Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:37])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=3[N+:34]([O-])=O)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12](=[O:37])[O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:31])[F:32])=[CH:25][C:24]=3[NH2:34])=[CH:20][CH:21]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3N)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102 %

Procedure:
To a stirred solution of 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl (4-methylphenyl)sulfonylcarbamate (step 1, 1.51 g, 2.71 mmol) in methanol (250 ml) was added 5% platinum-sulfided on carbon (600 mg). The mixture was stirred at room temperature for 5 h under hydrogen atmosphere (4 atm). The palladium catalyst was removed by filtration and washed with dichloromethane (100 ml). The filtrate was concentrated under reduced pressure to afford 1.46 g (99%) of the title compound as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[CH2:17].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:17]=[CH:16][N:18]1[C:19](=[O:28])[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cc1ccccc1C=CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 25.8 %

Procedure:
A mixture of 3-bromo-phenyl acetic acid tert-butyl ester (5.64 g, 20.80 mmol), N-vinyl phthalimide (3.60 g, 20.80 mmol), diisopropylethylamine (3.63 g, 28.08 mmol), palladium acetate (107 mg, 0.478 mmol), and tri-o-tolylphosphine (475 mg, 1.56 mmol) in acetonitrile (10 mL) was stirred at 90° C. for 20 h. The reaction was cooled to room temperature and ice water (50 mL) was added. EtOAc (50 mL) was added and the organic solution was washed with 5.5% HCl followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1 to 4:1) provided the title compound (1.95 g). MS 381 (M+18).
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].CS[C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1.CI>CO>[CH3:2][O:3][C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1
Reactant: C[O-]
Reactant: CSc1nnc(-c2ccccc2)c(=O)n1N
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CI
Product: COc1nnc(-c2ccccc2)c(=O)n1N
Reaction time: 1 h

Procedure:
2.3 g sodium are added to 500 ml methanol whereby a sodium methylate solution is formed. 23.4g 3-methylthio-4-amino-6-phenyl-1,2,4-triazine-5-one (1a) and 6.5 ml methyl iodide are added. The mixture is boiled for 1 hour. When cooling down the mixture, a crystalline precipitate separates. The crystals are removed by suction and recrystallized from methanol and optionally once more from acetic acid ester. The 3-methoxy-4-amino-6-phenyl-1,2,4-triazin-5one (33") thus obtained has a melting point of 167° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.[C-:17]#[N:18].[K+]>CN(C=O)C.CCOC(C)=O>[NH2:16][C:4]1[N:5]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:17]#[N:18])[N:3]=1
Reactant: [C-]#N
Reactant: CN(c1ccccc1)c1nc(N)nc(Cl)n1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(C#N)n1
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a stirring solution of 6-chloro-N-methyl-N-phenyl-[1,3,5]triazine-2,4-diamine (Intermediate 41, 360 mg, 2.67 mmol) in DMF (25 ml) was added potassium cyanide (435 mg, 6.68 mmol). The reaction was stirred at 120 C under nitrogen for 2 h. The reaction mixture was diluted with EtOAc (80 ml); the solution was then extracted with 5% aq. sodium hydrogencarbonate solution (2×20 mL), and saturated brine (2×5 mL). After evaporation of the solvent, the crude residue was purified by FCC over silica gel eluting with heptane:EtOAc 1:0 to 8:2 to 6:4 to furnish the desired product (380 mg, 63%). Method C HPLC-MS: MH+ requires m/z=227. Found: m/z=227, Rt=1.24 min (95%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc(N)c(F)c1
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A cooled solution of 2-Fluoro-4-vinylaniline (20-1, 0.96 g, 7 mmol) in pyridine (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.644 mL, 8.4 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:3) as eluant to afford N-(2-Fluoro-4-vinylphenyl)methanesulfonamide (20-2, LJO-325, 1.372 g, 91%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:14])[C:5]([F:13])=[C:6]2C(=O)[O:10][C:8](=[O:9])[C:7]=12.O.[OH-].[Li+].[CH2:19]([OH:21])[CH3:20]>O>[CH2:19]([O:21][C:3]1[C:2]([F:1])=[C:7]([CH:6]=[C:5]([F:13])[C:4]=1[F:14])[C:8]([OH:10])=[O:9])[CH3:20]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CCO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 140 °C
Yield: 77.5 %

Procedure:
4.4 g (20 mmol) of tetrafluorophthalic anhydride are dissolved in 3 g of water and 30 g of ethanol, 4.2 g of lithium hydroxide hydrate are added, and the mixture is heated at reflux for 48 hours. Then 50 g of water are added and an ethanol/water mixture (31.9 g) is distilled off until a head temperature of 100° C. is reached. Subsequently a pH of 0.6 is established by adding 19 g of 30% strength hydrochloric acid, and the mixture is extracted using a mixture of 20 g of 1,2-dichlorobenzene and 10 g of Hostarex A327. The organic phase is dried over MgSO4, heated at 140° C. for one hour until the evolution of gas comes to an end (decarboxylation) and then adjusted at 25° C. to a pH of 14 using 12.1 g of 35% strength sodium hydroxide solution. The mixture is extracted three times with in each case 50 g of dichloromethane, and the aqueous phase is adjusted to a pH of 0.7 by adding 9.4 g of 30% strength hydrochloric acid and extracted with MTBE. The mixture is dried over MgSO4 and filtered, and removal of the solvent leaves 3.4 g (15.5 mmol, corresponding to 77%) of yellowish 3-ethoxy-2,4,5-trifluorobenzoic acid (purity by GC>95%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:17])[C:9]([C:14]([OH:16])=O)=[CH:10][NH:11]2)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:17])[C:9]([C:14]([NH:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[O:16])=[CH:10][NH:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCOc1ccc2c(=O)c(C(=O)O)c[nH]c2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)c[nH]c2n1

Procedure:
7-Ethoxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.9 g) and N,N-carbonyldiimidazole (2 g) in dimethylformamide (50 ml) were stirred and heated at 100° for 4 hours. 5-Amino-1H-tetrazole (2.1 g) was added and the mixture stirred and heated at 100° for 30 minutes, and cooled. The solid was collected and dissolved in hot (60°) dilute sodium hydroxide and the solution was neutralised (pH 7) with dilulte hydrochloric acid. The solid was collected, washed with water and dried, m.p. above 319° (d), (75 %).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].C([N:19](CC)CC)C.ClC(OCC(C)C)=O.N>C(OCC)(=O)C>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:19])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Reaction time: 2 h
Yield: 78 %

Procedure:
2.29 g (10 mmoles) of BOC-HPro-OH are dissolved in 30 ml of ethyl acetate, 1.4 ml (10 mmoles) of triethylamine are added to the solution, and then 1.3 ml (10 mmoles) of isobutyl chloroformate are added dropwise at -10° C. After 15 minutes of stirring gaseous ammonia is passed through the mixture at -10° C. for 0.5 hours, and the resulting mixture is allowed to stand at 0°-5° C. for 2 hours. The separated precipitate is filtered off, the filtrate is evaporated, and the oily residue is dissolved in 30 ml of chloroform. The solution is shaken twice with 10 ml of n hydrochloric acid, each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The oily residue is crystallized from n-hexane, and the resulting 1.96 g of crude product are recrystallized from a mixture of ethyl acetate and ether. 1.78 g (78%) of BOC-HPro-NH2 are obtained; m.p.: 138°-140° C., Rf2 =0.43, [α]D25 =-24.85° (c=1%, in acetic acid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1.[CH:35]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:37][CH2:36]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH:35]4[CH2:37][CH2:36]4)(=[O:40])=[O:39])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(Nc3ccc(F)cc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)C1CC1)c1cnn2c(Nc3ccc(F)cc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 44.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (55 mg, 0.12 mmol) obtained in step 2 and cyclopropanesulfonamide (72 mg, 0.59 mmol), the title compound (30 mg, 44%) was obtained.
Reaction SMILES: C1N(CCO)CCN(CCS(O)(=O)=O)C1.[OH:16][C@H:17]1[O:24][C@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@H:19]([OH:20])[C@H:18]1[NH:27][C:28]([CH3:30])=[O:29].CC(N[C@H]1[C@@H](OP(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)O[C@H](CO)[C@@H](O)[C@@H]1O)=O>C(#N)C>[C:28]([NH:27][C@@H:18]1[C@@H:19]([OH:20])[C@H:21]([OH:22])[C@@H:23]([CH2:25][OH:26])[O:24][CH:17]1[OH:16])(=[O:29])[CH3:30]
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O
Agent: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Solvent: CC#N
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
The reaction solution contained 50 mM HEPES buffer, 10 mM MnCl2, 0.1% Triton-CF54, 1 mM pNp-α-GalNAc and 1.5 mM UDP-GlcNAc, to which 5 μl of β3Gn-T6 was added, so as to have a total volume of 20 μl. The reaction was carried out at 37° C. for 16 hours. After completion of the reaction, analysis was carried out using HPLC. The column used was Mightysil RP-18, 250×4 mm, the solvent was acetonitrile: H2O=10:90, and the detection was carried out in terms of the absorption at 210 nm. As standard samples, GlcNAcβ1-3GalNAcα-pNp (core 3 structure) and GlcNAcβ1-6GalNAcα-pNp (core 6 structure) were used (SIGMA). As a result, as for the standard samples, GalNAcα-pNp was eluted at 23.5 minutes, GlcNAcβ1-3GalNAcα-pNp was eluted at 18.6 minutes and GlcNAcβ1-6GalNAcα-pNp was eluted at 20 minutes. As for the β3Gn-T6 solution, the peak at 23.5 minutes (GalNAcα-pNp) and the peak at 18.6 minutes (GlcNAcβ1-3GalNAcα-pNp) were observed. Thus, β3Gn-T6 is a novel enzyme having an activity to transfer N-acetylglucosamine to a non-reducing terminal of N-acetylgalactosaminyl group through the β1,3-linkage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[N:27]([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[N:27]=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccccc1-n1nnnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (150 mg, 0.334 mmol) in acetic acid (0.5 mL) was treated with a solution of sodium nitrite (115 mg, 1.6 mmol) in water (0.5 mL) at 0° C. After 30 min, an additional 50 mg of sodium nitrite was added. After 10 min, 3 mL of 10% aqueous sodium hydroxide was added. The mixture was extracted with ethyl acetate and the organics dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography to give 286 as a colorless solid (111 mg). 1H NMR (dmso-d6, 400 MHz) δ 8.00 (m, 1H), 7.98 (m, 1H), 7.85 (m, 1H), 7.56 (m, 1H), 7.46 (m, 1H), 7.26 (m, 2H), 7.13 (m, 1H), 4.27 (t, 2H), 3.11 (t, 2H). MS (ESI) 461.1
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.CS([O-])(=O)=O.[C:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[C:27](O)[CH:26]=[CH:25]2)(=[NH:21])[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>CO.N1C=CC=CC=1>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19](=[NH:20])[NH2:21])[CH:23]=3)[C:28]=2[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:10])=[CH:7][CH:6]=1
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(O)ccc2c1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)[O-]
Solvent: c1ccncc1
Solvent: CO
Product: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
100 Milliliters of 20% hydrous pyridine was added to 3.16 g of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 2.94 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthol and 4.54 g of DCC, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 20 ml of DMF. The resulting solution was added dropwise to 500 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. To the collected precipitate was added 150 ml of methanol to dissolve the precipitate. To the solution was added 3 g of active carbon, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added 30 ml of methanol to dissolve the residue with heating. The resulting solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 2.5 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[CH3:13].[Li][CH:15](CC)C.CI>O1CCCC1>[CH2:12]([C:5]1[C:4]([CH3:13])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH3:15]
Reactant: [Li]C(C)CC
Reactant: COc1ccc(C(=O)O)c(C)c1C
Solvent: CI
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)ccc(OC)c1C
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
2.50 g of 4-methoxy-2,3-dimethylbenzoic acid (G1) are dissolved in 160 ml of tetrahydrofuran under a nitrogen atmosphere and cooled to (−) 78° C. 11.5 ml of sec-BuLi are subsequently added dropwise at such a rate that the temperature of the reaction solution does not exceed (−) 65° C. When the addition is complete, the reddish reaction solution is stirred for a further 30 min with cooling. 3.59 ml of methyl iodide are then slowly added drop-wise. The cooling is subsequently removed, and the mixture is stirred for 1 h. For work-up, 160 ml of water are carefully added. The solution is subsequently extracted twice with 130 ml of ethyl acetate each time. The aqueous phase is cooled in an ice bath with stirring, acidified using 1.0 M HCl and filtered after 30 min. The filter cake is rinsed with cold water and subsequently recrystallised from 2-propanol. The crystals are filtered off with suction and dried for 2 h at 70° C. in vacuo, giving 1.90 g of the title compound as a colourless, crystalline solid having a melting point of 176.7° C.; MS: 194.2 (M+); TLC: Rf=0.29 (diethyl ether/petroleum ether 1:1 parts by volume).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][CH:11]([CH2:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)/C=C/Cc1cc(F)c(F)cc1F
Reactant: NCc1ccccc1
Product: COC(=O)CC(Cc1cc(F)c(F)cc1F)NCc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
In a thick-walled glass vial equipped with a magnetic stir bar was placed methyl(E)-4-(2,4,5-trifluorophenyl)-but-2-enoate (IIa) (0.5 mmol, 115 mg) and reaction system was slowly heated to 60° C. under intensive stirring. Afterwards benzylamine (0.6 mmol; 66 mL) was slowly added to (IIa) and such reaction system was vigorously stirred (800 rpm) at 70° C. for 12 hours. The reaction mixture was than extracted with tert-butyl methyl ether (20 mL), organic phase was washed with brine (20 mL) and dried over anhydrous Na2SO4. After evaporation of organic solvent under reduced pressure we obtained crude product (Ib) (85 mg, 50% yield) which was analyzed and confirmed with 1H and 13C NMR.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:9]([NH2:11])=O.[ClH:17]>C(OCC)C>[ClH:17].[CH3:7][CH:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:9][NH2:11]
Reactant: CC(CC(F)(F)F)C(N)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(CN)CC(F)(F)F
Temperature: 0 °C
Yield: 141.3 %

Procedure:
To a suspension of lithium aluminum hydride (15.5 g) in diethyl ether (290 ml) was added a solution of 2-methyl-4,4,4-trifluorobutyramide (31.74 g) in diethyl ether (0.5 L) at a rate to obtain a gentle reflux. After heating at reflux for 12 hours and cooling to 0° C., the reaction was quenched with saturated sodium sulfate solution and allowed to warm to ambient temperature. The mixture was dried (Na2SO4) and filtered through diatomaceous earth with diethyl ether wash. The filtrate was treated with gaseous hydrochloric acid (14.9 g, 0.409 mol) and then the solvent was evaporated. The residue was dissolved in methylene chloride and combined with product from a similar reaction of 2-methyl-4,4,4-trifluorobutyramide (25 g). Recrystallization from methylene chloride and diethyl ether, followed by trituration with ethyl acetate, afforded 2-methyl-4,4,4-trifluorobutylamine hydrochloride (51.35 g, 79%) as a light pink solid; mp 224.5°-225.5° C.; MS(CI): 142 (M+H-HCl). Analysis for C5H11ClF3N: Calculated: C, 33.81; H, 6.24; N, 7.89. Found: C, 33.93; H, 6.13; N, 8.17.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[CH3:26][C:27]1([CH3:36])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:26][C:27]1([CH3:36])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:25])[CH2:28]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: CC1(C)CNc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccccc21

Procedure:
70 mg (0.21 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 30.33 mg (0.21 mmol) 3,3-dimethyl-2,3-dihydro-1H-indole, 71 mg (0.22 mmol) TBTU and 56 μL (0.40 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C:22]2[C:27]([CH2:28][CH2:29][O:30][CH3:31])=[C:26]([CH2:32][CH3:33])[C:25]([O:34]C(OC)=O)=[CH:24][C:23]=2[O:39]C(OC)=O)[CH:19]=[CH:20][CH:21]=1)[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C:22]2[C:27]([CH2:28][CH2:29][O:30][CH3:31])=[C:26]([CH2:32][CH3:33])[C:25]([OH:34])=[CH:24][C:23]=2[OH:39])[CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: CCOc1cccc(-c2c(OC(=O)OC)cc(OC(=O)OC)c(CC)c2CCOC)c1
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cccc(-c2c(O)cc(O)c(CC)c2CCOC)c1
Yield: 50 %

Procedure:
In the same manner as in Example 118, 1-[3-(3-ethoxyphenyl)-4,6-bis(methoxycarbonyloxy)-2-(2-methoxyethyl)phenyl]ethanone was obtained from Compound 121 (94 mg, 0.29 mmol) obtained in Example 121, using methyl chlorocarbonate (0.05 mL, 0.65 mmol), triethylamine (0.09 mL, 0.65 mmol) and tetrahydrofuran (3.0 mL); and from the resulting compound, obtained was 2-(3-ethoxyphenyl)-4-ethyl-1,5-bis(methoxycarbonyloxy)-3-(2-methoxyethyl)benzene, using sodium borohydride (30 mg, 0.79 mmol), water (2.0 mL) and tetrahydrofuran (2.0 mL). Then, the resulting compound was treated with methanol solution (5.0 mL) of 7 mmol/L ammonia to obtain Compound 133 (45 mg, 50%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:21]([OH:29])=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](OCC)(=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[O:28]=[C:26]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20](/[CH:19]=[CH:18]/[C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:13][CH:14]=3)[C:21]=2[O:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccccc3)cc2)c1O
Product: CCOC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2o1
Yield: 66 %

Procedure:
Following the process described in example 1 (point A), starting from 3'-[(E)-2-[4-(4-phenylbutoxy)phenyl]-ethen-1-yl]-2'-hydroxyacetophenone and diethyl oxalate, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 6:4 (66% yield).