Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11]O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:25])C.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:10]([OH:25])[CH3:11])[CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: OCCNCc1ccc(Cl)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN(Cc2ccc(Cl)nc2)C(C)O)cc1
Yield: 116.6 %

Procedure:
This compound was prepared in a manner analogous to that of Step A of Example 1, using 4.9 grams (0.026 mole) of 2-{[(6-chloro-3-pyridyl)methyl]amino}ethan-1-ol, 3.6 grams (0.026 mole) of 4-methoxybenzaldehyde, 8.3 grams (0.039 mole) of sodium triacetoxyborohydride and 5.8 grams (0.052 mole) of magnesium sulfate in 200 mL of 1,2-dichloroethane. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 100% methylene chloride and 100% diethyl ether as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 9.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:2][CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CCC(N)C(=O)OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminobutanoate hydrochloride 56 (25 g, 0.163 mol) was suspended in CH2Cl2 (100 mL) and triethylamine (50 mL) and 4-chlorobenzenesulfonyl chloride (37.8 g, 1.1 eq) were added to the mixture. The mixture was stirred at room temperature overnight. Diluted with 200 mL of CH2Cl2 and washed with water (3×50 mL), sat. NaHCO3 (2×50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by rotary evaporation to give the product 57 as a yellow oil. LCMS 292.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)=[C:5]2[Cl:24].C[O-].[Na+].[C:28](=O)(O)[O-:29].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:29][CH3:28])[C:6]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)=[C:5]2[Cl:24]
Reactant: O=C([O-])O
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 80 °C

Procedure:
A mixture of 6-bromo-2,4-dichloro-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (1.0 g, 2.3 mmol, Intermediate 9: step b) and sodium methoxide (1.2 g, 22 mmol) in dry toluene (12 mL) was heated to 80° C. under a positive pressure of nitrogen overnight. The mixture was allowed to cool to ambient temperature. Aqueous saturated sodium bicarbonate solution was added to the mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was purified by flash column chromatography (silica gel, 0-20% EtOAc-hexane) to provide the title compound as a white solid.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][N:20]1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH2:37]([O:39][C:40]1[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:41]=1[CH2:42]CN)[CH3:38].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH2:37]([O:39][C:40]1[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:41]=1[CH2:42][N:20]([CH3:19])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:9]=[N:10][C:11]2[NH:12][C:3](=[O:2])[CH2:4][CH2:5][C:6]=2[CH:7]=1)[CH3:38]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCOc1c(CCN)cccc1OC
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)cccc1OC
Yield: 88 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (2-ethoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (429 mg, 88%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.6 (s, 1H), 8.34 (d, J=13.2 Hz, 1H), 8.08-8.01 (m, 1H), 7.50 (dd, J=9.2, 2.0 Hz, 1H), 7.25 (dd, J=9.3, 5.5 Hz, 1H), 7.06-6.94 (m, 2H), 6.67 (dd, J=11.4, 4.7 Hz, 1H), 4.91 (br s, 1H), 4.78-4.64 (m, 2H), 4.02-3.95 (m, 2H), 3.79 (s, 3H), 3.09-2.86 (m, 5H), 2.55-2.49 (m, 2H), 1.30-1.26 (m, 3H); MS (ESI) m/e 396 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH3:13][N:14]([CH3:20])[C:15](=[O:19])[C:16]([CH3:18])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH3:13][N:14]([CH3:20])[C:15]([C:16]1([CH3:18])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)=[O:19]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CC(=O)C(=O)N(C)C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: CN(C)C(=O)C1(C)Oc2ccccc2-n2cccc21

Procedure:
A mixture of 1-(o-hydroxyphenyl)pyrrole (500 mg), N,N-dimethyl-pyruvamide (580 mg), described by W. F. Gresham in U.S. Pat. No. 2,429,877, issued Oct. 28, 1947, 1.7 g of phosphorus pentoxide, 0.5 g of diatomaceous earth (Celite) in 75 ml of benzene is stirred at room temperature for 15 min. and then at 70° C for 11/2 hr. The reaction mixture is filtered. The filtrate is washed with water, dried (MgSO4) and concentrated to give the title compound, identical to the product of Example 15.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][CH2:2][C:3]2[CH:18]=[CH:17][C:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[CH:5][CH:4]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
4-(4-Aminomethylbenzyl)-nitrobenzene (500 mg) was dissolved in dichloromethane (7 mL) and heated with 4-methoxybenzenesulfonyl chloride (426 mg) and triethylamine (0.3 mL). The mixture was stirred at room temperature for 15 hours, poured into dilute aqueous hydrochloric acid, and extracted with dichloromethane (3×). The solvent was evaporated to give 4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-nitrobenzene as a yellow solid (851 mg, ˜100%), and was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C=O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1ccc(C(C)C)cc1)OCC

Procedure:
To a mixture of 4-isopropylaniline (4.05 g, 30.0 mmol) and potassium carbonate (6.21 g, 45 mmol) in DMF (100 mL) at room temperature was added 2-bromo-1,1-diethoxyethane (6.50 g, 33.0 mmol). The mixture was then stirred at 80-90° C. until all of the 4-isopropylaniline was consumed (24 h). The solvent was removed in vacuo and the residue was treated with dichloromethane (150 mL), washed with water and brine, dried over anhydrous MgSO4, and then concentrated. Chromatography (silica gel, hexanes:ethyl acetate, 9:1) of the crude product, furnished the pure intermediate, N-(4-isopropylphenyl)-2,2-diethoxyethylamine, as a colorless oil (5.71 g, 75.8%). 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.18-1.32 (m, 12H), 2.75-2.91 (m, 1H), 3.24 (d, 2H), 3.52-3.62 (m, 2H), 3.67-3.79 (m, 2H), 3.87 (s, br, 1H), 4.70 (t, 1H), 6.60 (d, 2H), 7.05 (d, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][C:2]1=[O:7].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:26][C:27]([F:34])([F:33])[C:28]([F:32])=[C:29]([F:31])[F:30]>>[F:30][C:29]([CH:6]1[CH2:5][CH2:4][O:3][C:2](=[O:7])[O:1]1)([F:31])[CH:28]([F:32])[C:27]([F:34])([F:33])[F:26]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=C1OCCCO1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1OCCC(C(F)(F)C(F)C(F)(F)F)O1
Temperature: 73 °C

Procedure:
Example 6 was prepared by combining 1,3-dioxan-2-one (240 g, 2.35 moles) (Richman Chemical Inc., Lower Gwynedd, Pa.) with benzoyl peroxide (5 g, 0.02 moles) in a 600 mL Parr reactor. The reactor was heated to 73° C. and hexafluoropropene (16 g, 0.1066 moles) was fed into the reactor over a 2 h period. The reactor was maintained at the set temperature for an additional 24 h. The reactor contents were collected and analyzed by GC/MS.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O.ClCCl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere sulfur trioxide pyridine complex (6.34 g, 39.8 mmol) was added portionwise to a chilled (0° C.) solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.30 g) and triethylamine (5.55 mL, 39.8 mmol) in dimethyl sulfoxide (11.5 mL) and dichloromethane (23 mL). The solution was stirred at 0° C. for another hour, poured into 70 mL of saturated aqueous ammonium chloride and then extracted with diethyl ether (3×100 mL). The combined organics were washed with water (2×30 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 3-oxoazetidine-1-carboxylate as a clear oil.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([Cl:52])[C:49]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[CH:55][CH:54]=3)=[C:48]([NH:76][C:77](=O)[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C:47]=2[Cl:85])=[CH:42][CH:41]=1)[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][CH3:38]>ClC1C=CC=CC=1>[CH2:23]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([Cl:52])[C:49]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])=[CH:55][CH:54]=3)=[C:48]([NH:76][C:77](=[S:10])[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C:47]=2[Cl:85])=[CH:42][CH:41]=1)[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][CH3:38]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(-c2cc(Cl)c(-c3ccc(OCCCCCCCCCCCCCCCC)cc3)c(NC(=O)c3ccccc3)c2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Clc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1ccc(-c2cc(Cl)c(-c3ccc(OCCCCCCCCCCCCCCCC)cc3)c(NC(=S)c3ccccc3)c2Cl)cc1

Procedure:
Next, a Lawesson's reagent (2.2 g, 5.5 mmol) and chlorobenzene (20 ml) were added to 1,4-bis(4-hexadecyloxyphenyl)benzoylamino-2,5-dichloro-benzene 3 (4.0 g, 4.6 mmol) prepared above, and the mixture was heated under reflux for about 4 hr. After the completion of the reaction, the precipitated yellow powder was collected by filtration, was washed with ethanol, and was dried. Thereafter, the yellow powder thus obtained was recrystallized from DMF to give 1,4-bis(4-hexadecyloxyphenyl)thiobenzoylamino-2,5-dichloro-benzene 4 as the target compound (yield 90.2%).
Reaction SMILES: C(S[CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1)(C)(C)C.[Cl:31]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:31][CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of 439 mg (1.0 mmol) of p-nitrobenzyl 2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 20 ml of dry methylene chloride is cooled to -50° C. and a solution of 166 mg of chlorine in 1.6 ml of carbon tetrachloride is added. After stirring for 30 minutes at -50° C., the solvent is evaporated in vacuo and the residue is recrystallized from methylene chloride/hexane, the product (348 mg) being obtained as a crystalline solid as a 6:4 mixture of the two diastereomeric title compounds.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1O.O[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]>C(OCC)(=O)C.CCCCCC>[C:16]1([CH:12]2[C:4]3[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=3[O:15][C:13]2=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccccc1
Yield: 37 %

Procedure:
Using 2,3,5-trimethylphenol and hydroxy(phenyl)acetic acid, the title compound was synthesized in the same manner as in Reference Example 2. Yield 37%. Melting point: 129-130° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=[O:23])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:9]=1[C:8]([OH:11])=[O:23])#[N:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2c(c1)C(=O)C(=NO)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CC#N)c(C(=O)O)c1
Temperature: 50 °C
Yield: 44.1 %

Procedure:
6-Methyl-2-hydroxyimino-1-indanone (37 g) and sodium hydroxide (19.7 g) were dissolved in water (287 mL), and p-toluenesulfonyl chloride (44.3 g) was added with stirring at 50° C. After the completion of the reaction, aqueous citric acid solution was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated. Ether was added to the precipitated crystals, and the crystals were collected by filtration to give 2-cyanomethyl-5-methylbenzoic acid (16.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])=[CH:16][C:15]=2[F:28])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[CH2:32]([O:39][CH2:40][CH2:41]O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:32]([O:39][CH2:40][CH2:41][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:17]1[CH:16]=[C:15]([F:28])[C:14]([CH:10]([O:11][CH2:12][CH3:13])[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=2)=[O:29])=[C:19]([F:20])[CH:18]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2O)cc1F
Reactant: OCCOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2OCCOCc2ccccc2)cc1F

Procedure:
In analogy to example 22.1, (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-hydroxy-biphenyl-4-yl)-2-ethoxy-acetamide was reacted in a Mitsunobu reaction with 2-benzyloxy-ethanol, diethyl azodicarboxylate and triphenyl phosphine in THF to give (RS)-2-[2′-(2-benzyloxy-ethoxy)-3,5-difluoro-biphenyl-4-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide. Yellow oil. MS 557.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:18][C:19](OC(C)=O)=[O:20]>N1C=CC=CC=1>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:20])[CH3:18])=[CH:7][CH:6]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of 5 g (19.3 mmol) of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 25 mL of pyridine was treated with 2.2 mL (23.3 mmol) of Ac2O. The mixture was stirred at 60° C. for 2 hours and the solvent partially evaporated. The residue was distributed between a diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 5.7 g of crude N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide that was dissolved in 100 mL of DMF, treated with 3.4 mL (22.7 mmol) of DBU and then dropwise at 0° C. with 3.8 mL (22.7 mmol) of TESCl. The mixture was stirred at RT for 10 hours and then poured into a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 8.3 g of crude N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide which was dissolved in 100 mL of THF and treated with 3.4 mL of a 1M B3*THF-solution in THF. The mixture was kept at reflux for 4 hours and the solvent partially evaporated. After addition of a saturated aqueous solution of NH4Cl and Et2O, the phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 9:1 yielded 7.5 g (96%) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine, light yellow oil, MS: 402 (MH+).
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[C@H:53](C)[C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C.O1CCCC1>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (737 mg) in anhydrous acetonitrile (20 ml), N,N'-carbonyldiimidazole (281 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (0.75 ml) and a solution of the compound (1.157 g), which had been obtained in (2), in anhydrous tetrahydrofuran (10 ml) were added. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (1.394 g) was obtained as an amorphous substance.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:10]1[NH:11][C:12]([C:21]#[N:22])=[C:13]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[N:14]=1)[CH2:8][CH3:9].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH2:7]([C:10]1[N:11]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:12]([C:21]#[N:22])=[C:13]([C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[N:14]=1)[CH2:8][CH3:9]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(=O)C(C)(C)C)c(C#N)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(=O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
1.08 g of potassium t-butoxide was added, whilst ice-cooling, to a solution of 2.00 g of 2-propyl-4-pivaloylimidazole-5-carbonitrile (prepared as described in Preparation 41) in 20 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at same temperature for 10 minutes. 6.10 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide were then added to the solution, and the resulting mixture was stirred at 50° C. for 4 hours. At the end of this time, ethyl acetate and water were added to the mixture, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The syrupy residue was purified by column chromatography through silica gel, using 1:3 and 1:2 by volume mixtures of ethyl acetate and hexane as the eluent, to give 5.44 g of the title compound as crystals, melting at 107°-110° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].B.O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: COCCCCCCC(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCCCCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a solution of the title product of Example 2 (18.3 g, 114 mmol) in 60 mL of tetrahydrofuran at 0° C. was added dropwise a solution of borane in tetrahydrofuran (175 mL, 1M). After stirring at room temperature for 3 days, 300 mL of water was added followed by solid K2CO3 (31.7 g, 229 mmol). The layers were separated and the aqueous phase extracted with three portions of diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by distillation at reduced pressure (8 mm Hg) to give the title compound (12 g), b.p. 107-110° C. The structure was verified by NMR.