Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:23][N:24]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:20]([C:18]1[N:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:15]=[CH:16][CH:17]=1)=[O:21]
Reactant: CNC1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylic acid (247 mg) in dichloromethane (5 ml) are added, at room temperature, N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (130 mg), 4-dimethylaminopyridine (10 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (162 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-{6-[methyl(1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]pyridin-2-yl}piperidine-1-carboxylate (219 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:16]=1.[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18]>CN1CCCC1=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:16]=1)=[CH2:18]
Reactant: CC(=O)NCCc1coc2ccc(I)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=Cc1ccc2occ(CCNC(C)=O)c2c1

Procedure:
15 mmol of the product obtained in Step B, 16 mmol of vinyl tributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium, are heated at 110° C., with stirring, for 3 hours in 30 ml of N-methylpyrrolidinone. After removal of the solvent by evaporation, the residue is taken up in 20 ml of dichloromethane and treated with an aqueous 10% potassium fluoride solution. Extraction, concentration under reduced pressure and chromatography over silica gel yield the pure title product.
Reaction SMILES: [C:1]1([C:7]2(O)[C:19]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.S(Cl)([Cl:29])=O>>[Cl:29][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]2[CH:18]=[N:17][CH:16]=[N:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: O=S(Cl)Cl
Reactant: OC1(c2ccccc2)c2ccccc2-c2ncncc21
Solvent: c1ccccc1
Product: ClC1(c2ccccc2)c2ccccc2-c2ncncc21

Procedure:
Five grams of 5-phenyl-5H-indeno[1,2-d]pyrimidin-5-ol were stirred at reflux temperature in 25 ml of thionyl chloride and 100 ml of benzene for 5 hours. The solvents were removed by evaporation and the residue was tritrated with benzene and filtered. The solid was crystallized from diethyl ether to provide 3 g of the desired title product, m.p. 119°-120° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[N:12][CH:11]=2)=O)=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.[CH3:24][NH:25][NH2:26].N1C=CC=CC=1>C(#N)C>[Cl:23][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:25]([CH3:24])[N:26]=[C:8]([C:10]3[N:14]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=4)[CH:13]=[N:12][CH:11]=3)[C:7]=12
Reactant: CCc1ccc(-n2cncc2C(=O)c2c(Cl)ncnc2Cl)cc1
Reactant: CNN
Solvent: CC#N
Solvent: c1ccncc1
Product: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(Cl)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4,6-dichloropyrimidin-5-yl)[1-(4-ethylphenyl)-1H-imidazol-5-yl]methanone (C21) (136 mg, 0.392 mmol) in acetonitrile (3 mL) was added to a solution of methylhydrazine (18.1 mg, 0.393 mmol) in acetonitrile (3 mL). After addition of pyridine (41 mg, 0.52 mmol), the reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptane) afforded the product, along with recovered starting material (35 mg, 0.10 mmol). Yield: 81 mg, 0.24 mmol, 61% (82% based on recovered starting material). LCMS m/z 339.0 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.21 (t, J=7.6 Hz, 3H), 2.62 (q, J=7.6 Hz, 2H), 4.11 (s, 3H), 7.11-7.15 (m, 4H), 7.52 (d, J=0.8 Hz, 1H), 7.85 (d, J=1.0 Hz, 1H), 8.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:17]([CH:6]([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
(1)-(b) To 19.0 g of methyl 4-(4-chlorobenzoyl)butyrate was added 14.5 g of aniline, 0.6 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene, and the mixture was refluxed with dehydration for 22.5 hours. The solvent was evaporated off under reduced pressure, and the residue was dissolved in 200 ml of methanol. A solution of 40 ml of an aqueous 20% sodium hydroxide solution and 3.0 g of sodium borohydride were added at 0° C., and the mixture was stirred at -3° to +5° C. for 1 hour. The reaction temperature was raised to room temperature, and then heated at 60° C. for 1 hour. After removal of solvent, the residue was diluted with 60 ml of water, adjusted to pH 6 to 7 with concentrated hydrochloric acid, extracted with ethyl acetate. The ethyl acetate extract was washed with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried, and treated with activated charcoal. After removal of charcoal and the solvent, the residue was recrystallized from isopropyl ether to give 18.5 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid as colorless prisms.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[C:23]([CH2:25][C:26]([OH:28])=O)#[N:24].[C:29]([N:37]1[CH2:42][CH2:41][NH:40][C@H:39]([CH3:43])[CH2:38]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:29]([N:37]1[CH2:42][CH2:41][N:40]([C:26](=[O:28])[CH2:25][C:23]#[N:24])[C@H:39]([CH3:43])[CH2:38]1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)CC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
DCC (2.43 g) and triethylamine (5 ml) were added into a solution of cyanoacetic acid (1.00 g) and (R)-N-benzoyl-3-methylpiperazine (2.84 g) in THF (50 ml). After reaction stirred at room temperature for 12 hours, solvents were removed under vacuum to give a residue which was purified by silica gel column chromatography to afford 3 g of (R)-N-benzoyl-3-methyl-N′-(2-cyano-acetyl)piperazine. MS m/z: (M+H)+ calcd for C15H18N3O2 272.14, found 272.17. HPLC retention time: 0.93 minutes (column H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>CC(O)C>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68 %

Procedure:
Acetophenone (2 ml, 17 mmol) was dissolved in 2-propanol (80 ml) and purged with nitrogen. Then the catalyst solution was added followed by potassium hydroxide solution (3.3 ml of 0.1M solution in 2-propanol). The mixture was stirred at ambient temperature under nitrogen for 10 h. This gave 1-phenylethanol Yield 68%, ee 49%. The initial turnover number, integrated over 1 h, was 318 h−1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH:27]([C:29]([NH2:31])=[O:30])[NH:26][CH2:25]2)[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[C@H:27]([C:29]([NH2:31])=[O:30])[CH2:28][C:24]4([CH2:22][CH2:23]4)[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CC2(CC2)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1CC2(CC2)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 16.8 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 50 mg, 176 μmol) was reacted with 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135 b, 37.3 mg, 211 μmol) and purified by chiral HPLC to obtain the title compound (12 mg, 17%) as colorless oil, MS (EI): m/e=407.3 [MH+].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@@H:22]12[CH2:28][C@@H:25]([CH2:26][CH2:27]1)[CH2:24][NH:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C@@H:22]12[CH2:28][C@@H:25]([CH2:26][CH2:27]1)[CH2:24][N:23]2[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1C[C@H]2C[C@@H]1CN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2CC[C@H]1C2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,4R)-2-azabicyclo[2.2.1]heptane hydrochloride (175275-72-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=364.5 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][C:32]2[N:37]=[C:36]3[CH2:38][O:39][C:40](=O)[C:35]3=[CH:34][CH:33]=2)[CH2:25][CH2:24]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:40]1[C:35]2[C:36](=[N:37][C:32]([CH2:31][CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]3)=[CH:33][CH:34]=2)[CH2:38][O:39]1
Reactant: O=C1OCc2nc(CCCN3CCC(O)CC3)ccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCCN3CCC(O)CC3)ccc21
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (163 mg, 1.09 mmol.) in THF (2 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (3.6 mL of a 1M in THF, 3.6 mmol, 5 eq.) is added slowly at 0° C. and the resulting solution is stirred for 20 min. The ice-bath is then removed and a solution of 2-[3-(4-Hydroxy-piperidin-1-yl)-propyl]-7H-furo[3,4-b]pyridin-5-one (200 mg, 0.72 mmol) in THF (1 mL) is added dropwise to the reaction mixture. The lactone does not dissolve well, so rest of the lactone is added as a solid. The resulting solution is stirred for 3 h and then poured into 10% aqueous HCl solution (50 mL) and stirred for 48 h at room temperature. Extraction with EtOAc followed by chromatography (silica gel, MeOH/Chloroform) provides the title compound (10 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.S(Cl)(Cl)(=O)=O.[CH2:18]([N:36]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1)[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][CH3:35].Cl>N1C=CC=CC=1>[CH2:49]([N:36]([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][CH3:35])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](=[O:45])(=[O:46])[NH:1][C:2]2[C:3]3[C:8](=[CH:7][C:6]([OH:12])=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)[CH:39]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cc(O)ccc12
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cccc3cc(O)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred solution of 5-amino-2-naphthol (8.0 g, 0.05 mol) in pyridine (80 ml) was added the sulfonyl chloride, N,N-dioctadecyl-3-chlorosulfonylbenzamide (Example 5) (36.2 g, 0.05 mol). The reaction was stirred overnight at room temperature and then poured into excess dilute hydrochloric acid. The mixture was extracted with dichloromethane, washed with water, dried over magnesium sulfate and suction-filtered through a pad of decolorizing carbon. The filtrate was concentrated to an oil which was crystallized from acetonitrile to yield 26.5 g of product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].CO[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([N:11]1[CH2:12][CH:4]2[CH2:5][CH2:6][O:1][C:2](=[O:7])[CH:3]2[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCCC2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 6 h
Yield: 82.87 %

Procedure:
To a solution of 5,6-dihydro-2H-pyran-2-one (1.00 g, 1 eq) in CH2Cl2 (150 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.2 eq). After the mixture was cooled to 0° C., a solution of TFA in CH2Cl2 (0.1 eq, 1M) was added slowly. The reaction mixture was slowly heated to room temperature and stirred for 6 h. The reaction mixture was washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as colorless oil (1.95 g, 82.87%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 232.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:26])C.ClCCl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Dissolve 2-chloro-4-trifluoromethylbenzonitrile (405 mg, 1.97 mmol) in anhydrous toluene (7 mL) and cool in a dry ice/ethanol bath. Add diisobutylaluminum hydride (DIBAL) (3.94 mL, 3.94 mmol, 1.0 M in toluene) slowly. Stir 30 min. Warm to room temperature, add acetic acid (2 mL) and wafer (10 mL) and stir for 2 hours. Extract the aqueous layer with ethyl acetate twice. Wash the organic layer with potassium sodium tartrate solution (Rochelle salt) twice. Dry (magnesium sulfate), filter, and concentrate to give a residue. Chromatograph the residue on silica gel eluting with a gradient of 100:0 to 1:1 hexanes:dichloromethane to give 2-chloro-4-trifluoromethylbenzaldehyde (123 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.05 (d, 1H, J=8.0 Hz), 7.75 (s, 1H), 7.66 (d, 1H, J=8.0 Hz).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-].[Na+].CO.Cl>O>[C:3]1([CH:8]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 1.02 g (7.49 mmol) of 2'-hydroxyacetophenone, 0.49 g (3.65 mmol) of 1,4-benzodicarboxaldehyde, 1.5 g NaOH (in 5 mL of water) and 30 mL MeOH was stirred for 21 hours before the solution was poured into 200 mL water. The resulting mixture was neutralized with dilute HCl and the yellow precipitate was collected by filtration. Recrystalization from MeOH gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 20 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 22% overall yield. MP: 385°-387° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 1.2. Extinction coefficient εmax (M-1 cm-1) 36,000. λmax (abs)=380 nm and λmax (em)=560 nm.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[CH:16]=[C:15]([C:34]([F:37])([F:36])[F:35])[CH:14]=1>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[CH:16]=[C:15]([C:34]([F:36])([F:37])[F:35])[CH:14]=[C:13]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3ccc(C(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-trifluoromethylaniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=61%). MS ISP (m/e): 508.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (d, 1H), 7.65-7.45 (AA′BB′-System, 4H), 7.21 (d, 1H), 7.13 (d, 1H), 6.98 (dxd, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 6.75 (s, 1H), 6.54 (s, 1H), 6.50 (s, 1H), 3.72 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OCC)(O[CH2:25][CH3:26])(=O)=O.C(OCC)(=O)C.Cl>[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][CH3:26])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 2 h

Procedure:
N-t-butoxycarbonyl-L-tyrosine (II, EXAMPLE 1, (235 g, 835 mmol) is dissolved in sodium hydroxide (4N, 705 mL) at 20-25°. Diethyl sulfate (210 mL, 1.60 mol) is added over 15-20 min. The reaction mixture is stirred for 2 hr, then it is cooled with ice-bath (internal temperature around 15°). Ethyl acetate (1400 mL) is added, followed by slow addition of hydrochloric acid (3N, 1410 mL) for 1 hr. The ethyl acetate layer is separated, and the aqueous layer is extracted with ethyl acetate (1400 mL). The ethyl acetate phase is concentrated to about 200 mL, then hexane (1600 mL) is added. The mixture is stirred in an ice-bath for 2 hr, filtered, washed with hexane (800 mL) in 3 portions. The precipitate is dried to give the title compound. The filtrate is concentrated, suspended in ethyl acetate/hexane (80/450 mL) for 2 hr, filtered and washed with hexane (250 mL) in 3 portions and dried to give additional title compound, NMR (MeOH-d4) δ7.11, 6.80, 4.22, 4.05, 3.08, 2.86 and 1.36; CMR δ175.4, 159.3, 157.8, 131.3, 130.4, 115.4, 80.5, 64.4, 56.4, 37.9, 28.7 and 15.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]1[C@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([CH3:45])[C:43]=1[F:44])[CH2:39]Br>C1COCC1>[F:44][C:43]1[C:36]([CH3:35])=[CH:37][C:38]([CH2:39][C@H:8]([CH2:7][CH2:6][CH2:5]/[CH:4]=[CH:3]/[CH:2]([CH3:24])[CH3:1])[C:9]([N:11]2[C@H:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][O:13][C:12]2=[O:23])=[O:10])=[CH:41][C:42]=1[CH3:45]
Reactant: Cc1cc(CBr)cc(C)c1F
Reactant: CC(C)/C=C/CCCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C[C@H](CCC/C=C/C(C)C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a cooled (−78° C.) solution of (R)-3-((E)-8-methylnon-6-enoyl)-4-benzyloxazolidin-2-one (2.000 g, 6.071 mmol) in 40 mL of THF, was added LiHMDS (9.1 mL, 9.1 mmol, 1.0 M in THF). The resulting mixture was stirred at −78° C. under N2 for 1 h and then a solution of 3,5-dimethyl-4-fluorobenzyl bromide (1.450 g, 6.678 mmol) in 10 mL of THF was added. After being stirred at −78° C. for 1 h the reaction mixture was warmed to room temperature for 2 h, and then quenched with 80 mL of NH4Cl solution and extracted with dichloromethane (60 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (1.925 g, 68% yield). GC-MS: tR=8.8 min; m/z 465 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27]([N:31]=[C:32]=[O:33])[CH2:28][CH2:29][CH3:30]>CC(C)=O>[CH2:27]([NH:31][C:32]([NH:14][S:11]([C:10]1[N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1c(C(=O)OCC)cnn1-c1ccccn1
Yield: 95.2 %

Procedure:
To a 70 ml acetone mixture of 8.5 g of 4-ethoxycarbonyl-1-(2-pyridyl)pyrazole-5-sulfonamide and 6.0 g of anhydrous potassium carbonate, added was 3.3 g of n-butylisocyanate at room temperature, followed by heating under reflux for 3 hours. After the reaction was completed, acetone was evaporated under reduced pressure, and then the residue was emptied into ice water to filter insolbles off, and then the filtrate was precipitated with hydrochloric acid. Crystals precipitated was filtered, washed with water and dried to obtain 10.8 g of N-(n-butylcarbamoyl)-4-ethoxycarbonyl-1-(2-pyridyl)pyrazole-5-sulfonamide. m.p.: 180° to 181° C.