Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH:29]1[CH2:38][CH2:37][CH2:36][C@H:30]1[C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[CH3:34][N:33]([CH3:35])[C:31]([C@@H:30]1[CH2:36][CH2:37][CH2:38][N:29]1[C:24](=[O:25])[CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:10][CH:11]=2)[CH2:18][CH2:19]1)=[O:32]
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with H-Pro-NMe2, using general method C, to give (S)-1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylic acid dimethylamide. Off-white solid. MS 547.5 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (16.06 g, 37.3 mmol) in 75 mL of CH2Cl2 was treated with 75 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (7.82 g, 41.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature. After 30 min, the reaction was treated with 75 mL of CH2Cl2 and 75 mL of water and the layers were separated. The organic portion was then washed with 1% Na2CO3 solution (2×), water, brine, dried over Na2SO4, concentrated give 14.95 g of tert-butyl 2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[CH:32]1(O)CCCC1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:32][CH2:11][CH2:12]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17]
Reactant: OC1CCCC1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Product: Nc1ccc(OC2CCCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1

Procedure:
This intermediate was prepared according to the procedure described for the synthesis of (S)-2-(2-amino-5-cyclobutoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide Example 132, using cyclopentanol in place of cyclobutanol.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[OH:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:34]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:40]=[CH:41][C:15]([O:14][CH2:2][C:3]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:5][N:4]=3)=[CH:16][CH:17]=2)/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2noc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (335 mg), ethyl E-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (600 mg), potassium carbonate (432 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-8-phenyl-8-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]octanoate (267 mg, yield 32%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:18]=[CH:19][C:20]3[N:21]=[C:34]([C:30]4[C:29]([CH3:36])=[CH:28][C:27](/[CH:26]=[CH:25]/[C:24]([O:23][CH3:22])=[O:37])=[CH:32][C:31]=4[CH3:33])[NH:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)/C=C/c1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,4-diamino-N-(4-tert-butylphenyl)-benzamide (1.83 g, 6.46 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (1.55 g, 7.10 mmol) (from Example 6-17) in DMF (25 mL) and water (2.5 mL) was added oxone (2.66 g, 4.33 mmols) and the mixture was stirred at ambient temperature for 1 h. The mixture was poured into ethyl acetate, extracted once with water and five times with brine, and the organic layer was dried, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed using a 50-90% gradient of heptane/ethyl acetate to give methyl (E)-3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-acrylate.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH2:27]>>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:27][CH2:26][C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:5][CH:4]=1)#[N:2]
Reactant: NCc1ccco1
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Product: CC(C)(C(=O)NCc1ccco1)c1ccc(-c2cncc(C#N)n2)cc1
Yield: 30 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and furan-2-ylmethanamine. Yield 30%. 1H NMR (400 MHz, dMSO): δ 1.51 (s, 6H), 4.23-4.25 (d, 2H), 6.06-6.07 (d, 1H), 6.34-6.35 (t, 1H), 7.48-7.50 (d, 2H), 7.53 (t, 1H), 7.97-8.00 (t, 1H), 9.16 (s, 1H), 9.56 (s, 1H); MS+H (347).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8](=[N:16][NH2:17])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3](OC)=[O:4].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[CH2:7][N:2]([CH3:1])[C:3](=[O:4])[NH:17][N:16]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)N(C)CC(=NN)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CC(c2ccc(Cl)cc2)=NNC1=O
Yield: 50.2 %

Procedure:
68.24 g (267 mmol) of 2-(N-methyl-N-(methoxycarbonyl)-amino)-4′-chloroacetophenone hydrazone was dissolved in 400 ml of tetrahydrofuran. To this solution was added 30 ml of 20% potassium tert-butoxide in tetrahydrofuran. The resulting reaction mixture was refluxed for two hours, concentrated in vacuo, slurried in 500 ml of 50/50 diethyl ether/hexanes and filtered. The golden solid was washed with water and dried yielding 30 g of the title compound, mp 195–197° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])=[CH:10][CH:9]=2)[C:5](=[O:24])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH:31]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.[I-].[Na+]>C(#N)C>[CH:31]1([N:36]2[CH2:37][CH2:38][N:39]([CH2:2][CH:3]3[CH2:7][N:6]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH:19]5[CH3:23])=[CH:10][CH:9]=4)[C:5](=[O:24])[CH2:4]3)[CH2:40][CH2:41]2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CC1CCCN1CCCOc1ccc(N2CC(CCl)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(N2CC(CN3CCN(C4CCCC4)CC3)CC2=O)cc1
Yield: 15 %

Procedure:
A mixture of 4-(chloromethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one a56 (0.26 g, 0.74 mmol, 1 eq), potassium carbonate (0.4 g, 2.96 mmol, 4 eq), 1-cyclopentylpiperazine a58 (0.34 g, 2.22 mmol, 3 eq) and a catalytic amount of sodium iodide in acetonitrile (20 ml) is stirred at reflux for 4 days. Potassium carbonate is filtered and the mixture is concentrated under vacuum, then the residue is dissolved in ethyl acetate, and washed twice with a saturated solution of aqueous sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give 0.17 g of crude material. This product is purified by chromatography over silicagel (dichloromethane/methanol/ammonia 94/6/0.6) to afford 0.052 g of 4-[(4-cyclopentylpiperazin-1-yl)methyl]-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 44 as an orange oil.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:13][CH2:14]Cl)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[CH2:40]([O:42][C:43](=[O:62])[CH2:44][S:45]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH3:41]>CC(C)=O>[CH2:40]([O:42][C:43]([C:44]1([S:45]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:14][CH2:13][N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3]1)=[O:62])[CH3:41]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride (6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K2CO3 (30 gm, excess) in dry acetone (250 ml), (4-benzyloxy-phenylsulfonyl)-acetic acid ethyl ester (8.01 gm, 24 mmol) was added in a round is bottom flask and the reaction mixture was heated at reflux for 16 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H2O. The organic layer was further washed well with water, dried over MgSO4, filtered and concentrated. The dark brown reaction mixture was purified by silica gel column chromatography by eluting it with 30% ethylacetate:hexane and the product 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester was isolated as Brown oil. Yield:6.5 g, 55%; MS:494 (M+H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]\[C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)#[CH:2].I[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.O>CN(C)C=O.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])/[C:6]/3=[CH:13]\[C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Temperature: 70 °C

Procedure:
A solution of (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.43 mmol) (from Example 82) and 4-iodophenol (104 mg, 0.47 mmol) (Aldrich) in N,N-dimethylformamide (2 mL) and triethylamine (2 mL) was degassed by bubbling argon through the solution for 15 minutes. Copper(I) iodide (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (25 mg, 0.021 mmol) (Aldrich) were added, and the reaction was heated at 70° C. for 16 hours. Water (15 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane to give (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 121 mg, 86%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2F)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][CH3:31])([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 61b (2 g, 3.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 98%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][C:10]1[C:15](O)=CC=C[CH:11]=1>>[C:10]([C:5]1[CH:4]=[CH:3][C:2]([CH3:8])=[CH:1][C:6]=1[OH:7])([CH3:15])([CH3:11])[CH3:9]
Reactant: Cc1cccc(O)c1
Reactant: Cc1ccccc1O
Product: Cc1ccc(C(C)(C)C)c(O)c1
Yield: 95 %

Procedure:
Run B of Example 1 is repeated except that 3-cresol is substituted for the cresylic acid mixture. The process results in a selectivity of better than 95 percent of 6-t-butyl-3-cresol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[C:10]([Cl:14])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
Ethyl-4-aminophenylacetate (20 g, 112 mmol) was dissolved in chloroform (300 ml) and treated with N-chlorosuccinimide (14.92 g, 112 mmol) and stirred for 15 minutes at room temperature under argon. Reaction mixture was washed with water, brine and dried over magnesium sulphate. Evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0-45%) in hexane to give the title compound as a orange oil (10.12 g, 47.4 mmol). LC/MS: Rt=2.59, [MH]+ 214.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11](=O)[CH3:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:11]([CH3:12])[CH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9]
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of crude 1-(2,4,6-trichloro-phenyl)-propan-2-one prepared as described in example P1, (12 g, 0.050 mol) in methanol (100 ml) was added pyridine (6.8 ml, 0.084 mol), followed by O-methyl-hydroxylamine hydrochloride (6.70 g, 0.080 mol). The resulting mixture was stirred at ambient temperature for 18 hours. Methanol was removed under reduced pressure and the residue poured in 1N hydrochloric acid (300 ml) which was extracted with ethyl acetate (3×100 ml). Organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime E/Z-mixture (12.3 g, 92%), which was taken up for the next reduction step.
Reaction SMILES: ClC1C2C(=CC(C(O)(C3[N:17]=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3)C(C)C)=CC=2)C=CC=1C(OC)=O.[Cl:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([C:56]([OH:84])([C:60]3[N:61]=[CH:62][N:63](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:64]=3)[CH:57]([CH3:59])[CH3:58])=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[C:85](O)=[O:86].[NH4+].ON1C2C=CC=CC=2N=N1>>[Cl:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([C:56]([OH:84])([C:60]3[N:61]=[CH:62][NH:63][CH:64]=3)[CH:57]([CH3:59])[CH3:58])=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[C:85]([NH2:17])=[O:86]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1Cl
Reactant: CC(C)C(O)(c1ccc2c(Cl)c(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Product: CC(C)C(O)(c1ccc2c(Cl)c(C(N)=O)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 1-chloro-6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 1-chloro-6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with 1-hydroxybenzotriazole ammonium salt (533 mg) in a similar manner as described in Example 24-(i) to give the titled compound (904 mg) as a colorless powder.
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C(C2C(OC)=CC=CC=2P(C2OC=CC=2)C2OC=CC=2)=C(P(C2OC=CC=2)C2OC=CC=2)C=CC=1.[H][H]>CO>[CH2:3]([N:10]1[CH2:14][C@@H:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C@@H:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: COc1cccc(P(c2ccco2)c2ccco2)c1-c1c(OC)cccc1P(c1ccco1)c1ccco1
Agent: O=O
Solvent: CO
Product: O=C(O)[C@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
An autoclave was charged under argon in a glove box (O2 content<2 ppm) with 1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.00 g, 3.19 mmol), [Ru(OAc)2((S)-2-furyl-MeOBIPHEP)] (9.72 mg, 0.01 mmol) (2-furyl-MeOBIPHEP=(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(di-2-furylphosphine) and methanol (30 ml). The asymmetric hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen (>95% conversion, determined by NMR). After the pressure was released, the grey suspension was evaporated to dryness to yield 1.01 g of the crude title compound. The crude product was dissolved in methanol (15 mL) and heated to reflux for 1 h. After cooling to ambient temperature it was stirred for 2 h at 0° C. The resulting suspension was filtered and dried (40° C., 15 mbar) for 2 h. affording the title compound (0.984 g, 95%, e.e. 99.8% R,R (chiral HPLC)) as white solid. MS m/e: 316.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1)(C)(C)C.[F:31][CH2:32][C:33]1[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:18])([F:19])[F:20])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:39]([C:36]3[CH:35]=[N:34][C:33]([CH2:32][F:31])=[CH:38][N:37]=3)=[O:40])[CH:24]=[C:23]([F:28])[C:22]=2[F:29])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(CF)cn1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-(fluoromethyl)pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (dd, J=13.6, 3.8 Hz, 1 H), 3.19 (dd, J=13.6, 3.0 Hz, 1 H), 3.43 (dd, J=7.5, 3.4 Hz, 1 H), 3.86-3.99 (m, 1 H), 4.39-4.67 (m, 3 H), 4.74 (quin, J=7.1 Hz, 1 H), 5.76 (d, J=45.5 Hz, 2 H), 8.10 (ddd, J=11.4, 6.8, 2.8 Hz, 1 H), 8.77 (s, 1 H), 9.46 (s, 1 H), 9.69 (s, 1H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][C:20]#[CH:21].[OH-].[Na+]>>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][C:20]#[C:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: C#CCOC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCC#CCOC1CCCCO1

Procedure:
A process for preparing the sex pheromone of Lymantria dispar L. effectively which comprises the steps of reacting 1-bromodecane and propargyl alcohol tetrahydropyranylether in the presence of sodium hydroxide to give 1-tetrahydropyranyloxy-2-tridecyne, treating the tetrahydropyranyloxy-2-tridecyne with p-toluenesulfonic acid to give 2-tridecyn-1-ol, catalystic-hydrogenating the 2-tridecyn-1-ol in the presence of Lindlar catalyst to give (Z)-2-tridecen-1-ol, oxidizing the (Z)-2-tridecen-1-ol with peroxide to give (±)-cis-2,3-epoxy-1-tridecanol, reacting the (±)-cis-2,3-epoxy-1-tridecanol with acid anhydride in the presence of hydrolase in an organic solvent for a stereoselective acylation and recovering unreacted optically active (2R, 3S)-cis-2,3-epoxy-1-tridecanol after the acylation, reacting the optically active (2R, 3S)-cis-2,3-epoxy-1-tridecanol with toluenesulfonylchloride to give (2R, 3S)-cis-1-p-toluenesulfoxy-2,3-epoxytridecane, and reacting the (2R, 3S)-cis-1-p-toluenesulfoxy-2,3-epoxytridecane with di(4-methylpentyl) lithium copper reagent to yield (7R, 8S)-cis-2-methyl-7,8-epoxyoctadecane which is the sex pheromone of Lymantria dispar L.