Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[S:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=3)[CH:3]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)s1

Procedure:
5-{3-[4-(5-Chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.31 g, 0.74 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.28 g, 0.81 mmol) according to the general procedure III. Obtained as light yellow oil (0.23 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.Br[CH:20]([CH3:24])[C:21]([OH:23])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: CC(Br)C(=O)O
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
599 mg (purity 87%, 2.00 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 90° C. Yield: 716 mg (purity 68%, 73% of theory)
Reaction SMILES: [O:1]1[C@H:3]([CH3:4])[CH2:2]1.[CH2:5]([Mg]Br)[CH2:6][CH2:7][CH:8]=[CH2:9].[NH4+].[Cl-]>C1COCC1>[CH3:4][C@@H:3]([OH:1])[CH2:2][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C[C@@H]1CO1
Reactant: C=CCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCCC[C@@H](C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
(R)-(+)-1,2-epoxypropane (1.12 ml, 16.0 mmol) is dissolved in dry THF (23 ml) and CuBr (230 mg, 1.6 mmol) is added therein, after which the temperature is reduced −78° C. The 1M 4-pentenylmagnesium bromide solution (23 ml, 23.5 mmol) prepared in the reaction (1) is added to reaction mixture. The temperature is gradually increased to a room temperature and the mixture is stirred for 4 hours. The reaction is finished with saturated NH4Cl solution (10 ml). An obtained product is extracted with Et2O (20 ml×2) and it is washed by water (10 ml). An organic layer is dried using anhydrous MgSO4. The solution is vacuum concentrated, and then the compound (III) (1.3 g, 65%) is isolated using flash column chromatography (Et2O/n-pentene, 5:1, v/v):
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][O:1][C:2]([CH3:19])([CH3:18])[CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 122.8 %

Procedure:
To a stirred solution of (S)-tert-butyl 4-(2-hydroxy-2-methylpropyl)-2,2-dimethyl-oxazolidine-3-carboxylate (0.93 g, 3.4 mmol) in anhydrous THF (8 mL), there was added NaH (60 wt % in mineral oil, 0.41 g, 10.2 mmol) followed by iodomethane (1.46 g, 10.2 mmol). The resulting mixture was stirred at rt until no starting material remained (˜5 h). The reaction was quenched by slow addition of water, the organic layer was separated, and aqueous layer was extracted with ether (2×5 mL). The combined organic layers were washed with 1 N aq HCl (5 mL), sat'd aq NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated to give crude (S)-tert-butyl 4-(2-methoxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.2 g, quant.) which was used without purification. MS m/z 310 (M+Na+).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H][H]>>[C:5]1([CH:3]([OH:4])[CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=C(CO)c1ccccc1
Product: OCC(O)c1ccccc1
Yield: 98 %

Procedure:
The reaction of α-hydroxyacetophenone was performed by the same method as in Example 3 except that the reaction was performed at a hydrogen pressure of 10 atm. As a result, optically active 1-phenyl-1,2-ethanediol with 97% ee was produced in a yield of 98%. The R and S isomers were not identified.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][C:3]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)ccc1I
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)ccc1I
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 4-iodo-3-methylaniline (4.37 g, 18.75 mmol) in CH2Cl2 (25 ml) was treated with pyridine (6.07 ml, 75 mmol) followed by drop wise addition of methanesulfonyl chloride (1.607 ml, 20.63 mmol) to give a reddish/orange mixture. The mixture was stirred for 2 h, concentrated and diluted with EtOAc. The EtOAc layer was washed with 1M HCl, water, saturated NaCl, dried (Na2SO4) and filtered. The EtOAc filtrate was treated with activated charcoal for 30 min at 50° C. and filtered through a 10 g silica plug and concentrated to give the title compound as a light yellow solid (5.5 g, 94%).
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:50][CH:51]=[C:45]([CH:46]=[CH:47]2)[O:44][CH2:43][CH:42]=[CH:41][CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:54])[CH3:53])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-:56].[Na+].OO>C1COCC1>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:47][CH:46]=[C:45]([CH:51]=[CH:50]2)[O:44][CH2:43][CH2:42][CH:41]([OH:56])[CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:53])[CH3:54])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COCC(O)CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.55 ml (773 μmol) (0.5M in THF) of 9-borabicyclo[3.3.1]nonane were added to a solution of 50 mg (77 pmol) of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)ureido]hexanoate (8-1B) in 1.5 ml of THF, and the mixture was stirred at RT overnight. Addition of 250 μl (1.49 mmol) of 6N sodium hydroxide solution and 207 μl (1.83 mmol) of hydrogen peroxide was followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:12][C:9]1[C:8]([O:10][CH3:11])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [Br-]
Reactant: COc1cc(N)cc(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1cc(N)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 62.7 %

Procedure:
3,5-Dimethoxyaniline (7.55 g) was dissolved in CH2Cl2 (100 mL) under N2 and the solution was cooled to −78° C. A solution of tetrabutylammonium tribromide (25 g) in CH2Cl2 (100 mL) was added and the mixture was stirred at that temperature for 45 min. The mixture was allowed to warm up to room temperature, stirred for 1.5 h and extracted with 1N HCl. The extract was neutralized with 3 N NaOH and extracted with AcOEt. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/AcOEt 4:1 to 2:3) to give 4-bromo-3,5-dimethoxyaniline (3.76 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[O:17]=[C:16]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]=2[NH:1]1
Reactant: CCOC(=O)C(C)c1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
A solution of Ethyl 2-(3,4-diaminophenyl)propanoate (217 mg, 1.04 mmol) in CH2Cl2 (4 mL) was added 1,1′-carbonyldiimidazole (189 mg) and DBU (330 mg, in CH2Cl2 (4 mL)) at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:19][N:18]=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Solvent: CO
Solvent: O
Product: FC(F)(F)c1cc(-c2ccc(Br)cc2)[nH]n1

Procedure:
A stirred solution of compound 34 (15.0 g, 50.0 mmol) and hydrazine hydrate (10.0 g, 56 mmol) in methanol 150 mL was heated to reflux for 1 h. After cooling in an ice bath for 10 min, the solvent was removed, water (100 mL) added, and the reaction mixture extracted with ethyl acetate (50 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated crude. The crude product was purified by column chromatography using 10% ethyl acetate in hexane, to afford the crude pyrazole intermediate 34a.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][NH:10][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][CH2:16]1
Reactant: NCCCN1CCOCC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCCCN1CCOCC1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and 4-(3-aminopropyl)morpholine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N:15]([CH2:24][C:25]([O:27]CC)=[O:26])[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17].[OH-].[Na+].O1CCCC1>CO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N:15]([CH2:24][C:25]([OH:27])=[O:26])[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of ethyl N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-N-(2-thienylsulfonyl)aminoacetate (0.29 g), 1N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated to give the title compound (0.19 g, yield 69%) as colorless crystals. melting point>218° C. (decomposition).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:9]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:9]=2)=[O:36])=[CH:30][C:29]=1[O:38][CH3:39]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a stirred mixture of methyl 2-(2-pyrrolidinyl)methoxypyridine-5-carboxylate (370 mg, 1.57 mmol), 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (525 mg, 1.57 mmol), 4-DMAP (230 mg, 1.88 mmol) in DMF (10 ml) was added EDC.HCl (360 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air-dried. The crude solid was purified by silica-gel (30 ml) column chromatography with CHCl3—EtOH (98:2, v/v) as eluent and crystallized with Et2O to give methyl 2-[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenyl acetyl]-2-pyrrolidinylmethoxy]pyridine-5-carboxylate (600 mg, 69%) as an amorphous solid. 1H-NMR (CDCl3) δ0.21 and 2.01 (each m, 4 H), 3.45-4.50 (series of s and m, 13H which contains amide-isomers), 6.58-8.83 (series of s and m, 12 H which contains amide-isomers)
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:20])[NH:12][CH:11]([CH3:13])[CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9]1.[Cl:21][CH:22]([Cl:26])[C:23](Cl)=[O:24]>C(N(CC)CC)C>[CH3:20][C:8]1([CH3:7])[N:12]([C:23](=[O:24])[CH:22]([Cl:26])[Cl:21])[CH:11]([CH3:13])[CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9]1
Reactant: CC1NC(C)(C)OC1c1ccccc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1C(c2ccccc2)OC(C)(C)N1C(=O)C(Cl)Cl
Reaction time: 0.5 h

Procedure:
Twenty-three (23) ml. of a benzene solution containing 5.7 g. of 2,2,4-trimethyl-5-phenyl oxazolidine was mixed with 25 ml. of benzene and 3.1 g. of triethylamine and stripped at room temperature, while 4.4 g. of dichloroacetyl chloride was added dropwise. After standing for about 30 minutes, the mixture was washed with water, separated, dried over magnesium sulfate and stripped under vacuum. The product which crystallized was extracted with ether and precipitated with pentane. There was obtained 3.9 g. of a solid, the title compound, m.p. 126° C.
Reaction SMILES: Cl.C1COCC1.CC1(C)[O:32][CH2:31][C:11]2([CH2:14][C:13]([C:20]3[N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:23]4=[N:22][N:21]=3)([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH2:12]2)[CH2:10][O:9]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[N:22]1[N:21]=[C:20]([C:13]2([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][C:11]([CH2:31][OH:32])([CH2:10][OH:9])[CH2:14]2)[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:23]=12
Reactant: CC1(C)OCC2(CO1)CC(c1cccs1)(c1nnc3n1CCCCCC3)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OCC1(CO)CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
1M Hydrochloric acid was added to a THF (10 ml) solution of 3-[7,7-dimethyl-2-(2-thienyl)-6,8-dioxaspiro[3,5]non-2-yl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2270 mg) and the whole was stirred at room temperature for 30 minutes. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=9:1) to obtain 1862 mg of [3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocin-3-yl)-3-(2-thienyl)cyclobutane-1,1-diyl]dimethanol (colorless solid).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1.98 g of caffeic acid was dissolved in 100 mL of dimethylformamide. 2.28 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 5.7 mL of phenethyl bromide in 10 mL dimethylformamide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 200 mL of water and extracted with ethyl acetate (3×100 mL). The combined organic extract was washed with 100 mL of 1N HCl and water (3×100 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from ethyl acetate/hexane by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 600 mg and the purity was greater than 90%.
Reaction SMILES: [C:1]([N:8]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([N:8]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
The compound obtained in Example 12-2 (351.3 mg) was dissolved in methanol (3.5 ml) and THF (3.5 ml). After the addition of 1 mol/l aqueous solution of sodium hydroxide (3.5 ml), the mixture was stirred for 2 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in distilled water (1.2 ml) and aqueous solution of hydrochloric acid (1 mol/l) was added to adjust the pH to 4. The mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain the target compound (277.9 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25])[CH3:21]>C(Cl)(Cl)Cl.CO>[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH:25][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:21]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(C)C

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-valine ethyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.2 in 97:3 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:32])[C@H:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[NH2:26].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH:25]([NH:26][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[C:24]([O:23][CH3:22])=[O:32]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(Cl)c4Cl)cc3)c2cc1OC
Yield: 100 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2,3-dichlorophenyl isocyanate (0.05 ml) was added, and the admixture was refluxed with heat for 20 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 84 mg of the title compound (yield: 100%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH:12]=[C:13]([C:15]([OH:17])=O)[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:35])([F:34])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[NH2:23].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[F:20][C:21]([F:34])([F:35])[CH:22]([NH:23][C:15]([C:13]1[O:14][C:10]2[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:19]=[CH:18][C:11]=2[CH:12]=1)=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)O)oc2c1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 6-(tert-butoxycarbonyl)-1-benzofuran-2-carboxylic acid (350 mg, 1.33 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (357 mg, 1.46 mmol) in N,N-dimethylformamide (5 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (304 mg, 1.46 mmol) and stirred in a closed vessel at 50° C. overnight. The cooled reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat. sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. This leaves 453 mg as a mixture of the tert-butyl ester and of the free acid, which was used for the next step without further purification.