Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:46][CH3:47]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH2:46][CH3:47])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(CC)CCc2ccc(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a 320 ml anhydrous THF solution of ethyl 7-benzyloxychromane-2-carboxyate 14.6 g (46.6 mmol) was added hexamethylphosphoramide (10.5 ml, 60.4 mmol). Upon cooling in a dry ice-acetone bath, sodium bis(trimethylsilyl)amide (1.0M/THF) (60.5 ml, 60.5 mmol) was added via syringe over 15 min period. The resulting orange solution was stirred at that temperature for 30 min before iodoethane (18.6 ml, 233 mmol) was added via syringe. The reaction was slowly warmed to rt and stirred overnight. The solvent was removed under reduced pressure, and the residue was diluted with AcOEt and aqueous NH4Cl (NH4Cl 7.2 g/200 ml water). The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 7.5% AcOEt/hexanes to give the title compound 15.2 g (96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]=[C:8]=[S:9])=[O:5])[CH3:2].[CH2:10]([N:14]1[C:19]([NH:20][NH2:21])=[CH:18][C:17](=[O:22])[N:16]([CH2:23][CH2:24][CH3:25])[C:15]1=[O:26])[CH2:11][CH2:12][CH3:13]>O1CCOCC1>[CH2:10]([N:14]1[C:19]([NH:20][NH:21][C:8]([NH:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[S:9])=[CH:18][C:17](=[O:22])[N:16]([CH2:23][CH2:24][CH3:25])[C:15]1=[O:26])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCn1c(NN)cc(=O)n(CCC)c1=O
Reactant: CCOC(=O)CN=C=S
Solvent: C1COCCO1
Product: CCCCn1c(NNC(=S)NCC(=O)OCC)cc(=O)n(CCC)c1=O

Procedure:
Ethoxycarbonylmethylisothiocyanate (15 g) was added dropwise to a stirred solution of 1-butyl-6-hydrazino-3-propylpyrimidine-2,4(1H,3H)-dione (11 g) in dioxane (100 ml).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-c2cn(C3CCN(S(C)(=O)=O)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and methylsulfonyl chloride (343.6 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=20:1) to yield the target product as white solid powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23](O)=[O:24])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23]([NH:30][C:31]2[S:32][CH2:33][CH2:34][N:35]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: NC1=NCCS1
Reactant: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)NC2=NCCS2)cc1

Procedure:
5-(4-Methoxyphenyl)-2-(3-nitrophenyl )imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-aminothiazoline are reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(3-nitrophenyl)-N-(2-thiazolinyl)imidazole-4-carboxamide.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23](=O)[CH3:24])=[CH:14]1>O.C(O)C>[Cl:9][C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23](=[N:2][OH:3])[CH3:24])=[CH:14]1
Reactant: CC(=O)Cc1cn(Cc2ccccc2Cl)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(Cc1cn(Cc2ccccc2Cl)c2ccccc12)=NO
Yield: 79 %

Procedure:
2.5 G of hydroxylamine hydrochloride and 2.5 g of sodium acetate dissolved in 10 ml of water are added to 2 g (0.023 mole) of 1-(2-chlorobenzyl)-3-(2-oxopropyl)indole dissolved in 100 ml of 96% ethyl alcohol. Stirring takes place for 12 hours at 20° and the oxime formed is filtered. The product is recrystallised from di-isopropyl ether.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[OH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 54 %

Procedure:
To a stirred suspension of 4-amino-2-nitrobenzoic acid (9.895 g, 54.326 mmol) in water (17 ml) was added concentrated H2SO4 (12 ml). The resulting homogenous solution was cooled in an ice bath and additional water (10 ml) added to aid stirring. Crushed ice (50 ml) was added followed by the drop-wise addition of NaNO2 (4.124 g, 59.759 mmol) in water (9 ml). The temperature was kept below 5° C. during the addition and then stirred for 1.25 h at 0° C. The reaction mixture was quenched by adding urea (6 g), stirred for 10 minutes at 0° C., filtered and the filtrate added drop-wise into a boiling solution of concentrated H2SO4 (39 ml) and water (27 ml). After the addition, the entire mixture was refluxed for 3 hours then cooled. The reaction mixture was extracted with ethyl acetate (6×50 ml) and the combined organics washed with brine, filtered and concentrated to a small volume which was then purified by flash chromatography on silica. The first column was eluted with ethyl acetate and 20% MeOH/EtOAc. The second column was eluted with 10% MeOH/CHCl3 and the third column was eluted with 60% EtOAc/Hexane. The purification process gave 4-hydroxy-2-nitrobenzoic acid (5.331 g, 29.112 mmol, 54%) as an orange solid, dec. 232-236° C. 1H NMR (DMSO-d6) δ 7.05 (dd, 1H), 7.15 (s, 1H), 7.78 (d, 1H) 11.10 (s, 1H), 13.38 (s, 1H); mass spectrum [ES(−)], m/z 182 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:8][C:9]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])=O)C.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:7]2[C:6]([CH2:4][OH:3])=[C:11]([CH:12]([CH3:14])[CH3:13])[N:10]=[C:9]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[N:8]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Ethyl 2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-carboxylic acid (100.0 g) and toluene (500.0 mL) were added to a reactor under nitrogen atmosphere. The reaction mixture was cooled to −78° C. A solution of diisobutylaluminium hydride in toluene (1.5 M, 200.0 mL) was slowly added thereto. The temperature of the reaction mixture was adjusted to 0° C. The reaction mixture was stirred for over 1 hour and then water (500.0 mL) was added thereto. The separated organic layer was sequentially washed with 1N hydrochloric acid solution (500.0 mL), 5% sodium bicarbonate solution (500.0 mL), and then water (500.0 mL), and then concentrated under reduced pressure. n-Hexane (300.0 mL) was added to the resulting residue under stirring. The resulting suspension was filtered under reduced pressure, and then dried to obtain N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide as a white solid (72.3 g, yield 81%).
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:9])([CH:6]([CH3:8])[CH3:7])[C:4]#[N:5].[OH-].[Na+].O.[Br:13][CH:14]([CH2:18][Br:19])[C:15](Cl)=[O:16]>ClCCl>[C:4]([C:3]([NH:9][C:15](=[O:16])[CH:14]([Br:13])[CH2:18][Br:19])([CH3:2])[CH:6]([CH3:8])[CH3:7])#[N:5]
Reactant: O=C(Cl)C(Br)CBr
Reactant: CC(C)C(C)(N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)C(C)(C#N)NC(=O)C(Br)CBr

Procedure:
A mixture of 4.5 g (0.03 mole) of the 2,3-dimethyl-2-aminobutyronitrile hydrochloride, 4.8 g (0.06 mole) of 50% aqueous sodium hydroxide, 15 ml of dichloromethane and 15 ml of water was prepared. A second solution of 7.5 g (0.03 mole) of 2,3-dibromopropionyl chloride in 15 ml dichloromethane was added with rapid stirring to the first mixture at 10°-15° C. The mixture was then allowed to reach room temperature.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=O)[CH3:10])=[CH:4][C:3]=1[CH3:12].Cl.[NH2:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1>>[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[N:14][O:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=2)[CH3:10])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(=O)c1cc(C)c(O)c(C)c1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cc(C)c(O)c(C)c1
Yield: 55.8 %

Procedure:
Following a procedure similar to that described in Example 46, but using 0.22 g of 4'-hydroxy-3',5'-dimethylacetophenone and 0.40 g of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 0.30 g of the title compound was obtained as an amorphous powder, melting at 53°-65° C. (softening point).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:28]>>[NH2:28][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH3:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Reactant: N
Product: COC(CNC(C)Cc1ccc(OCC(N)=O)cc1)c1cccc(Cl)c1

Procedure:
The title compound was prepared, as an oil, from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine and 0.88 ammonia, by an analogous procedure to that described in Example 4. The product was used in Example 24 without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].[F:23][C:24]([F:35])([F:34])[CH2:25]OS(C(F)(F)F)(=O)=O.CO>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([CH2:25][C:24]([F:35])([F:34])[F:23])[CH:8]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cn(CC(F)(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 65.5 %

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in dehydrated DMF (40 ml) was added 60% NaH in oil (596 mg) while stirring under ice-cooling, and the mixture was stirred at the same temperature for 0.5 hr. Then, trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (2.6 g) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added methanol, and the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g).
Reaction SMILES: C1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])CCCC1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.O>[OH:6][C:7]1[CH:8]=[C:9]([N:15]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1OC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid (10.0 g, 23.9 mmol) was dissolved in DCM and 22.3 g (167 mmol) of AlCl3 was added. The dark brown solution stirred at room temperature overnight under N2. The reaction mixture was diluted with 100 mL of DCM and 100 mL of H2O and the pH of the aqueous phase adjusted to 5.5. The aqueous phase was extracted with 500 mL of EtOAc and the combined organic fractions were concentrated to dryness giving the desired compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccccc1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[CH3:37])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:37][C:8]1[CH:9]=[CH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[N:23][C:22]=3[CH3:36])=[O:20])[CH2:14]2)=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)COc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc([C@@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1OCC(=O)O
Temperature: 25 °C
Yield: 96.4 %

Procedure:
A mixture of (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-acetic acid ethyl ester (146 mg, 0.26 mmol), potassium carbonate (71 mg, 0.52 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 130 mg (94%) of (S)-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-acetic acid as a white solid.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>C(OCC)(=O)C.CCCCCC>[F:23][C:24]([F:33])([F:34])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Nc1ccccc1OC(F)(F)F
Yield: 73 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and (2-(trifluoromethoxy)phenyl)amine, the title compound was synthesized in the same manner as in Example 297. Yield: 73%. Melting point: 196-197° C. (ethyl acetate-hexane).
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([NH:22][NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][C@@H:30]3[CH2:33][N:27]2[C:28](=[O:42])[N:29]3[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=O)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:35]([O:34][N:29]1[C:28](=[O:42])[N:27]2[CH2:33][C@H:30]1[CH2:31][CH2:32][C@H:26]2[C:24]1[O:21][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:19][CH2:18]2)=[N:22][N:23]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
Pyridine (2.6 mL, 35.0 mmol) was added to a solution of tert-butyl-4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl) hydrazinecarbonyl)piperidine-1-carboxylate (901 mg, 1.8 mmol) in DCM (200 mL). Then, (CF3SO2)2O (2.6 mL, 9.0 mmol) was added slowly at −10° C. The reaction mixture was stirred at rt for 3 hrs then saturated NaHCO3 was added very slowly at −10° C. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography (2:1 EtOAc/hexanes) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (719 mg, 82%) as a slight yellow solid. ESI-MS (EI+, m/z): 484.2 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:11][CH:10]=2)O1.Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=1>>[CH3:33][C:31]1[CH:32]=[C:27]([C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])=[CH:13][CH:14]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cncc(Br)c1
Product: Cc1cncc(-c2ccc([C@@H]3C[C@H]3NS(=O)(=O)C(C)C)cc2)c1

Procedure:
Example 11 was prepared from trans-N-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}-2-propanesulfonamide (Intermediate 8) (69 mg, 0.189 mmol) and 3-bromo-5-methylpyridine (65 mg, 0.378 mmol) according to a similar procedure as for Example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:29])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
The desired compound was prepared according to the previous example from 4-(2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8yl)-amide (3 CF3COOH salt) and acetic anhydride. 1H-NMR (300 MHz, methyl-d3 alcohol-d): δ 1.15 (d, 3H), 1.23 (s, 3H), 1.39 (s, 3H), 1.98 (s, 3H), 2.24 (d, 1H), 2.38 (m, 1H), 2.68 (m, 1H), 2.92 (d, 1H), 3.24 (m, 1H), 3.98 (m, 2H), 4.22 (m, H), 7.78 (d, 1H), 7.98 (m, 2H), 8.27 (d, 1H), 8.84 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.54 min. MS (M+H+): 458.
Reaction SMILES: Cl.[C:2]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)C(OCC)=O)(=[O:4])[CH3:3]>>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:5][C:2](=[O:4])[CH3:3])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccncc1)C(C)=O
Agent: Cl
Product: CC(=O)CCc1ccncc1
Yield: 110.1 %

Procedure:
Next, 6 N hydrochloric acid (8 ml) was added to ethyl 2-acetyl-3-(4-pyridyl)propionate (1.20 g, 4.81 mmol), and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, 2-propanol (10 ml) was added to the concentrate, and the whole was concentrated under reduced pressure again. Ethyl acetate was added to the resulting solid, and the solid was filtered off to give 0.79 g (89%) of 4-(4-pyridyl)-2-butanone as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[C:11]([CH3:29])=[C:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:13](=[O:20])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].Cl[CH:32]([F:34])[F:33]>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[C:11]([CH3:29])=[C:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=1)[C:13]([O:20][CH:32]([F:34])[F:33])=[N:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)Cl
Reactant: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(F)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(F)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [3-(4-bromobenzyl)-8-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid tert-butyl ester and chlorodifluoromethane.