Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:33][CH2:32]2)[CH2:25][NH:26][CH2:27][CH3:28])[CH:20]=[CH:21][C:22]=1[Cl:23].ClC1C=C([C@H](CCN2CCC(C3C=CC=CC=3[S@](C)=O)CC2)CNC)C=CC=1Cl.ClC(OCC)=O>>[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:35][CH2:36]2)[CH2:25][N:26]([CH2:27][CH3:28])[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:15])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CCNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1
Agent: CCOC(=O)Cl
Agent: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: CCN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12

Procedure:
Using standard acylation conditions, 3-cyano-1-naphthoic acid (0.118 g) was converted to the acid chloride and reacted with N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-ethylamine (0.336 g) (prepared according to methods described for N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine, except ethyl chloroformate was used in place of acetyl chloride for the amine acylation prior to amide reduction). mp 115-118° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d), 8.10 (m), 7.95-7.15 (m), 6.50 (m), 3.60 (s), 3.25-2.95 (m), 2.95-2.40 (m), 2.40-1.70 (m), 1.35 (m), 0.9 (m); MS APCI, m/z=646 (M+).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH2:7]([O:10][C:11]([NH:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=2)(=[O:30])=[O:29])[CH:22]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:12])[CH:8]=[CH2:9]>O1CCOCC1>[CH2:7]([O:10][C:11]([NH:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH:32]=2)(=[O:30])=[O:29])[CH:22]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:12])[CH:8]=[CH2:9]
Reactant: CCCN=C=O
Reactant: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc(N)c2)c1
Solvent: C1COCCO1
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc(NC(=O)NCCC)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
9.6 g of propyl isocyanate were added to a solution of 50 g of enantiopure ethyl 3-{[(allyloxy)-carbonyl]-amino}-3-{{3-{[(3-aminophenyl)-sulfonyl]-amino}-phenyl}}-propanoate from fraction 1 from Example II.2.f in 500 ml of dioxane, and the mixture was stirred for 18 h at 50° C. After evaporation of the solvent, 1.5 L of 1 M hydrochloric acid were added, and the solution was extracted with dichloromethane. The organic phase was dried over magnesium sulphate and concentrated. Chromatography on silica gel (dichloromethane/methanol=30:1) yielded 19.1 g of the compound.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>[Sn](Br)Br.C1OCCOCCOCCOCCOCCOC1>[CH2:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH:12]1[O:14][CH2:13]1
Reactant: ClCC1CO1
Reactant: CC(C)CCCCCO
Agent: Br[Sn]Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Product: CC(C)CCCCCOCC1CO1
Temperature: 130 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
A reactor of the kind described in Example 8 is charged with 130.23 g (1.0 mol) of isooctanol (mixture of isomers), 5.57 g (0.02 mol) of powdered tin dibromide and 5.28 g (0.02 mol) of 18-crown-6 (crown ether) and the charge is heated to 130° C. Then, with efficient stirring, 86.26 ml (1.1 mol) of epichlorohydrin are added over 30 minutes. The reaction is allowed to continue for 12 hours, during which time the temperature rises to about 135° C. The reaction mixture is cooled to 55° C. and then, at this temperature, 88 g (1.1 mol) of a 50% solution of sodium hydroxide are added dropwise with efficient stirring over 30 minutes. After stirring for 2.5 hours at 55°-60° C. and cooling to room temperature, the suspension is filtered and the filtrate is washed with ethyl acetate. The phases are separated, and the aqueous phase is extracted once with 100 ml of ethyl acetate. The combined organic phases are washed with as small an amount of 10% KH2PO4 solution as possible and then with water until neutral, dried over magnesium sulfate and filtered. The filtrate is freed from solvent on a rotary evaporator under vacuum (bath temperature 50° C.). Yield: 181.8 g (98% of theory) of yellowish isooctanol glycidyl ether (mixture of isomers) for which the following analytical values are obtained: epoxy value: 3.69 eq/kg (69% of theory); total chlorine content: 3.31%; hydrolysable chlorine content: 750 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:8]1[CH2:7][CH:6]2[CH2:12][O:13][CH2:14][CH2:15][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 82 mg, 0.362 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.076 mL, 0.434 mmol) and (bromomethyl)benzene (0.047 mL, 0.398 mmol) to give a yellow solution, which was stirred at room temperature for 48 hours. The mixture was subsequently diluted with ethyl acetate and then washed with aqueous saturated NH4Cl (2×5 mL) and brine (2×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an ISCO® silica gel cartridge (4 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (55 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 2.91-3.10 (m, 2H), 3.10-3.22 (m, 1H), 3.32 (s, 1H), 3.40-3.54 (m, 1H), 3.60-3.75 (m, 1H), 3.81-4.01 (m, 2H), 4.15-4.30 (m, 1H), 4.41 (s, 2H), 7.20-7.42 (m, 6H). ESI-MS m/z [M+H]+ calc'd for C16H17ClN4O, 317.11. found 317.3.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5]Cl)=[CH2:2].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]([O:3][CH2:4][CH2:5][C:16]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:10]([NH:11][C:7](=[O:17])[C:8]=12)=[O:12])=[CH2:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=COCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=COCCc1cccc2c1C(=O)NC2=O

Procedure:
2-Vinyloxy Ethyl Phthalimide was prepared via reacting 2-chloroethyl vinyl ether (25 g, 0.24 mol; CAS #110-75-8) and potassium phthalimide (25 g, 0.135 mol; CAS #1074-82-4) in 100° C. N,N-Dimethylformamide (DMF, 75 ml) using tetra n-butyl ammonium bromide (0.5 g; CAS #1643-19-2) as the phase transfer catalyst. This solution was heated for 6 h and then crashed out in water and filtered. This solid was then recrystallized twice from methanol to give white crystals.
Reaction SMILES: [NH2:1][C:2]1([CH2:18][CH2:19][OH:20])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]=[C:31]=[S:32])=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1COCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:2]([NH:1][C:31]([NH:30][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:34][CH:33]=3)=[S:32])([CH2:18][CH2:19][OH:20])[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([I:17])[CH:4]=3)[O:9][C:10]2=[N:11][CH:12]=1
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (0.930 g, 2.080 mmol) in THF (20.80 ml) was added cooled to 0° C. and solid 4-nitrobenzoyl isothiocyanate (0.442 g, 2.122 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was concentrated under reduced pressure to yield N-((3-bromo-5-(2-hydroxyethyl)-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)carbamothioyl)-4-nitrobenzamide as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[N:6][CH:7]=2)[CH2:41]1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: CN(C)[C@H]1CCNC1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CC[C@H](N(C)C)C5)cn3)C4)n[nH]c2c1
Yield: 41.4 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and (S)-3-dimethylaminopyrrolidine, (35 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method C to afford (38 mg, 40%) of the title compound as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([NH:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])=[CH:3][N:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccnnc1
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccnnc1

Procedure:
200 mg. of 4-aminopyridazine was suspended in 50 ml. of acetone. To the resulting suspension, 1.2 times the amount of phenyl isocyanate theoretically calculated was added and the mixture then reacted at room temperature overnight. The crystals formed were taken out by filtration. By recrystallization from an excess of methanol, N-(4-pyridazinyl)-N'-phenylurea was obtained (yield, greater than 80%); melting point higher than 250° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:35]=[CH:36][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:25])[CH2:15][C:16]([CH3:17])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:24])=[CH:6][CH:7]=3)=[CH:38][CH:39]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC(C)(C)c1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CC(C)(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-methyl-3-phenyl-butan-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C(O)(=O)CCCCC(O)=O.[O:11]=[C:12]1[CH2:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:14]([CH3:20])=[CH:13]1>>[CH3:20][C:14]1[CH2:13][C:12](=[O:11])[CH2:19][C:16]([CH3:18])([CH3:17])[CH:15]=1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=C(O)CCCCC(=O)O
Product: CC1=CC(C)(C)CC(=O)C1

Procedure:
After the addition of 38 g. of adipic acid to 553 g. of isophorone, the mixture is heated to boiling at atmospheric pressure. The β-isophorone C formed is distilled off via a rectification attachment. The reflux is controlled such that 11 ml. of β-isophorone/isophorone mixture distill over per hour. The distillate collected after 50 hours (456 g.) consists of 91% β-isophorone and 9% isophorone. The β-isophorone is separated from the isophorone by repeated rectification at 68°-69° C/11 mm Hg. There are obtained 412 g. of pure β-isophorone and 42 g. of isophorone. The conversion of isophorone to β-isophorone comes to 428 g.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])[CH2:2][CH3:3].[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CNOC
Reactant: CCCNc1cc(C(F)(F)F)ccc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCNc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 56.8 %

Procedure:
2-Propylamino-4-(trifluoromethyl)benzoic acid (147 mg, 0.594 mmol) in CH2Cl2 was reacted with N,O-dimethylhydroxy amine (82 mg), NMM (0.2 ml) and DMTMM (222 mg) at room temperature overnight. The reaction mixture was quenched by adding H2O (3 ml). The reaction solvent was removed under reduced pressure. Water (30 ml) was added to the resulting residue, which was extracted with ethylacetate (30 ml×3). The combined organic layer was washed with sat. NaHCO3 solution (30 ml), 1N HCl aqueous solution (30 ml) and brine (30 ml), and then dried over MgSO4. The filterate was concentrated in vacuo. The residue was purified with column chromatography to yield the title compound (98 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.CCCCCC.[F:20][CH2:21][C:22](OCC)=[O:23]>C1COCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:22](=[O:23])[CH2:21][F:20]
Reactant: Fc1ccccc1F
Reactant: CCOC(=O)CF
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CF)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a cooled (−78° C.) solution of 1,2-difluorobenzene (8.81 mL, 89 mmol) in THF (175 mL) was added dropwise butyllithium solution, 1.6M in hexane (61.5 mL, 98 mmol). After stirred for 2 h, ethyl fluoroacetate (8.64 mL, 89 mmol) ethyl fluoroacetate was added dropwise. The reaction was stirred for 1 h, the reaction was quenched with saturated NH4Cl and then warmed to room temperature. The resulted mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-30% EtOAc/hexane) to afford 6.3 g of desired product as colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:12][O-:13].[Na+]>CO>[F:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([CH2:2][O:13][CH3:12])[CH:10]=1
Reactant: N#Cc1ccc(F)cc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(F)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
A solution of 2-(bromomethyl)-4-fluorobenzonitrile (501 mg, 2.3 mmol) in methanol (5 mL) was treated with sodium methoxide (5.6 mL of 0.5 M solution in methanol, 2.81 mmol) and stirred for 1 hour at room temperature then heated to 55° C. for 2 hours. The mixture was cooled to room temperature, condensed to dryness and directly purified by normal phase flash column chromatography on a 20 g silica gel column (5-60% ethyl acetate/hexanes gradient). Pure fractions were pooled and concentrated in vacuo to yield 4-fluoro-2-(methoxymethyl)benzonitrile (110 mg, 0.66 mmol, 28% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (dd, J=8.46, 5.50 Hz, 1H), 7.46 (dd, J=9.53, 2.55 Hz, 1H), 7.39 (td, J=8.59, 2.69 Hz, 1H), 4.58 (s, 2H), 3.37 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)(Cl)=O.CCOCC.C(O)C.[NH3:22]>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH2:22])[CH:5]=[N:4][CH:3]=1
Reactant: N
Reactant: OCc1cncc(Br)c1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: NCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
3-Bromo-5-hydroxymethylpyridine (1.1 g, 5.8 mmol) was added to thionyl chloride (5 mL) at 0° C. under nitrogen over 5 min. The solution was stirred at room temperature for 1 h, re-cooled to 0° C., and dry ether (40 mL) was added. The resulting solid was filtered off, washed with ether and added to a stirred solution of ammonia (28%, 30 mL) and ethyl alcohol (40 mL) at 0° C. The solution was then stirred at room temperature for 20 h. The solvent was removed by rotary evaporation and the crude material partitioned between sodium hydroxide (2N, 30 mL) and dichloromethane (60 mL). The organic layer was dried (Na2SO4), the solvent removed by rotary evaporation and the residue purified by flash chromatography, using CHCl3: ethanol: concentrated aqueous ammonia solution (100:6:1) as eluent, to afford (5-bromo-3-pyridyl)methylamine (785 mg, 72% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([C:24]1[CH:25]=[CH:26][C:27]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:29]=1)=[CH:18][C:19]([O:21]CC)=[O:20])[CH:2]([CH3:4])[CH3:3].[H][H].[OH-].[Na+].Cl>C(O)C.[C].[Pd].O.C(Cl)(Cl)Cl>[C:32]([CH2:31][CH2:30][C:28]1[CH:29]=[C:24]([CH:17]([C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:18][C:19]([OH:21])=[O:20])[CH:25]=[CH:26][C:27]=1[O:35][CH2:36][CH:37]([CH3:38])[CH3:39])([OH:34])=[O:33]
Reactant: [H][H]
Reactant: CCOC(=O)C=C(c1ccc(OCC(C)C)c(CCC(=O)O)c1)c1ccc(OCC(C)C)cc1OCC(C)C
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)COc1ccc(C(CC(=O)O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
In 6 ml of ethanol is dissolved 0.60 g of 3-{5-[1-(2,4-diisobutoxyphenyl)-3-ethoxy-3-oxo-1-propenyl]-2-isobutoxyphenyl}propanoic acid. After adding 0.12 g of 5% palladium-carbon, the mixture is stirred at ambient temperature for one hour in a stream of hydrogen. The reaction mixture is filtered with Celite, and the solvent is distilled off from the filtrate under a reduced pressure to obtain a crude product. The crude product is dissolved in 4 ml of ethanol, 0.7 ml of 5 mol/L sodium hydroxide is added, and the mixture thus obtained is stirred at ambient temperature for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.53 g of 3-[3-(2-carboxyethyl)-4-isobutoxyphenyl]-3-(2,4-diisobutoxyphenyl)propanoic acid is obtained as a white foaming product.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:19]([O:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC(Cn1ccnc1)c1ccc2ccccc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(OC(Cn1ccnc1)c1ccc2ccccc2c1)c1ccccc1

Procedure:
A solution of 1.19 g. 1-[2-hydroxy-2-(2-naphthyl)ethyl]imidazole in 20 ml. of pyridine is treated dropwise with stirring with 0.72 ml. of benzoyl chloride and the mixture stirred overnight. The resulting solution is poured into 100 ml. water, extracted with ethyl acetate and the extracts washed, dried (MgSO4) and evaporated in vacuo to remove residual pyridine and afford 1-[2-benzoyloxy-2(2-naphthyl)ethyl]imidazole. The residue is dissolved in ether, treated with ethereal hydrogen chloride and the resulting precipitate recrystallized from acetone/methanol to give 1.3 g. of hydrochloride salt, m.p. 219°-219.5° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](OC)=[O:25].[H-].[Na+]>C(OCC)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[CH:24][OH:25])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1OCCCCOc1ccccc1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C(=CO)c1ccccc1OCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.3 %

Procedure:
A mixture of 30 g (0.10 mole) of methyl 2-(4-phenoxybut-1-yloxy)-phenylacetate, 12.5 g (0.21 mole) of methyl formate and 100 ml of diethyl ether is added dropwise at room temperature to a suspension of 3.4 g (0.14 mole) of sodium hydride in 50 ml of diethyl ether. The mixture is stirred for 12 hours at room temperature and is then hydrolyzed by adding ice. The aqueous, alkaline phase is extracted with diethyl ether, acidified with dilute HCl and again extracted by shaking with diethyl ether. After the organic phase has been evaporated down, 21 g (71%) of methyl alpha-[2-(4-phenoxybut-1-yloxy)-phenyl]-β-hydroxyacrylate are obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42](C)=[CH2:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:53].[Na+].CC(=O)OCC>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:42]([C:39]1[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]([N:13]2[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]4[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=4[C:30]4[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=4)[CH2:49][CH2:50]2)=[C:11]([C@H:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:40]=1[CH3:41])(=[O:53])[CH3:43]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(prop-1-en-2-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (45 mg, 0.064 mmol, 1 equiv) was dissolved in dioxane (1934 μl) and water (645 μl). To this solution was added sodium periodate (444 mg, 2.076 mmol, 3.5 equiv) and 4% osmium tetraoxide (372 μl, 0.030 mmol, 0.05 equiv). The mixture was stirred at r.t. for 2 hours. Yellow solid was observed in the meantime. To the mixture was added water (20 mL) and EA (20 mL). The aqueous layer was separated. the organic layer was washed by brine, dried over MgSO4, filtered and concentrated to give a yellow oil, which is used as is for the next reaction. LCMS (ESI, M+1): 700.3.