Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[C:12]1(=O)[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN1C(=O)CCC1>[F:8][C:7]1[C:2]2[N:1]=[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a solution of 2-amino-3,4,6-trifluorothiophenol (1.79 g, 10 mmol) in NMP (5 ml) was added dropwise a solution of succinic anhydride (1.0 g, 10 mmol) in NMP (5 ml) at ambient temperature under a nitrogen stream and the mixture was heated to 100° C. for 1 hour. The resultant mixture was basified by dilution with aqueous sodium carbonate and washed with ether. The aqueous layer was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield crude crystals, which were washed with hexane-isopropyl ether to give 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid 2.16 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([CH:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[C:8]([OH:10])=[O:9])[O:4][N:3]=1.O.NN.C(O)(=O)C>O>[NH2:11][C@@H:7]([C@H:5]1[O:4][N:3]=[C:2]([Br:1])[CH2:6]1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C(C1CC(Br)=NO1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CC(=O)O
Product: N[C@H](C(=O)O)[C@@H]1CC(Br)=NO1
Reaction time: 7 h
Yield: 46.8 %

Procedure:
To 710 mg (2.3 mmole) of 3-bromo-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid in 15 ml of water is added 260 μl of hydrazine hydrate and the solution stirred at 50° for 7 hours. After cooling, the solution is adjusted to pH 5.5 with acetic acid (80 μl), filtered, and the precipitate washed with 13 ml water. The filtrate is diluted with 200 ml of 2-butanol and allowed to ⟦crystallized⟧ crystallize in the refrigerator for 18 hours. Filtration yielded 240 mg of (αS,5S)-α-amino-3-bromo-4,5dihydro-5-isoxazole acetic acid; concentrating the mother liquors approximately 15% afforded 50 mg of a second crop of (αS,5S)-α-amino-3-bromo-4,5-dihydro-5-isoxazole acetic acid (71%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][CH:28]([CH3:33])[CH2:29][C:30](Cl)=[O:31]>>[CH3:27][CH:28]([CH3:33])[CH2:29][C:30]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:31]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(C)CC(=O)Cl
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)CC(C)C)c4)CC3)cccc2n1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 3-methylbutanoyl chloride.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.[CH2:27]([O:34][CH2:35][C@@H:36]1[CH2:41][C:40]([F:43])([F:42])[CH2:39][CH2:38][C@H:37]1[CH:44]=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[CH2:27]([O:34][CH2:35][CH:36]1[CH2:41][C:40]([F:43])([F:42])[CH2:39][CH2:38][CH:37]1[CH:44]([OH:45])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([S:14][CH3:13])=[CH:20][CH:19]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C[C@@H]1CCC(F)(F)C[C@H]1COCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(SC)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc(SC)cc1)C(O)C1CCC(F)(F)CC1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 2.1 M solution of n-BuLi (11 mL, 23 mmol) in hexanes was added slowly to a 0° C. solution of diisopropylamine (4.0 mL, 28 mmol) in THF (10 mL). Stirring was continued at this temperature for an additional 10 min prior to cooling to −78° C. A solution of ethyl [4-(methylthio)phenyl]acetate (4.64 g, 18.9 mmol) in THF (15 mL) was then introduced and the mixture was stirred at −78° C. for 10 min, −40° C. for 10 min and finally at 0° C. for 5 min. The solution was recooled to −78° C. and a solution of (1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexanecarbaldehyde (4.64 g, 18.9 mmol) in THF (15 mL) was added down the flask wall over 5 min. Stirring was continued at −78° C. for 30 min then at −40° C. for 1 h. A saturated aqueous solution of NH4Cl was added and the reaction mixture was warmed to rt and partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous NaCl solution and dried over Na2SO4. Concentration in vacuo and flash chromatography on silica gel eluting with 3/7 ethyl acetate/hexanes gave ethyl 3-{2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-3-hydroxy-2-[4-(methylthio)phenyl]propanoate as a faint-yellow, thick syrup. 1H NMR (400 MHz, d6-acetone) δ 7.43-7.33 (5H, m), 7.33-7.29 (2H, m), 7.15-7.11 (2H, m), 4.66 (1H, m), 4.57-4.49 (2H, m), 4.16-4.00 (2H, m), 3.74 (2H, d, J= 10.7 Hz), 3.45 (1H, dd, J=2.8, 9.5 Hz), 2.46 (3H, s), 1.84-1.75 (2H, m) 13.5 Hz), 1.73-1.63 (1H, m), 1.17 (3H, t, 7= 7.1 Hz).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[O:19][CH2:20][O:21][CH3:22].CN(C)CCN(C)C.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[C:10]([O:19][CH2:20][O:21][CH3:22])=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:13][C:14]=1[CH3:1]
Reactant: COCOc1c(C(OC)OC)cccc1C(F)(F)F
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COCOc1c(C(F)(F)F)ccc(C)c1C(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A n-butyllithium-1.59M n-hexane solution (40.0 ml, 64.4 mmol) was added dropwise to a solution of 1-(dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (12.0 g, 42.9 mmol) obtained in Example (6-4) and N,N,N′,N′-tetramethylethylenediamine (9.70 ml, 64.4 mmol) in tetrahydrofuran (100 ml) at −40° C. over 5 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. After the reaction mixture was cooled to −40° C., methyl iodide (5.3 ml, 85.85 mmol) was added thereto and the mixture was further stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to give 2-(dimethoxymethyl)-3-(methoxymethoxy)-1-methyl-4-(trifluoromethyl)benzene as an oil (7.19 g, yield: 57%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.C([O-])(O)=[O:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[O:12]1[CH:8]2[CH:7]1[CH2:6][C:5]1[C:10]([CH2:9]2)=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: C1=CCc2ccccc2C1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(c1)CC1OC1C2
Reaction time: 1 h

Procedure:
1,4-Dihydronaphthalene (5 g) was dissolved in methylene chloride (250 ml) and saturated aqueous NaHCO3 (280 ml). The mixture was stirred vigorously at room temperature while meta-chloroperbenzoic acid (70%, 10.0 g) was added in portions. After 1 hour, an aqueous solution of Na2S2O3 (1M, 100 ml) and methylene chloride were added. The methylene chloride layer was separated, washed with water and brine, dried (MgSO4) and evaporated to give a brownish crude mixture, which was chromatographed on a flash column (silica gel; ether:hexane=1:6) to give 2,3-epoxy-1,2,3,4-tetrahydronaphthalene (3.45 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[CH:7]=[C:8]([C:12]3[N:17]=[CH:16][N:15]4[CH:18]=[CH:19][CH:20]=[C:14]4[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1>>[OH:22][C:23]1[CH:24]=[C:25]([C:29]#[C:30][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:21])[CH:7]=[C:8]([C:12]4[N:17]=[CH:16][N:15]5[CH:18]=[CH:19][CH:20]=[C:14]5[CH:13]=4)[O:9]3)=[CH:4][CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=c1cc(-c2cc3cccn3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1cccc(O)c1
Product: O=c1cc(-c2cc3cccn3cn2)oc2cc(C#Cc3cccc(O)c3)ccc12
Yield: 71 %

Procedure:
7-(3-hydroxy-phenylethynyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one was prepared in 71% yield using the method described in example 23A, starting from 7-bromo-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one (example 120C) and 3-hydroxyphenylacetylene. The title compound was isolated as a brown powder.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=[O:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[N+:25]([CH3:28])([O-:27])=[O:26].Cl>C1COCC1>[O:1]([C:9]1[CH:10]=[C:11]([C@@H:12]([OH:13])[CH2:28][N+:25]([O-:27])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
100 mg (0.26 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.30 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 79.3 mg (1.3 mmol) of nitromethane was added dropwise to the mixture. After 67-hour reaction time, 2 ml of 1 N aqueous solution of hydrochloric acid was added to stop the reaction. Then, after 50 ml of ethyl accetate was added, the mixture was subjected to oil-water separation twice with 20 ml of saturated salt solution and once with 20 ml of water, and the ethyl accetate layer was dehydrated with sodium sulfate anhydride and concentrated within evaporator, followed by the purification of the concentrate by silica gel chromatography (n-hexane/acetone=10/1), after which (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 92% e.e. was obtained in a yield of 93%.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[O:18]([CH2:25][CH2:26][NH2:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[O:18]([CH2:25][CH2:26][NH:27][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCOc1ccccc1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccccc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound A (400 mg, 1, 63 mmol), 2-phenoxyethylamine (638 μl) and sodium hydrogencarbonate (1.37 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-phenoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (66 mg).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:4]>C([O-])(O)=O.[Na+].CO>[C:3]([CH:5]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: COc1ccc(C=C(C#N)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C#N)C(=O)O)cc1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (30.2 g) is added portionwise over a period of 2 hours to a stirred mixture of α-cyano-4-methoxycinnamic acid (52.5 g) in aqueous saturated NaHCO3 (200 ml) and methanol (600 ml) cooled to about 15° C. The reaction mixture is allowed to warm to RT, stirred at RT for 30 min and concentrated in vacuo. The residue is partitioned between water and ether and the aqueous layer acidified and extracted with ether. The ether extract is washed, dried over Na2SO4, filtered and the filtrate evaporated in vacuo producing a liquid which is crystallized from toluene yielding the desired product as a solid, M.P. 94°-95° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:12][C:13]=1[C:14]#[C:15][CH2:16][C@@:17]([OH:37])([C:33]([F:36])([F:35])[F:34])[CH2:18][C:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[S:29]([CH3:32])(=[O:31])=[O:30])([CH3:21])[CH3:20])(C)(C)C.C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:21])([CH3:20])[CH2:18][C@:17]([CH2:16][C:15]2[NH:7][C:8]3=[CH:9][N:10]=[C:11]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:12]=[C:13]3[CH:14]=2)([OH:37])[C:33]([F:36])([F:35])[F:34])=[C:23]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(S(C)(=O)=O)cc1C#CC[C@](O)(CC(C)(C)c1ccc(Cl)cc1S(C)(=O)=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)(C[C@@](O)(Cc1cc2cc(S(C)(=O)=O)ncc2[nH]1)C(F)(F)F)c1ccc(Cl)cc1S(C)(=O)=O
Temperature: 70 °C
Yield: 99.5 %

Procedure:
To a solution of the {4-[(S)-6-(4-chloro-2-methanesulfonylphenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-6-methanesulfonylpyridin-3-yl}carbamic acid tert-butyl ester (18.3 g, 28.0 mmol) in 200 mL of methanol was added DBU (12.5 mL, 84.0 mmol). The reaction was heated to 70° C. for 1.5 hours. The reaction was added to a solution of saturated aqueous ammonium chloride solution resulting in the precipitation of a white solid that was collected by vacuum filtration. The solid was washed with water and, after drying under vacuum for 30 minutes, was suspended in 50 mL of cold diethyl ether then vacuum filtered again and washed with 50 mL of cold diethyl ether. The colorless solid was dried on the filter paper under suction to provide (R)-4-(4-chloro-2-methanesulfonylphenyl)-1,1,1-trifluoro-2-(5-methanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol (15.4 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20])[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.9 %

Procedure:
tert-Butyl [3-chloro-4-(trifluoromethyl)phenoxy]acetate (1.2 g, 3.8 mmol) was added trifluoroacetic acid (TFA) (3 ml). The mixture was stirred for 5 hours at ambient temperature. The solvent was removed under reduced pressure to give the residue, which was applied to a recrystallization from hexane-methylene dichloride to furnish 251 mg (80% yield) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][C:40]=1[F:41])[O:9][C:10]1([C:33](OCC)=[O:34])[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][C:28]([CH3:30])=[N:27][CH:26]=4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:17][N:18]=[C:11]12.[Cl-].[NH4+]>C1COCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][C:40]=1[F:41])[O:9][C:10]1([CH:33]([OH:34])[CH2:1][CH3:2])[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][C:28]([CH3:30])=[N:27][CH:26]=4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:17][N:18]=[C:11]12
Reactant: CC[Mg]Br
Reactant: CCOC(=O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21

Procedure:
Under an argon atmosphere, ethylmagnesium bromide (1 M THF solution, 11.8 mL) was added to a suspension of ethyl 8-(3,4-difluorophenoxy)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1200 mg) in THF (12 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (400 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1.CCCCCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:22][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH:24]=2)[OH:27])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 4-bromothioanisole (10.0 g, 49.0 mmol) in 60 mL of anhydrous tetrahydrofuran was cooled to -78° C. under nitrogen and 32 mL (49 mmol) of 1.55M n-butyllithium in hexane was was added dropwise at a rate to maintain temperature below -60° C. The reaction was stirred an additional 15 minutes after addition was complete, and a solution of crude 3-(tert-butyldimethylsilyloxy)benzaldehyde (11.6 g, 49 mmol) in 50 mL of dry tetrahydrofuran was added dropwise over 20 minutes. The reaction was stirred another 30 minutes and quenched at -78° C. with saturated aqueous ammonium chloride. After warming to room temperature, the reaction was diluted with 200 mL of diethyl ether and washed with 50 mL of water and 50 mL of saturated aqueous sodium chloride. After drying over sodium sulfate, the solvent was removed to give 17.5 g (99%) of crude (4-methylthiophenyl) (3-tert-butyldimethylsilyloxyphenyl)methanol as an orange oil.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[C:17]([O:16][C:10]1[CH:9]=[CH:8][C:7]([Br:6])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])(=[O:19])[CH3:18]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Br)cc1C(=O)O

Procedure:
Concentrated sulfuric acid (0.5 ml) was added under stirring to a mixture of 100 g (0.46 mol) of 5-bromosalicylic acid and 105 ml of acetic anhydride. Several minutes later, 1,000 ml of water were added, and the resulting precipitate was collected by filtration and then washed with water. A white matter, which had been collected by filtration, was dissolved in 1,000 ml of ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium chloride (2×300 ml) and was then dried over Na2SO4. The solvent was distilled off under reduced pressure, whereby 105 g of 2-acetyloxy-5-bromobenzoic acid were obtained as white crystals (yield: 88%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>O1CCOCC1.C(N(CC)CC)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:26]([C:25]4[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a stirred solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) (2.8 g, 11.9mol) in 1.4-dioxane (150 mL) and triethylamine (7 mL) was added a solution of N-acetylsulfanilyl chloride (3.5 g, 15 mmol) in 75 mL of 1,4-dioxane at room temperature. The reaction was stirred for 18 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride and washed with diluted hydrochloric acid. The white solid in water layer was collected and dried to give the title compound as a white solid (2.5 g, 43%); 1H NMR (300 MHz, DMSO-d6) δ 1.92 (brs, 4H), 2.06 (s, 3H), 3.68 (brs, 4H), 3.93 (s, 4H), 7.06 (d, J=8.4 Hz, 2H), 7.33 (brs, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0Hz, 2H), 10.24 (brs, 1H), 10.38 (s, 1H); MS (ES) m/z: 432.3 (MH+); HRMS Calcd. for C21H25N3O5S(M+): 431.1515. Found: 431.1530.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.C(OC([N:22]1[C:27](=[O:28])[CH:26]2[CH:24]([CH:25]2[C:29]([O-:31])=[O:30])[CH:23]1[C:32]([O-:34])=[O:33])=O)(C)(C)C.O>C(Cl)Cl>[C:29]([CH:25]1[CH:26]([C:27]([CH:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][NH:6]2)=[O:28])[CH:24]1[CH:23]([C:32]([OH:34])=[O:33])[NH2:22])([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: c1ccc2c(c1)CCNC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.6 %

Procedure:
To a solution of AlCl3 (48.7 mg, 0.36 mmol) in dry CH2Cl2 (1 mL) at 0° C., tetrahydroisoquinoline (88 μl, 0.70 mmol) in CH2Cl2 (1 mL) was added dropwise. The mixture was stirred at room temperature for 10 min, and then ethyl (1SR, 2SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (96 mg, 0.28 mmol) in dry CH2Cl2 (1 mL) was added. After stirring at room temperature for 3 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 2/1) to give 95 mg of the desired compound (71% yield).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:3].C1COCC1>[C].[Pd].C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:2]([NH2:1])=[O:3])[CH:9]=1
Reactant: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1C(N)=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(N)cc1C(N)=O
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of ethyl {[2-(aminocarbonyl)-4-nitrophenyl]amino}(oxo)acetate (2.292 g) in a mixed solvent of THF (100 mL)-ethanol (50 mL) was added 10% palladium carbon (405 mg), and the mixture was subjected to catalytic reduction under hydrogen atmosphere at room temperature for 8 hr. The catalyst was filtered off, and the filtrate was concentrated. The obtained crude crystals were washed with diisopropyl ether to give ethyl {[4-amino-2-(aminocarbonyl)phenyl]amino}(oxo)acetate (1.96 g, 96%).