Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH2:6][NH:5][C:4]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@H:3]1[CH2:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][NH:5][C:4]1=[O:14])=[O:26])=[CH:19]2
Reactant: N[C@H]1Cc2ccccc2CNC1=O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1Cc2ccccc2CNC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (S)-4-amino-2,3,4,5-tetrahydro-2-benzazepin-3(1H)-one hydrochloride (all of that prepared above), tetrahydrofuran (25 mL), 5-chloroindole-2-carboxylic acid (198 mg), 1-hydroxy-7-azabenzotriazole (150 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (210 mg) was stirred at room temperature. Diisopropylethylamine (202 mg) was added, and after 16 h the resulting yellow solution was evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), and this was washed sequentially with 1.0 M aqueous hydrochloric acid (50 mL twice), 1.0 M aqueous sodium hydroxide (50 mL), water (50 mL), and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to provide crude product. The product was crystallized by dissolving in warm methanol (40 mL) and adding diethyl ether (100 mL). The crystals were filtered, washed with diethyl ether (30 mL twice), and dried under vacuum to provide the title compound (181 mg). HPLC/MS [M+H]+, 354.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22](Cl)=[O:23])[CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([C:22]([C:19]2[CH:18]=[C:17]([CH3:16])[O:21][N:20]=2)=[O:23])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Cc1cc(C(=O)Cl)no1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 20.6 g (0.1 mole) of 2,6-di-tert-butylphenol and 15.6 g (0.107 mole) of 5-methylisoxazole-3-carboxylic acid chloride in 100 mL of CS2 is added 14.3 g (0.107 mole) of AlCl3 at +5° C. Vigorous stirring is maintained at that temperature for 1 hour and then at room temperature for 1 hour. The CS2 is decanted off and the residue treated with 350 mL of ice cold IN HCl and extracted with Et2O. The extracts are washed with saturated NaHCO3 solution and brine, dried with Na2SO4 and evaporated to give a mixture of products. The desired product is separated by flash chromatography (0% to 50% CH2Cl2 /n hexane) on silica gel to give 4.4 g of the crude ketone which is recrystallized from n-pentane to give 2.3 g (14%) of pale yellow crystals, [3,5-bis(1,1 dimethylethyl)-4 -hydroxyphenyl(5-methyl-3-isoxazolyl)methanone, mp 120° C.; 1H NMR (CDCl3)δ1.48 (s, 18H, tert-butyl), 2.52 (s, 3H, CH3), 5.85 (s, 1H, OH), 6.48 (s, 1H, isoxazole aromatic), 8.23 (s, 2H, phenyl aromatics); IR (KBr) 1590, 1600, 1650, 3600 cm-1 ; MS (DEI) m/e 315 (M+), 300 (M-CH3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)C=O.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21]([CH2:23]Br)=[O:22]>O>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21]([CH2:23][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:22]
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cooled slurry of 35 g. of imidazole in 25 ml. of dimethylformamide is added 24.9 g. of bromomethyl 2-naphthyl ketone. The mixture is stirred for 2 hours at 0° C., and then allowed to come to room temperature and stirred overnight. The solution is poured into water and the resulting sticky solid filtered off, washed with water and dissolved in benzene. Thereafter the resultant benzene solution is dried (azeotroped) to afford 1-(2-naphthoylmethyl)imidazole which is converted to its hydrochloride acid addition salt by addition of ethereal hydrogen chloride until precipitation is complete. The salt is crystallized by the addition of ethyl acetate and the resulting solid recrystallized from methanol/acetone to yield colorless needles of 1-(2-naphthoylmethyl)imidazole hydrochloride, m.p. 226°-228.5° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[N:15]=[C:14]3[O:26]C)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[NH:15][C:14]3=[O:26])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1nc2c(c(=O)n(C)c(=O)n2C)n1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Product: Cn1c(=O)c2c([nH]c(=O)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 130 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To 7-[4-(4-chlorobenzoyl)benzyl]-1,3-dimethyl-8-methoxyxanthine (400 mg) was added concentrated hydrochloric acid (8 ml) at room temperature and the mixture was stirred at 130° C. for 1 hour. After cooling, the resulting precipitate was collected by filtration and rinsed with water and ether to provide the title compound as colorless powder (333 mg, 86%). 1H-NMR (CDCl3 +5% CD3OD) E: 3.36(3H,s), 3.45(3H,s), 5.23(2H,s), 7.40-7.80(8H,m).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH3:1][N:2]([CH2:5][CH2:6][CH2:7][CH:8]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:3]
Reactant: BrCCCC=C(c1ccccc1)c1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Next, an aqueous solution (40%) of dimethyl amine (25 equivalents) is added slowly to a THF solution of 1.0 equivalent of 5-bromo-1,1-diphenyl-1-pentene that has been obtained in the previous step. The mixture is then stirred at room temperature for 24 hours, and worked up in the usual manner to yield 5-(N,N-dimethyl)amino-1,1-diphenyl-1-pentene as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH2:18][NH2:19])[N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH2:18][NH:19][C:30](=[O:32])[CH3:31])[N:11]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2nc(-c3cccc(CN)c3)n[nH]2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(-c3cccc(CNC(C)=O)c3)n[nH]2)cc1
Reaction time: 1.5 h
Yield: 794.9 %

Procedure:
A solution of 3-[5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzylamine hydrochloride (1:1) (50 mg, 0.016 mmol) and triethylamine (32 mg, 0.032 mmol) in CH2Cl2 (5 ml) was stirred at r.t. for 30 min. Acetyl chloride (12 mg, 0.016 mmol) was then added and the mixture stirred for 1.5 hrs. The reaction mixture was evaporated and chromatographed over SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4. This afforded a yellow oil, which was then dried under high vacuum at 50° C. to afford the title compound (41 mg, 72% yield) as a light yellow solid. MS: m/e=323.3 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:32]([C:38]1[S:42][C:41]([C:43](Cl)=[O:44])=[CH:40][CH:39]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>O>[CH2:32]([C:38]1[S:42][C:41]([C:43]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:22]3[N:23]=[CH:24][C:19]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][N:21]=3)=[CH:30][CH:29]=2)=[O:44])=[CH:40][CH:39]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCc1ccc(C(=O)Cl)s1
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CCCCCC)s3)cc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.1 %

Procedure:
15 ml of pyridine was added to 0.80 g (2.36×10-3 mol) of 4-(5-dodecyl-2-pyrimidinyl)phenol, followed by cooling on an iced water bath. To the mixture, 0.54 g (2.36×10-3 mol) of 5-hexylthiophene-2-carboxylic chloride was added, followed by stirring for 5 hours at room temperature. After the reaction, the reaction mixture was poured into 100 ml of water and acidified with conc. hydrochloric acid, followed by three times of extraction with 50 ml of isopropyl ether. The organic layer was washed with water repeatedly until the washing liquid reacted neutrality, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of a hexane/ethyl acetate =10/1 mixture solvent and recrystallized from ethanol to obtain 0.38 g of a pure product (yield: 30.2%). ##STR29##
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5([C:30]#[N:31])[CH2:29][CH2:28]5)[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:34][C:35](Cl)=[O:36].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:30]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:32])[CH2:29][CH2:28]1)#[N:31]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)CCl
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2c1
Yield: 16.5 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (0.11 g, 0.25 mmol) produced in Example A35(iv), chloroacetyl chloride (0.23 g, 2.0 mmol), and 1-methylpiperazine (0.40 g, 4.0 mmol), and in the same manner as in Example A31, the title compound (24 mg, 17%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (110 mg, 0.484 mmol) in DMF (1 mL) was added a suspension of NaH (60.0 mg, 1.45 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (423 mg, 1.45 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 10-methyl-7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].B(O)(O)O.[CH2:13](O)[CH2:14][C:15]#C.C(OC)(=O)CC(C)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[O:4]=[C:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH2:15][C:14]#[CH:13])=[O:6]
Reactant: C#CCCO
Reactant: COC(=O)CC(C)=O
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: C#CCCOC(=O)CC(C)=O
Yield: 71.7 %

Procedure:
Methyl acetoacetate (1 g, 8.6 mmol) was dissolved in 40 mL dry toluene. Boric acid (53 mg, 0.86 mmol) and 3-butyn-1-ol (1 g, 14.3 mmol) were added to the methyl acetoacetate/toluene solution under a N2 atmosphere and the mixture was refluxed for 24 hr using a Dean-Stark condenser. Solvents were then removed under reduced pressure. The crude product was purified by flash column chromatography (SiO2, hexane/ethylacetate:15/1) to obtain compound 2 (950 mg, 73% yield), a pale yellow to colorless liquid. 1H NMR 300 MHz (ppm, CDCl3): 4.21 (2H, t J=6.8 Hz), 3.48 (2H, s), 2.59-2.54 (2H, dt J=6.8, 2.7 Hz), 2.29 (3H, s), 2.00 (1H, t J=2.7). 13C NMR (CDCl3, 75 MHz): 200.22, 166.83, 79.70, 70.12, 62.99, 49.92, 30.16, 18.89. ESI-MS: (M+H)+=m/z 155.18 (calculated MW of C8H10O3: 154.16 Da).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:38][O:39][CH2:40][CH:41]=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:41][CH2:40][O:39][CH3:38])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCC=O
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Product: COCCN1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-methoxy-ethyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using methoxyacetaldehyde instead of acetone and was obtained as a colorless oil. MS m/e: 616.4 [M]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([O:36]C)=[O:35])=[CH:23][CH:22]=2)[C:7]([CH2:11][NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CO>O>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([OH:36])=[O:35])=[CH:23][CH:22]=2)[C:7]([CH2:11][NH:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CNS(=O)(=O)C(F)(F)F)n1Cc1ccc(C(=O)c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(CNS(=O)(=O)C(F)(F)F)n1Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Butyl-1-[4-(2-carbomethoxybenzoyl)benzyl]-4-chloro-5-[(trifluoromethylsulfonamido)methyl]imidazole (150 mg, 0.26 mmol, 1 eq), 1.000 N NaOH (0.55 mL, 0.55 mmol, 2.1 eq), methanol (20 mL), and water (0.5 mL) were mixed and stirred for 5 hours at room temperature under N2. The solvent was removed in vacuo. Water (50 mL) was added and the pH was adjusted to 4 with 1 N HCl. Tan solids precipitated. These were collected and dried to yield 80 mg. NWR (200 MHz, DMSO-d6) δ 7.98 (d, 1H, J=7Hz); 7.70 (t, 1H, J=7Hz); 7.68 (t, 1H, J=7Hz); 7.63 (d, 2H, J=10Hz); 7.37 (d, 1H, J=7Hz); 7.10 (d, 2H, J=10Hz); 5.34 (s, 2H); 4.20 (s, 2H); 2.50 (t, 2H, J=7Hz); 1.49 (t of t, 2H, J=7,7Hz); 1.27 (t of q, 2H, J=7,7Hz); 0.80 (t, 3H, J=7Hz). Mass calcd. for C24H23ClF3N3O5S: 557.0999. Found: 557.0988
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[C:15]1(C)C=CC=C[C:16]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C=C>C(#N)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:15]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[CH2:16]
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=Cc1ccc(NC(=O)C(C)(C)C)nc1
Temperature: 85 °C
Yield: 738.1 %

Procedure:
A solution of N-(5-bromopyridin-2-yl)-2,2-dimethylpropionamide (5.60 g, 21.8 mmol) in acetonitrile (20 ml) and triethylamine (5.49 ml) was treated with palladium acetate (177 mg, 0.8 mmol) and tri-o-tolylphosphine (795 g, 2.6 mmol). The mixture was placed in a pressure reactor under 130 psig of ethylene pressure and heated at 85° C. for 18 hours. The reaction mixture was cooled, vented, diluted with ethyl acetate and filtered. The ethyl acetate solution was washed sequentially with dilute citric acid, water and brine and then dried over sodium sulfate. The dried solution was filtered and evaporated. Chromatography of the residue on silica gel, eluting with dichloromethane/ethyl acetate (24:1) afforded 3.92 g (88%) of the title product as an oil. 1H NMR (CDCl3): δ=8.21 (m, 2 H); 8.03 (br, 1 H); 7.76 (d of d, 1 H); 6.63 (d of d, 1 H); 5.71 (d, 1 H); 5.25 (d, 1 H); 1.29 (s, 9H). MS (Cl): m/z=205 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19](N(C)C)=[O:20])[O:16][C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1.[OH-:26].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([OH:26])=[O:20])[O:16][C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(COCc2cnc3oc(C(=O)N(C)C)cc3c2)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(COCc2cnc3oc(C(=O)O)cc3c2)cc1
Temperature: 25 °C

Procedure:
In a sealed tube, a mixture of a solution of 5-(((4-methoxybenzyl)-oxy)-methyl)-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide (2.4 g, 7.1 mmol) in methanol (28 mL) and a solution of potassium hydroxide (0.79 g, 14 mmol) in water (7 mL) was heated at reflux for 1 h. After cooling to ambient temperature, the reaction mixture was partitioned between saturated aqueous citric acid solution and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated to give the title compound. MS: m/z=314.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[BH4-].[Na+].O.C(OCC)(=O)C>CO.[Ni](Cl)Cl>[OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1cccc(/C=C/C(=O)OC(C)(C)C)c1CO
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(CCC(=O)OC(C)(C)C)c1CO
Reaction time: 4 h
Yield: 99.3 %

Procedure:
To a solution of 789 mg of tert-butyl (2E)-3-[2-(hydroxymethyl)-3-methylphenyl]acrylate in 16 ml of methanol was added 82 mg of nickel chloride (II). Then, 240 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 4 hours under ice-cooling. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 790 mg of tert-butyl 3-[2-(hydroxymethyl)-3-methylphenyl]propanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[N:11]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([OH:17])[C:13]([N+:18]([O-:20])=[O:19])=[C:14]([OH:16])[N:15]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(F)c(-c2nc(O)cc(O)n2)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(F)c(-c2nc(O)c([N+](=O)[O-])c(O)n2)c1
Temperature: 50 °C

Procedure:
To a suspension of 2-(2-Fluoro-5-methoxyphenyl)-4,6-dihydroxypyrimidine (12 g) in 35 mL of acetic acid is added 12 mL of 90% nitric acid and the mixture is heated at 50° C. for 45 min. The reaction mixture is diluted with 150 mL of water and the product is collected, washed with water and ethanol and oven dried to afford 2-(2-Fluoro-5-methoxyphenyl)-5 -nitro-4,6-dihydroxy-pyrimidine as a pink solid.
Reaction SMILES: Cl.[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(OC([NH:39][C@@H:40]([CH2:44][C:45]1[S:46][CH:47]=[CH:48][CH:49]=1)[C:41](O)=[O:42])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:19]=3)[CH2:17][CH2:16][N:15]([C:41](=[O:42])[C@@H:40]([NH2:39])[CH2:44][C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(NCC1CCCCC1)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(C(=O)NCC2CCCCC2)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carboxylic acid cyclohexylmethylamide hydrochloride (0.169 mmol; 0.08 g) in DMF (3 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (0.203 mmol; 55.1 mg), N,N-diisopropyl-N-ethylamine (0.338 mmol; 0.059 mL) and HBTU (0.203 mmol; 77 mg), and the resulting mixture was stirred at room temperature for 20 min. The mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in 1,4-dioxane (3 mL) and a 4N HCl solution in 1,4-dioxane (3 mL) was added. The resulting solution was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Methyl 2-amino-4-chlorobenzoate (1.5 g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH (429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0° C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0° C. with saturated Na2SO4 (50 mL), extracted with Et2O (2×70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69% yield); 1H NMR (400 MHz, MeOD) δ ppm 4.50 (s, 2H), 6.58 (dd, J=8.06, 2.01 Hz, 1H), 6.70 (d, J=2.01 Hz, 1H), 7.01 (d, J=8.06 Hz, 1H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO 157.03.