Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][C:33]#[CH:34]>C1(C)C=CC=CC=1.C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][Cl:29])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: C#CCCCCl
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
Ethyl 6-chloro-8-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 73, Step 2) (1.50 g, 3.47 mmol), tetrakis-(triphenylphosphine)palladium(0) (0.2 g, 0.174 mmol), copper(I)iodide (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4 mmol) were dissolved in toluene (50 mL). 5-Chloro-1-pentyne (0.53 g, 5.20 mmol) was added via syringe and the mixture stirred for 18 hours at room temperature. The reaction was diluted with diethyl ether (50 mL), extracted with 0.5 N HCl (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield an orange oil. The crude material was purified by flash chromatography in 2% ethyl acetate in hexane. Recrystallization from hexane afforded the ester as a white solid (0.96 g, 68%): mp 84.8–85.9° C. 1H NMR (CDCl3/300 MHz) 7.61 (s, 1H), 7.33 (d, 1H, J=2.6 Hz), 7.14 (d, 1H, J=2.6 Hz), 5.79 (q, 1H, J=6.7 Hz), 4.37–4.29 (m, 2H), 3.75 (t, 2H, J=6.7 Hz), 2.67 (t, 2H, J=6.7 Hz), 2.11–2.03 (m, 2H,), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 424.1 (M+NH4+). ESHRMS m/z 424.0694 (M+NH4+, Calc'd. 424.0694). Anal. Calc'd. for C18H15Cl2F3O3: C, 53.09; H, 3.71;, Cl, 17.41. Found: C, 53.02; H, 3.90; Cl, 17.63.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1Cl)(=[O:5])=[O:4].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1C1C2C(=CC=CC=2)C=C(C)C=1O>>[F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:25]1[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][C:26]=1[Cl:28])(=[O:5])=[O:4]
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1O
Reactant: Cc1cc2ccccc2c(Cl)c1OS(=O)(=O)C(F)(F)F
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1OS(=O)(=O)C(F)(F)F

Procedure:
1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yl trifluoromethanesulfonate was prepared in a similar manner as compound 4C in Example 2, except starting from 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-ol instead of 4B. 1H-NMR: 400 MHz, (CDCl3) δ: 7.85-7.90 (m, 2H), 7.62 (d, 1H), 7.55 (app dt, 1H), 7.41-7.48 (m, 2H), 7.32-7.49 (m, 2H), 2.64 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:17]=[C:16]([O:31][CH3:32])[N:15]=2)[CH:9]=1)C.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][NH:20][C:18]1[N:17]=[C:16]([O:31][CH3:32])[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:7]([NH:6][CH2:5][C:4]([OH:34])=[O:3])=[O:33])[CH:19]=1
Reactant: CCOC(=O)CNC(=O)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(=O)NCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
A mixture of (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoylamino)-acetic acid ethyl ester [120 mg, 0.24 mmol, Example 58], lithium hydroxide (20 mg, 0.48 mmol) in THF (1 mL), MeOH (1 mL) and water (1 mL) is stirred for 20 hours at ambient temperature. The mixture is acidified to pH 1 with 10% hydrochloric acid and extracted three times with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoylamino)-acetic acid [49 mg, 43%, Example 59]. LCMS: RT=2.77 minutes, MS: 475 (M+H). IC50=0.8 nM
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[N:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: COc1cncc(B(O)O)c1
Product: COc1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 2 tR=1.694 min, m/z=465.2; 1H NMR (CDCl3) 1.34 (m, 1H), 1.53 (m, 3H), 1.68 (m, 1H), 1.94 (m, 3H), 2.18-2.32 (m, 3H), 2.95 (m, 1H), 3.56 (m, 2H), 3.88 (s, 3H), 5.69 (m, 1H), 7.01 (m, 4H), 7.24 (m, 3H), 7.31 (m, 2H), 8.25 (m, 1H), 8.34 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@@H:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C@@H:30]([OH:31])[CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCc1ccc(OC[C@@H]2CO2)cc1
Product: CCc1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 207 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=137-138° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, 1H, J=7.8 Hz), 7.82-7.78 (m, 2H), 7.57 (dt, 1H, J=2.0, 6.8 Hz), 7.10 (d, 2H, J=5.6 Hz), 6.85 (d, 2H, J=8.2 Hz), 4.86 (bs, 1H), 4.03-3.80 (m, 3H), 3.07 (s, 2H), 2.88-2.74 (m, 2H), 2.58-2.41 (m, 2H), 2.02-1.94 (m, 2H), 1.88-1.78 (m, 2H), 1.14 (t, J=7.9 Hz, 3H). LCMS: 480 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])([O-:3])=[O:2].[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)=[O:17].[H-].[Na+].Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][N:21]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=2)[CH:22]=1)=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Reactant: COC(=O)c1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(-c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred, 0° C. solution of 1,2-dinitro-4-fluorobenzene (325 mg, 1.74 mmole) and methyl-4-imidazolecarboxylate (200 mg, 1.59 mmole) in THF (5 mL) was added NaH (70 mg, 1.74 mmole) in one portion. The resulting mixture was stirred at 0° C. for 3 hours, then diluted with toluene and acidified with 6N HCl. The phases were separated and the aqueous phase washed with toluene, cooled to 0° C., and basified with conc. NH4OH. Ethyl acetate was added and the resulting mixture stirred until all solids dissolved. Phases separated, organic phase washed with brine, dried over Na2SO4, filtered, concentrated in vacuo. The mixture of regioisomers were separated and purified via flash chromatography (silica gel, 5%→>20% ethanol/ethyl acetate gradient) to fford the desired adduct 19 (225 mg, 48%) as an off-white solid. 1H NMR (500 MHz, dmso d6): 8.41 (1H, d); 8.13 (1H, d); 7.5 (1H, broad s); 7.28 (1H, s); 7.02 (1H, d); 3.80 (3H, s)
Reaction SMILES: [CH2:1]([Si:9]([CH3:14])([CH3:13])N(C)C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:15][C:16]([F:27])([F:26])[C:17]([O:19]C(=O)C(F)(F)F)=[O:18]>>[F:15][C:16]([F:27])([F:26])[C:17]([O:19][Si:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH3:14])[CH3:13])=[O:18]
Reactant: CCCCCCCC[Si](C)(C)N(C)C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCC[Si](C)(C)OC(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing octyldimethyl(dimethylamino)silane as the silicon compound B and trifluoroacetic anhydride as the acid B, the trifluoroacetic anhydride is rapidly reacted to form octyldimethylsilyl trifluoroacetate as the acid A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [Pd]
Solvent: CO
Product: Nc1cc(O)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitrophenol (2.67 g, 15.4 mmol) in methanol (30 ml) is stirred for 24 h under a hydrogen atmosphere in the presence of a catalytic amount of Pd/C. After this time, the reaction mixture is filtered through Celite and then concentrated. It is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1)#[N:10].[F:19][C:20]([F:25])([F:24])[C:21](N)=[NH:22]>CO>[F:19][C:20]([F:25])([F:24])[C:21](=[N:18][NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)[NH2:22]
Reactant: N=C(N)C(F)(F)F
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NN=C(N)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Triethylamine (1.54 mL, 11 mmol) and then 4-cyanophenylhydrazine hydrochloride (1.71 g, 10 mmol) were added to a solution of trifluoroacetoamidine (1.57 g, 14 mmol) in methanol (10 mL). The mixture was stirred overnight. The solvent was removed under reduced pressure. 20 mL of water and 50 mL of ethyl acetate-tetrahydrofuran (9:1) were added to the residue and the organic layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate-tetrahydrofuran (9:1). A combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was isolated by filtartion, washed with diisopropyl ether-hexane, and dried in vacuo to give 2,2,2-trifluoro-N′-(4-cyanophenyl)ethanehydrazonamide (2.07 g, 90.5% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[CH:19]([OH:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
Ethyl 4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate (680 mg) is reduced using NaBH4 (60 mg) in ethanol (10 ml) to yield ethyl 4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-hydroxypentanoate
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH2:38]([C@H:35]1[CH2:36][CH2:37][C@H:32]([C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH2:33][CH2:34]1)[CH:39]=[CH:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 5.1 g of propyl-triphenylphosphonium bromide in 80 ml of t-butyl methyl ether was treated within 5 minutes with 1.48 g of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred at room temperature for a further 60 minutes. Thereafter, the mixture was treated with 5 minutes at 0° C. with a solution of 2.0 g of [trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde in 25 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 45 minutes at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The residue was dissolved in 20 ml of ethyl acetate and the solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the yellowish, oily residue (3.33 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 2.1 g of p-[trans-4-(2-pentenyl)cyclohexyl]benzonitrile as a colourless oil containing 92.7% of p-[trans-2-(2Z-pentenyl)cyclohexyl]benzonitrile and 6.6% of p-[trans-4-(2E-pentenyl)cyclohexyl]benzonitrile. The material was reacted further without additional purification. If desired, however, this mixture of isomers can be separated by chromatography on silica gel coated with silver nitrate (as illustrated in paragraph d).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].[N+:12]([O-])([OH:14])=[O:13].C(OCC)(=O)C>C(O)(=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([OH:11])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2]
Reactant: N#Cc1cc(C=O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 5-formyl-2-hydroxybenzonitrile (200 mg, 1.36 mmol) in acetic acid (4 mL) was added slowly concentrated nitric acid (0.8 mL) at 0° C. The resulting mixture was stirred for 5 hours. Then the mixture was poured into ice-water (40 mL) and ethyl acetate (100 mL). Organic was washed with brine (80 mL), dried over sodium sulfate and evaporated in vacuo, followed by column chromatography (petroleum ether/ethyl acetate=3:1) to give Intermediate 61 (250 mg, yield 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1.[NH3:17].[OH-].[NH4+]>>[NH2:17][C:2]1[CH:7]=[N:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1
Reactant: N
Reactant: O=S(=O)(c1ccccc1)c1cnc(Cl)cn1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1cnc(S(=O)(=O)c2ccccc2)cn1

Procedure:
The 2-chloro-5-phenylsulfonylpyrazine can then be allowed to react with ammonia or ammonium hydroxide in a high pressure reaction vessel, at a temperature of about 100° to about 200° C. to yield the 2-amino-5-phenylsulfonylpyrazine intermediate. Reaction conditions may vary depending on the chemical structure of the phenylsulfonyl grouping.
Reaction SMILES: [CH3:1][O:2][C:3](=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>CCCCCC.C1COCC1>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:32]([CH:33]=[CH:1][O:2][CH3:3])[C:31]=1[Cl:30]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=Cc1cccc(Cl)c1Cl
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
Into a flask under argon containing 700 ml of dry THF was placed 159 g (0.47 mole) of methyl(triphenylphosphoranylidene)acetate. To the stirred suspension cooled in an ice/water bath was added dropwise 320 ml (0.47 mole) of 1.45M n-butyllithium in hexane. After stirring for 20 min, 74 g (0.42 mole) of 2,3-dichlorobenzaldehyde in 700 ml of dry THF was added. After 2 hr the reaction mixture was washed with an ammonium chloride solution, brine and dried (MgSO4). The solvent was evaporated in vacuo. The residue was taken up in ether, the undissolved solid was filtered off, and the solvent was evaporated in vacuo. The residue was distilled in a Kugelrohr apparatus at 0.005 mm Hg and the fraction distilling between 80°-100° C. collected. The distillate was distilled at 0.005 mm Hg using a Vigro column and the product collected between 101°-116° C. A preparative hplc on silica gel using hexane as the elutant gave 28.02 g of the title compound as an oil (33%).
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.C(OC([NH:44][C@@H:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)=O)(C)(C)C>C(Cl)Cl>[NH2:44][C@@H:45]1[CH2:49][CH2:48][N:47]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)[CH2:46]1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Product: N[C@@H]1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1
Temperature: 130 °C
Yield: 14 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (100 mg, 0.20 mmole) and (3R)-3-(N-tert-butoxycarbonylamino)pyrrolidine; (380 mg, 10 equiv) in a sealed tube was heated at 130° C. for 35 hr. The reaction mixture was taken up in DCM, washed water and dried (Na2SO4). After removal of the solvent the residue was taken up in DCM (1.5 mL) and TFA (1 mL) was added. The solvents were removed and the residue was dissolved in DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 1 to 5% MeOH) to afforded the title compound as an oil (13 mg, 14%). 1H NMR (CDCl3) δ 1.49 (br s, 2H), 1.66 (m, 1H), 2.29 (m, 1H), 2.43 (m, 1H), 3.69 (m, 1H), 3.87 (d, 1H, J=13.5 Hz), 3.96 (d, 1H, J=13.5 Hz), 5.58 (s, 2H), 6.49 (d, 1H, J=3 Hz), 6.8-7.6 (m, 7H), 7.92 (s, 1H), 8.04 (s, 1H), 8.26 (d, 1H, J=2 Hz); MS: 457 (M+H)+; HPLC Ret Time: 1.15 min (YMC Xterra ODS S7 C18, 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [C:1]1([CH:7]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:26])[CH2:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:34]2[CH2:38][C@H:37]([NH:39][C:40](=[O:50])[C@H:41]([O:43]C3C=CC=CC=3)[CH3:42])[C@@H:36]([OH:51])[C@H:35]2[OH:52])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>CCO.C1COCC1.[OH-].[Pd+2].[OH-]>[C:1]1([CH:7]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([N:19]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:26])[CH2:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:34]2[CH2:38][C@H:37]([NH:39][C:40](=[O:50])[C@H:41]([OH:43])[CH3:42])[C@@H:36]([OH:51])[C@H:35]2[OH:52])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](Oc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of (R)—N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-2-phenoxy-propionamide (83 mg, 0.104 mmol) in EtOH (20 ml) and THF (5 ml) under an inert atmosphere is treated with palladium hydroxide (20% w/w on carbon, 32 mg) followed by acetic acid (2 ml). The reaction mixture is placed under an atmosphere of hydrogen for two weeks after which time, the mixture is filtered and concentrated in vacuo. The resulting crude product is washed with EtOH (3 times), filtered and then concentrated in vacuo. The residue is dissolved in MeOH (2 ml) and purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% NH3) affords the title compound as a white solid. (MH+ 707.4)
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([O:24][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:26](=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCC(=O)NCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(=O)CCCCCNC(=O)CCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.2 %

Procedure:
1.57 g of 3-hydroxyoctadecanoic acid t-butyl ester and 1.30 g of 6-decanamidohexanoic acid were mixed with 30 ml of methylenechloride and after adding thereto 50 mg of DMAP and 930 mg of DCC while stirring, the mixture was stirred for 2 days at room temperature. Precipitates formed were removed by filtration and the filtrate was washed with 10 ml of 0.1N hydrochloric acid, and then washed twice with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was subjected to column chromatography and eluted with chloroform to provide 610 mg of 3-(6-decanamidohexanoyloxy)octadecanoic acid t-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)Cl>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:29])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Solvent: ClCCl
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1

Procedure:
This object is achieved according to the present invention, which is characterized by the steps of reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl-thio]-1H-benzimidazole (below denoted Compound I) with m-chloroperoxybenzoic acid in a methylene chloride solution at a substantially constant pH of about 8.0 to 8.6; extracting the reaction with aqueous NaOH; separating the aqueous phase from the organic phase; and adding an alkyl formate to the aqueous phase, resulting in crystallization of omeprazole.