CH:22]=[C:21]([CH2:23][C:24]3[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)[CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:32][CH3:33])[CH2:11][CH2:10]1>C(O)(=O)C.O>[CH:9]1([CH2:12][O:13][C:14]2[CH:22]=[C:21]([CH2:23][C:24]3[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)[CH:20]=[C:19]3[C:15]=2[C:16]([CH2:1][N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[CH:17][N:18]3[CH2:32][CH3:33])[CH2:11][CH2:10]1
Reactant: CCn1ccc2c(OCC3CC3)cc(Cc3cnc(N)nc3N)cc21
Reactant: C1COCCN1
Reactant: C=O
Solvent: O
Solvent: CC(=O)O
Product: CCn1cc(CN2CCOCC2)c2c(OCC3CC3)cc(Cc3cnc(N)nc3N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Formaldehyde (35% aqueous solution, 41 μL, 0.48 mmol) was added at room temperature to a solution of morpholine (142 mg, 1.60 mmol) in acetic acid (1.6 mL) and water (0.2 mL). After 10 min 5-(4-cyclopropylmethoxy-1-ethyl-1H-indol-6-ylmethyl)-pyrimidine-2,4-diamine (Example 7a; 134 mg, 0.40 mmol) was added, then after 45 min the solution was concentrated. 1M aqueous sodium hydroxide solution (10 mL) was added to the viscous residue, then the suspension formed was stirred at room temperature for 1 h, the solvent was removed and the gummy precipitate washed with water and dried to afford the title compound (121 mg, 69%). Off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[CH:4][C:3]=1[S:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15][C:14]=1[Cl:32].Cl[Sn]Cl>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[CH:4][C:3]=1[S:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]2)=[O:22])=[CH:15][C:14]=1[Cl:32]
Reactant: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cc(N)c([N+](=O)[O-])cc3Cl)c(Cl)c2)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3cc(N)c(N)cc3Cl)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a stirred solution of nitrobenzene from Example 144A (170 mg, 0.34 mmol) in 2 mL of EtOH was added SnCl2 (325 mg, 1.72 mmol). The mixture was then refluxed under nitrogen atmosphere for 2 hours. The reaction was allowed to cool to ambient temperature, quenched with sat. NaHCO3, extracted with EtOAc(2×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was then purified on Gilson preparative HPLC as described in Example 38B to give the title compound (70 mg, 44% yield) as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.04 (s, 3H), 3.42-3.80 (m, 8H), 4.84 (s, 2H), 5.32 (s, 2H), 6.51 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 7.26 (d, J=15.6 Hz, 1H), 7.41 (d, J=15.6 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H). MS (APCI+) (M+H)+ at m/z 465, 467, 469, 471.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:18][CH3:19])[CH2:15][O:14]C(C)(C)[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO>[CH2:1]([O:8][CH2:9][C:10]([CH2:15][OH:14])([CH2:18][CH3:19])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1(COCc2ccccc2)COC(C)(C)OC1
Solvent: CO
Solvent: O
Product: CCC(CO)(CO)COCc1ccccc1
Reaction time: 3 h

Procedure:
5-Benzyloxymethyl-2,2-dimethyl-5-ethyl-1,3-dioxane (15.0 g.) and Dowex 50×8-200 ion exchange resin (H+ form) (2.0 g.) in methanol (250ml.) containing water (50 ml.) was refluxed, with stirring, for three hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Benzyloxymethyl-2-hydroxymethyl-butan-1-ol was obtained as a yellow oil (9.7 g.).
Reaction SMILES: C(O[C:4](=[O:36])[C@:5]([O:11][CH2:12][C@@:13]([C:28]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=1[F:35])([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37]>CO>[Br:34][C:32]1[CH:31]=[CH:30][C:29]([F:35])=[C:28]([C@:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:8])([F:7])[F:9])[C:4]([NH2:37])=[O:36])[CH:33]=1
Reactant: CCOC(=O)[C@@](C)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Reactant: N
Solvent: CO
Product: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F

Procedure:
A solution of (R)-2-[(R)-2-(5-bromo-2-fluoro-phenyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (26.6 g, 44.2 mmol) in 7N NH3 in MeOH (75 ml) was stirred for 16 h at 50° C. The solvent was removed under reduced pressure and the residual solid re-crystallized from Et2O to give the title compound as yellow crystals: TLC (hexane-EtOAc 1:1): Rf=0.35; HPLC RtH5=1.184 min; ESIMS: 589, 591 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.85 (d, 1H), 7.64 (m, 3H), 7.44 (d, 1H), 7.41 (dd, 1H), 7.26 (m, 1H), 6.68 (br s, 1H), 6.57 (dd, 1H), 6.19 (s, 1H), 5.54 (br s, 1H), 4.24 (d, 1H), 3.93 (d, 1H), 1.79 (s, 3H), 1.67 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:4]=1[NH2:5].[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1.CCOCC>[CH3:13][O:12][C:6]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[C:4]=1[N:5]=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)c(N)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cc(OC)c(N=C=O)c(OC)c1
Reaction time: 3 h

Procedure:
A suspension of 2,4,6-trimethoxyaniline (71 g, 0.324 mol) in a 12.5% wt/wt solution (540 mL) of phosgene in toluene was heated on a steam bath with periodic swirling for 3 hours. Additional phosgene in toluene solution (2×270 mL) was added after 1 and hours. The suspension was allowed to cool, placed under house vacuum, and stirred for 2.5 days. The mixture was rotoevaporated to a dark purple solid. The residue was dissolved in ether (450 mL), filtered, rotoevaporated, and dried in vacuo to give a purple amorphous solid; yield 66.9 g (98.7%), mp 67°-70° C.
Reaction SMILES: C1CO[C:3]2([CH2:12][CH2:11][C@H:10]3[C@:5]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=4)([CH2:6][CH2:7][N:8]([CH3:14])[C:9]3=[O:13])[CH2:4]2)[O:2]1.CCOCC.[Na+].[Cl-].C(OCC1C(=O)N(C)CCC=1C1C=CC=C(OC)C=1)=O>C1COCC1>[O:13]=[C:9]1[C@@H:10]2[C@@:5]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)([CH2:4][C:3](=[O:2])[CH2:12][CH2:11]2)[CH2:6][CH2:7][N:8]1[CH3:14]
Reactant: COc1cccc([C@]23CCN(C)C(=O)[C@H]2CCC2(C3)OCCO2)c1
Agent: COc1cccc(C2=C(COC=O)C(=O)N(C)CC2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc([C@]23CCN(C)C(=O)[C@H]2CCC(=O)C3)c1
Reaction time: 60 h

Procedure:
Ketal cis-34 (Example 16) (20 mg, 0.06 mmol) was dissolved in 1:1 THF/1 N H2SO4 (2 mL) and stirred for 60 h. Ether (2 mL) and saturated NaCl (1 mL) were added, the aqueous phase washed with ether (1 mL), and the combined organic phases washed with saturated NaCl (2 mL), dried, and evaporated to yield 17 mg (99%) of pure cis-9: NMR δ 7.30 (t,J=9 Hz, 1H), 6.9 (m, 3H), 3.78 (s, 3H), 7.87 (s, 3H), 2.63 (s, 2H); IR 1712, 1634, 1603, 1580 cm-1 ; mass spectrum m/e (rel intensity) 287 (32), 218 (26), 55 (100). Anal. Calcd for C17H21NO3 : C, 71.0; H, 7.4; N, 4.9. Found: C, 71.0, H, 7.4; N, 4.9.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.C[Si]([C:17]#[CH:18])(C)C>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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1)#[CH:18]
Reactant: Cc1ccc(Br)c2ccccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
6 g of 1-bromo-4-methylnaphthalene, 0.11 g of dichlorobis(triphenylphosphine)palladium, 0.17 g of triphenylphosphine, 0.19 g of copper iodide, and 3.1 g of trimethylsilylacetylene were added to 60 ml of triethylamine, and the mixture was allowed to react at 90° C. for 16 hours. After evaporation of the solvent by an evaporator, the compounds obtained were extracted with added ethyl ether. The ethyl ether layer was washed thrice with 300 ml of distilled water, dried over anhydrous magnesium sulfate for 24 hours, and filtered, and after removal of the solvent in the filtrate by vaporization, the residue was purified by column chromatography, by using hexane as the developing solvent. 30 ml of diethylene glycol and 4.4 g of potassium hydroxide were added to the compound obtained, and the mixture was stirred at room temperature for 3 hours. The compounds generated were extracted with added ethyl ether. The ethyl ether layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate for 24 hours and filtered, and the solvent in the filtrate was evaporated. The residue was purified by column chromatography by using methylene chloride/hexane (1/4) as the developing solvent, to give 1.6 g of 1-ethynyl-4-methylnaphthalene.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[CH3:19]O>Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Yield: 95.1 %

Procedure:
Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (6.2 g, 23.1 mmol) in hot methanolic solution of anhydrous hydrogen chloride (42 mL of a methanol containing 3.2 g of anhydrous hydrogen chloride). Reflux for 42 minutes, evaporate the solvent invacuo, dissolve the residue in methylene chloride and wash with water. Dry (MgSO4), filter through silica gel, washing the gel with methylene chloride. Combine the organic washings and evaporate the solvent in vacuo to give the title compound as a clear oil (6.21 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:26][CH2:27][CH:28]1[CH2:30][CH2:29]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: O=C(O)c1cccc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC1CC1)c1cccc(Cl)n1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
6-Chloropyridine-2-carboxylic acid (5.00 g, 31.7 mmol) was dissolved in DCM (100 mL) and DMF (0.5 mL) and oxalyl chloride (6.54 mL, 76.2 mmol) were added dropwise. The reaction mixture was stirred for 2 h, concentrated in vacuo and azeotroped with DCM. The residue was dissolved in DCM (100 mL), DIPEA (22.6 mL, 127 mmol) and aminomethylcyclopropane (5.51 mL, 63.5 mmol) were added dropwise and the reaction mixture was stirred for 4 h. The reaction mixture was washed with sat aq NaHCO3 solution (250 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (6.50 g, 97%) as a light brown gum. LCMS (ES+): 211.2 [MH]+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH2:11][CH:12]([CH3:28])[CH2:13][C@@H:14]1[CH2:18][N:17]([C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1>C(Cl)Cl>[F:7][CH2:11][CH:12]([CH3:28])[CH2:13][C@@H:14]1[CH2:18][N:17]([C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1
Reactant: CC(CO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(CF)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: -78 °C
Yield: 37 %

Procedure:
To DAST (1 g, 6.2 mmol) in CH2Cl2 (20 mL) at −78° C. was added the alcohol 37 in CH2Cl2 (10 mL). After 1 hour at −78° C. the solution was warmed to room temperature. After 7 hours the solution was carefully quenched with a saturated aqueous solution of sodium bicarbonate and the two layers separated. The organic phase was dried (MgSO4) and concentrated. Flash chromatography (90% to 66% hexane/acetone) of the residue gave the product as an oil (600 mg, 37%). MS m/z 264 (M+H, 100%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1.C(#N)C>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A solution of 35.3 grams of 1-hexadecyl-sn-glycerol, 37.3 grams of triphenylchloromethane and 22.44 grams of dry triethylamine in a mixture of 470 ml dry tetrahydrofuran and 120 ml dry acetonitrile was refluxed for 15 hours under a nitrogen atmosphere. After cooling to room temperature the reaction mixture was filtered. The filtrate poured on ice (500 grams) and then extracted thrice with 200 ml chloroform. The organic phase was washed successively with 500 ml water, 500 ml of 0.15 N HCl, 500 ml saturated aqueous NaHCO3, and again with water. The extract was dried over Na2SO4 and the solvent was removed under reduced pressure. The obtained yellow residue was dissolved in 500 ml warm hexane and the obtained clear solution was refrigerated (5±3° C.) overnight. During this time, precipitation occurred. After filtration of the precipitate, the solvent from the filtrate was removed under reduced pressure, yielding 58.3 grams of 1-hexadecyl-3-trityl-sn-glycerol. The yield was 95%.
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].CCO>C1(C)C=CC=CC=1.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>[CH2:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: N#Cc1ccccc1B1OCCCO1
Reactant: CCCCCCc1ccc(N)c(Br)c1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc2nc(N)c3ccccc3c2c1
Yield: 39.8 %

Procedure:
13.1 g (69.8 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 16.3 g (63.4 mmol) 2-bromo-4-hexylaniline, 1.62 g (1.40 mmol) tetrakis(triphenylphosphine)palladium(0), and 23.6 g (171 mmol) potassium carbonate where refluxed in 250 ml toluene and 100 ml EtOH under N2 atmosphere for 20 hours. HPLC and TLC revealed almost complete consumption of the aniline. The reaction mixture was cooled and passed through a filter. The solids were washed with ethyl acetate to remove organics from the collected base. The filtrate was then evaporated down and dried on silica. The sample was purified using silica gel chromatography with 100% ethyl acetate as the eluent. The product fractions were then evaporated down to a minimal amount and hexanes added to crystallize the product as off white solids (7.05 g, 39.8% yield, GC-MS confirmed).