Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C([O:12][C:13](=[O:15])[CH3:14])(=O)C>[O-2].[O-2].[Mn+4].C(O)(=O)C>[C:13]([OH:12])(=[O:15])[CH2:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Reactant: CC(=O)OC(C)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCCCCCCCCC(=O)O
Yield: 75 %

Procedure:
A process similar to the instant case is described in the Belgian Patent Specification 734,184 and while this known process may give a good yield of (ar)alkane carboxylic acid, this acid, upon further analysis is found largely to consist of a reaction product in which two carbonyl compounds are bonded to said (ar)alkene per ethylene group of the (ar)alkene one of which compounds can be removed by hydrolysis. If the carbonyl compound is a combination of acetic acid and acetic anhydride, the product formed will mainly be gamma-acetoxyalkanoic acid in the case of an alpha-olefin instead of the commercially far more important alkanoic acid without an acetoxy group in the gamma position. In Example I of the afore-mentioned patent specification, using as starting materials octene-1 and a mixture of 500 ml of acetic acid and 100 ml of acetic anhydride with manganese dioxide as a coupling reagent, there is obtained a 75% yield of n-decanoic acid. However, the percentage indicated can only have been arrived at due to a misinterpretation of the results of the analysis. The same comment applies with respect to Example IX of the Belgian patent specification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:38][C@H:39]1[CH2:43][NH:42][CH2:41][C@@H:40]1[OH:44].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[NH2:38][C@@H:39]1[C@@H:40]([OH:44])[CH2:41][N:42]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([Cl:28])([F:26])[F:27])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:43]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: N[C@H]1CNC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncc(F)c2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 44 h

Procedure:
2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 70 mg, 0.160 mmol) and DIPEA (0.196 mL, 1.121 mmol) were added to a vial containing iPrOH (2 mL). (3S,4S)-4-Aminopyrrolidin-3-ol (30 mg, 0.168 mmol) was added. The mixture was stirred at 80° C. for 44 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced to give the crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/MeOH, from 95:5 to 8:2) to afford the title product as a beige solid. HPLC (Condition 10) tR=5.83 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=494.2/496.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.91 (dd, J=11.53, 2.93 Hz, 1H) 3.22-3.28 (m, 1H) 3.36-3.46 (m, 2H) 3.59-3.66 (m, 1H) 4.02-4.08 (m, 1H) 5.48 (d, J=3.91 Hz, 1H) 7.35 (d, J=8.60 Hz, 2H) 7.87 (m, J=9.00 Hz, 3H) 8.13 (d, J=2.35 Hz, 1H) 8.55 (s, 1H) 8.64 (d, J=2.74 Hz, 1H) 8.79-8.83 (m, 1H) 10.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.I[CH2:14][CH2:15][CH3:16]>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=12
Reactant: CCCI
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: CCCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 95 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and 1-iodopropane, the titled compound was obtained as a white solid. (Yield: 95%)
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:40]=[CH:39][C:20]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH2:35][CH:36]4[CH2:38][O:37]4)=[C:29]([C:32]#[N:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[CH:19][C:18]=1[F:41]>O>[C:32]([C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH2:35][CH:36]1[CH2:38][O:37]1)[N:25]=[CH:24][CH:23]=[C:22]2[O:21][C:20]1[CH:39]=[CH:40][C:17]([NH:16][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[O:15])=[C:18]([F:41])[CH:19]=1)#[N:33]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCC1CO1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding dimethylformamide (2 ml) and 4-fluorophenyl isocyanate (0.15 ml) to 4-(4-amino-3-fluorophenoxy)-7-oxiranylmethoxy-quinoline-6-carbonitrile (400 mg), the mixture was stirred overnight at room temperature. Water was added to the reaction solution and the precipitated crystals were filtered off to obtain the title compound (480 mg) as light yellow crystals.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)/C=C/C(O)=O>CS(C)=O.C(O)(C)C>[CH:27]1([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C1Cc2c(ccc3c2OC(CNCC2CCCCC2)CO3)N1
Temperature: 80 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (0.80 g, 2.13 mmole), and cyclohexylmethylamine (1.33 g, 11.7 mmole) were combined in 15 ml of dry DMSO and heated to 80° C. for 6 hours under a nitrogen atmosphere. The reaction was allowed to cool and was partitioned between 100 ml of ethyl acetate and 150 ml of deionized water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield a black oil. This oil was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 to remove impurities. A concentration of 2% methanol/CH2Cl2 eluted the desired product, which was as an oil (0.38 g, 56%) upon concentration in vacuum. This oil was crystallized from isopropanol with the addition of a solution of fumaric acid (0.15 g, 1.3 mmole) in hot isopropanol to give 0.39 g of the (S) enantiomer of the title compound as an off-white solid monofumarate, half hydrate, m.p. 187°-188° C.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:3].[CH2:13]([O:15][N:16]=[CH:17][CH3:18])[CH3:14].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:13]([O:15][N:16]1[CH:17]([CH3:18])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:14]
Reactant: CC=NOCC
Reactant: C=C(C)C1CCCCCCC1=O
Agent: CCON1C(=O)CCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclooctanone (1.50 g, 9.02 mmol), acetaldehyde O-ethyl oxime (1.18 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (1.98 g, 87% yield). E isomer>96%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[C:33]([F:42])=[C:34]([C:38]([Cl:41])=[CH:39][CH:40]=1)[C:35](O)=[O:36])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:41][C:38]1[CH:39]=[CH:40][C:32]([CH2:31][NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:33]([F:42])[C:34]=1[C:35](=[O:36])[NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 47.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-7, 87 mg, 0.285 mmol), 3-(((tert-butoxycarbonyl)amino)methyl)-6-chloro-2-fluorobenzoic acid (130 mg, 0.428 mmol), oxalyl chloride (81 mg, 0.64 mmol), DMF (1 drop) and DIPEA (111 mg, 0.86 mmol) in CH2Cl2 (4 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.66 (s, 1H), 10.14 (s, 1H), 8.82 (d, 1H), 8.71 (s, 1H), 8.36 (m, 2H), 8.23 (d, 1H), 7.73 (t, 1H), 7.66 (t, 1H), 7.51 (m, 2H), 7.42 (m, 2H), 4.18 (d, 2H), 1.40 (s, 9H); MS [M+H]+: 590.08.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCCC1
Reactant: O=C(O)Cc1c[nH]cn1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](CC(C)C)C2)cc1OC1CCCC1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclopentyloxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 33, Compound 121) as starting materials. Product as a light brown solid (11%). LC/MS (Method B) 2.69 min, [M+1]+ 441.1. Potency class A.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=3)[CH:7]=[CH:6]2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccccc2Br)c1
Product: CCOC(=O)c1ccc(-c2ccccc2Cn2ccc3cc(C(=O)O)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 38, using 1-(2-bromobenzyl)-1H-indole-5-carboxylic acid instead of the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide and the (4-(ethoxycarbonyl)phenyl)boronic acid instead of the phenylboronic acid. ESI-MS (m/z): 400 [M+H]+.
Reaction SMILES: CC1(C)C2CC[C@@]31[C@H](C2)N([C:12](=[O:23])[C@H:13]([CH3:22])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH:17]=[CH2:18])S(=O)(=O)C3.[OH-:27].[Li+].Cl>O1CCCC1>[CH2:20]([O:19][C@H:14]([CH2:15][CH2:16][CH:17]=[CH2:18])[C@@H:13]([CH3:22])[C:12]([OH:23])=[O:27])[CH3:21]
Reactant: [OH-]
Reactant: C=CCC[C@@H](OCC)[C@@H](C)C(=O)N1[C@H]2CC3CC[C@@]2(CS1(=O)=O)C3(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC[C@@H](OCC)[C@@H](C)C(=O)O
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of (2R,3R)-1-((1R,5S)-10,10-dimethyl-3,3-dioxo-3lambda*6*-thia-4-aza-tricyclo[5.2.1.0*1,5*]dec-4-yl)-3-ethoxy-2-methyl-hept-6-en-1-one (245 mg, 0.64 mmol) in tetrahydrofuran (12 mL) was added a lithium hydroxide solution (2 M aqueous, 5 mL). The mixture was heated to reflux for 16 hours then cooled to room temperature and acidified to pH 1 with 2 M hydrochloric acid (15 mL). The aqueous layer was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a colourless gum, which was purified by silica gel chromatography using iso-hexanes/ether 1:1 to give the title compound (78 mg, 65%) as a colourless gum. 1H NMR (300 MHz, CDCl3) δ 1.17 (d, J=7.1 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H), 1.55-1.65 (m, 2H), 2.05-2.30 (m, 2H), 2.72-2.83 (m, 1H), 3.52-3.62 (m, 3H), 4.95-5.10 (m, 2H), 5.75-5.90 (m, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH2:8]2)=[CH:5][CH:6]=1.Cl.O.CO>CN(C=O)C.[Pd]>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C1C[C@@H](c2ccccc2)Oc2cc(O)cc(O)c21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C[C@H](c2ccccc2)Oc2cc(O)cc(O)c21
Yield: 90 %

Procedure:
4.8 g of the benzyl protected pinocembrin in R-configuration obtained in Example 4 was dissolved in 100 ml of DMF, 20 ml of 10% aqueous HCl and 3.5 g of 10% Pd—C with a water content of 62.9% were added, and then a hydrogenation at normal pressure was performed. The reaction was monitored by TLC until completion (about 5 h). Then stop stirring, the reaction mixture was filtered and extracted with ethyl acetate and water. The organic phase was collected, evaporated to remove solvent and recrystallized with 95% ethanol to give a white solid of (R)-pinocembrin (3.1 g, yield 90%) with specific rotation [α]D20=+45.83° (c=0.515, methanol), and e.e %>99.3%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C-:22]#[N:23].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:22]#[N:23])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 20 h

Procedure:
5.0 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine and 1.5 g of potassium cyanide in 50 ml of dimethylformamide were heated at 50° C. for 4 hours and then stirred at 23° C. for 20 hours. The mixture was then poured into 200 ml of water. The aqueous phase was extracted three times with 100 ml of tertbutyl methyl ether each time. The combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=9:1). Yield: 2.7 g (53%) of a yellow oil which slowly crystallized.
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH2:8][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][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[I:40]I.[I-]>C1C=CC=CC=1>[CH2:6]([I:40])[CH2:7][CH2:8][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][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: II
Reactant: CCCCCCCCCCCCCCCCC=CCCCCCCCCCCCCCCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCI
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 44.8 g. (0.15 mole) of Cp2ZrCl2 in 800 ml. tetrahydrofuran under Argon was added 24.7 g. (0.086 mole) of NaAlH2 (OCH2Ch2OCH3)2 in benzene via syringe. After stirring 2 hours at room temperature, 36.8 g. (0.077 mole) of the olefin, 17-tetratriacontene, was added and the mixture kept at 40° C. for 7 days. After cooling in an ice bath, solid iodine (34.0g., 0.134 mole) was added. The mixture was filtered and the solvent removed in vacuum. NMR analysis indicated an olefin:iodide ratio of 25:75. The residue was dissolved in hexane and percolated through dry silica gel to remove impurities. Recrystallization from hexane gave 13.0 g. pure iodide, m.p. 75°-6° C. and 14.4 g. of a 58:42 olefin:iodide mixture.
Reaction SMILES: [IH:1].[C:2](=[NH:7])(SC)[NH:3][NH2:4].[NH2:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1>C(O)C>[IH:1].[NH2:4][NH:3][C:2]([NH:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1)=[NH:7]
Reactant: CSC(=N)NN
Reactant: NCc1cnccn1
Agent: I
Solvent: CCO
Product: N=C(NN)NCc1cnccn1

Procedure:
A solution of 3.66 g. of methyl thiocarbazimidate hydriodide and 3.42 g. of (aminomethyl)pyrazine [A. Hirschberg and P. Mattner, J. Med. Chem., 11, 911 (1961)] in 50 ml. of absolute ethanol is heated at reflux for 20 hours and then concentrated to dryness under reduced pressure to give the desired product as an orange solid.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=1)([OH:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[CH:11][CH:10]=[C:9]([CH3:26])[N+:8]=1[O-:35])([OH:3])=[O:2]
Reactant: COc1ccc(CCCCOc2ccc(C)nc2/C=C/CC(=O)O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CCCCOc2ccc(C)[n+]([O-])c2/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-methylpyridine (13.6 g, 38.2 mmol) was dissolved in dry CH2Cl2 (100 mL,) and cooled to 0° C. To this was added 50% mCPBA (13.2 g, 38.3 mmol) in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 h at room temperature. The reaction was poured into aqueous NaHCO3 and the product extracted into CH2Cl2. The organic extract was washed with H2O and brine and dried (MgSO4). The crude product was obtained as a yellow solid and was used without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=O)C.Cl>CO>[O:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][OH:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: OCc1cccc(Oc2ccccc2)c1
Yield: 90 %

Procedure:
2.42 g. (0.01 mole) of 3-phenoxybenzyl acetate, 5 cm3. of methanol and 5 cm3. of 2N hydrochloric acid solution are refluxed for three hours. Then the methanol is distilled off. The organic phase is dissolved in 30 cm3. of methylene chloride, washed with 10 cm3. of water, 10 cm3. of 1N sodium hydroxide solution and 10 cm3. of water then evaporated. 1.8 g. of 3-phenoxybenzyl alcohol are obtained. nD20 : 1.593, yield 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1Cl
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of 51.4 g of o-chlorophenol, 58.8 g of ethyl chloroacetate, 55.3 g of potassium carbonate and 250 ml of acetone was heated under reflux for 7 hours. The mixture was then cooled to room temperature and an insoluble material was filtered off. The filtrate was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography to give 69.0 g of the title compound as an oil, boiling at 134°-137° C./2 mm Hg (267 Pa).
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH3:27][O:28][C:29]1[CH:45]=[CH:44][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[CH2:42]O)=[CH:31][CH:30]=1>C(Cl)Cl.C1COCC1>[I:25][CH2:42][C:36]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C:32]1[CH:44]=[CH:45][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(COc2ccc(C)cc2CO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C)cc2CI)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of imidazole (1.52 g, 22.32 mmol) and triphenylphosphine (5.85 g, 22.32 mmol) in methylene chloride (30 mL)/THF (15 mL) is added iodine (5.67 g, 22.32 mmol) in portions and the mixture is stirred at RT for 3 h. To this is added dropwise a solution of [2-(4-methoxybenzyloxy)-5-methylphenyl]-methanol (4.80 g, 18.6 mmol) in THF (15 mL) and the mixture is stirred at RT for 18 h. The mixture is concentrated and the insoluble material is filtered. The filtrate is evaporated and the residue is purified by column chromatography using a gradient of 0-75% EtOAc/hexane as eluent to give the title compound as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Cl)[CH:11]=2)[CH:6]=1.COC(C1C=C(OCC2C=CC=CC=2)C2C(=CC=C(F)C=2)C=1)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(Cl)ccc2c1
Agent: [Pd]
Agent: COC(=O)c1cc(OCc2ccccc2)c2cc(F)ccc2c1
Solvent: CO
Product: COC(=O)Cc1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (4-benzyloxy-6-chloro-naphthalen-2-yl)-acetic acid methyl ester (340 mg, 1.0 mmol, prepared using a method analogous to the one described above for the preparation of 4-benzyloxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester, 1st-7th step for example 1-1) in methanol was added 10% palladium on carbon (10 mg). The resulting mixture was vigorously stirred at room temperature overnight under a hydrogen atmosphere (balloon) and then filtered. The filtrate was concentrated in vacuo to give (4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (200 mg, 92.6%) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:43]=[C:44]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:45][NH:46][C:47](=[O:61])[C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:50][CH:49]=1>CN(C=O)C.O>[CH3:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:65]1[CH2:66][CH2:67][N:62]([C:44](=[O:43])[CH2:45][NH:46][C:47](=[O:61])[C:48]2[CH:49]=[CH:50][C:51]([O:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:52][CH:53]=2)[CH2:63][CH2:64]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(Oc4ccccc4)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
DIPEA (0.138 mL, 0.80 mmol) was added drop wise to 2,4-Dimethylbenzoic acid (48 mg, 0.32 mmol) in DMF (5 mL). EDCI (127 mg, 0.67 mmol) and HOBT (43 mg, 0.32 mmol) were added consecutively. After 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 60:40 EtOAc:hexane as eluent) afforded N-{2-[4-(2,4-dimethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 56% yield. LC-MS purity: 98%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.1 (m, 7H), 4.1 (d, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H), 2.3 (s, 3H), 2.2 (s, 3H).