Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11]C2C3C(=CC=CC=3)C=CC=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][C:1]=2[OH:11])[CH:6]=1
Reactant: c1ccc2c(Oc3cccc4ccccc34)cccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Oc1cccc2ccccc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Naphthylether 10 (19.8 g, 81 mmol) was dissolved in a dry DCM (400 mL) and the solution cooled to −70° C. A solution of BBr3 (1M in DCM, 160 mL, 160 mmol) was added dropwise while maintaining an internal temperature below −60° C. The mixture was aged at this temperature for an additional 30 min, then allowed to warm up to RT and aged for additional 2 h at rt. The mixture was then again cooled to −70° C., treated with absolute ethanol (20 mL), and the resulting mixture was aged at rt overnight. The solution was poured into a cold NaHCO3 solution (500 mL, saturated aq) and vigorously stirred. The organic layer was washed with dilute HCl solution (0.1N, 200 mL) and with water (200 mL), and the solvent removed. Column chromatography of the resulting residue using 20% ethyl acetate in hexanes yielded the naphthylester 12 (17.6 g, 76.4 mmol) in 94% yield.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(Cl)(Cl)[Cl:13].C(=O)([O-])[O-].[Na+].[Na+]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]=12
Reactant: Cc1c[nH]c2c1ccc[n+]2[O-]
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c[nH]c2nccc(Cl)c12
Temperature: 25 °C

Procedure:
1.00 g (6.75 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (from example XXXVII) is suspended in 5 ml of phosphoryl chloride. 2 ml of chloroform are then added, and the mixture is heated under reflux overnight. The mixture is allowed to cool to RT and poured into ethyl acetate/ice water. Solid sodium carbonate is then added. The phases are separated and the aqueous phase is washed with ethyl acetate. The organic phases are dried over sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, mobile phase: cyclohexane:methanol=4:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](=S)=[S:15].[OH-].[K+]>C(O)C>[CH2:11]([S:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:14]([SH:15])=[N:1][C:2]=2[CH:7]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(O)c(N)c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc2oc(S)nc2c1

Procedure:
To a solution of 1-amino-5-ethylsulfonyl-2-hydroxybenzene (20.13 g, 100.0 mmol, 1.0 equiv) in ethanol (200 mL) were added carbon disulfide (190.0 g, 150 mL, 2494 mmol, 25.0 equiv) and potassium hydroxide (6.73 g, 120 mmol, 1.2 equiv) and the reaction mixture heated to reflux over night. The solvent was evaporated, the residue treated with 1 M hydrochloric acid, extracted with ethyl acetate (3×150 mL) and the combined organic fractions dried over MgSO4. Evaporation of the organic solvent gave the crude product which was recrystallized from ethyl acetate to yield the title compound as yellowish solid. MS (ISN): 242.4 [M−H]−.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[C@H:10]([OH:19])[CH2:9]1)C1C=CC=CC=1.N>CCOC(C)=O.CO>[F:18][C:15]([F:16])([F:17])[C@:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[OH:19]
Reactant: O[C@@H]1CN(Cc2ccccc2)CC[C@@]1(O)C(F)(F)F
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@@H]1CNCC[C@@]1(O)C(F)(F)F

Procedure:
The product was obtained analogously to intermediate product IP 5d starting from (3R,4S)-1-benzyl-4-trifluoromethylpiperidin-3,4-diol. Yield: 665 mg (91% of theoretical); C6H10F3NO2 (M=185.144); calc.: molpeak (M+H)+: 186; found: molpeak (M+H)+: 186; Rf value: 0.35 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 7:3:0.3).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:10][CH:9]=1)=[O:7].I[CH3:32]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH3:32])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[O:21][C:22]([CH3:25])=[N:23][N:24]=3)[CH:17]=[CH:16][C:15]=2[CH3:26])=[CH:12][CH:13]=1)=[O:7]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4Cl)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccccc4Cl)cc3)c2)o1

Procedure:
N-(2-Chlorobenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(2-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.77,(1H, b), 7.62-7.33,(9H, m), 4.78-4.62,(2H, m), 2.95,(3H, s), 2.56,(3H, s), 2.33-2.29,(3H, m). LCMS; retention time 3.54 min, MH+ 432/434.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:16])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:24]1[CH2:29][CH2:28][O:27][C:25]1=[O:26]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH:24]2[CH2:29][CH2:28][O:27][C:25]2=[O:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1O
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1CCOC1=O

Procedure:
51 g. of Methyl 4-acetylamino-5-chloro-2-hydroxybenzoate and 36.8 g. of anhydrous potassium carbonate were suspended in 350 ml. of N,N-dimethylformamide. To the suspension was added 55 g. of α-bromo-γ-butyrolactone, and the mixture was stirred at 60° C. for 12 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was dissolved in chloroform, and subjected to column chromatography on silica gel, using chloroform as the eluent. The product was recrystallized from methanol. By the above procedure there was obtained α-[(5-acetylamino-4-chloro-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone as pale yellow prisms, m.p. 118°-119° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1/[CH:5]=[CH:6]\[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:10]([OH:12])=[O:11].[CH2:22](I)[CH2:23]C>>[CH3:1][CH:2]1[CH2:4][CH:3]1/[CH:5]=[CH:6]\[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([N:16]([CH2:21][CH2:22][CH3:23])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: CCCI
Reactant: CC1CC1/C=C\c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Product: CCCN(c1cc(/C=C\C2CC2C)cc(C(=O)O)c1)S(C)(=O)=O

Procedure:
This compound was prepared analogously to 3-[(Z)-2-(2-methylcyclopropyl)vinyl]-5-[methyl(methylsulfonyl)amino]benzoic acid, the only difference being the substitution of methyl iodide with propyl iodide in Step D.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[N:40]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[C:31]1[CH:30]=[C:29]([C:28]2[CH2:27][C:26](=[O:42])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (80 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[N:6]=1)([CH3:3])[CH3:2]>CC(O)C.ClCCl.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:7]2[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[C:9]([N:11]3[CH2:12][CH:13]4[O:18][CH:16]([CH2:15][CH2:14]4)[CH2:17]3)[N:8]=2)=[CH:24][CH:23]=1
Reactant: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(-c2ccc(N)cc2)n1
Reaction time: 1 h

Procedure:
In a 250 mL round-bottomed flask was placed 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine (17, 74 mg, 0.200 mmol) in 2-propanol (7 mL) and dichloromethane (7 mL) to give a yellow solution. A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated to give the title compound in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N+:7]([O-:37])=[C:6]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1[N+]([O-])=C2c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg of (−)-cis-8,9-dimethoxy-6-(4-methanesulfonylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine are dissolved in 30 ml of dichloromethane, treated with 340 mg of m-chloroperbenzoic acid with ice-cooling and stirred in an ice bath for 3 h and at RT for 1 h. After removing the solvent under reduced pressure and chromatography on silica gel using ethyl acetate/triethylamine in the ratio 7:1, the title compound is obtained by concentrating the product fractions.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](OC(C)(C)C)[CH2:13][C@H:12]1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC([C@@H]1C[C@H](N)C[N:31]1CC1CCCCC1)=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:31])[CH2:13][C@H:12]1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Product: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4S)-4-Amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-tert-butoxy-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C15H18N3O3 [(M+H)+] 288, obsd. 288.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=3[CH:21]=[CH2:22])[C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd].O1CCOCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=3[CH2:21][CH3:22])[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C=Cc1ccc(C(=O)OC)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)OC)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 100.5 %

Procedure:
Into a reactor there are introduced 3 g (10 mmoles) of methyl 3-(1-adamantyl)-4-vinylbenzoate, 270 mg of palladium on charcoal (5%) and 50 ml of dioxan. Hydrogenation is effected at ambient temperature and under a pressure of 4 bars for 4 hours. The catalyst is filtered and the filtrate is evaporated. 3 g (100% yield) of the expected product in the form of a colorless oil are recovered.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1>CN(C)C=O>[O:19]=[C:13]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)N1CCN(c2ccccn2)CC1
Yield: 64.7 %

Procedure:
A solution of 1-(2-pyridyl)piperazine (1.63 g) and succinic anhydride (1.1 g) in dimethylf ormamide (5 ml) was stirred for 24 hours at room temperature. The reaction mixture was reduced under reduced pressure and the concentrate was recrystallized from ethanol to give the titled compound (1.7 g) as a pale yellow crystal.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(CCO)ccc2o1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1cc2cc(CCO)ccc2o1
Temperature: 55 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 75 mg (0.189 mmol) (2-{[5-(2-Hydroxy-ethyl)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (58) in 3 ml THF were added 1892 μl of 4M solution of HCl in dioxane. The reaction was stirred at 55° C. for 2 h. The solvent was evaporated, ethylacetate was added and the organic phase was washed with saturated aqueous sodium bicarbonate solution and brine and dried over Na2SO4. The solvent was removed to give 45 mg (0.152 mmol) 5-(2-Hydroxy-ethyl)-benzofuran-2-carboxylic acid (2-amino-phenyl)-amide (55); exact MW calc'd [M+H]: 297.12; MW found [M+H]: 297.1.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[N:14]([CH2:17][CH:18]([S:32][S:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[C:3]([CH2:2][O:23][C:21](=[O:22])[C@@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH:18]([S:32][S:33][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:17][N:14]=[N+:15]=[N-:16])#[N:4]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
Bromoacetonitrile (62 μl, 0.911 mmol) and N,N-diisopropylethylamine (79 μl, 0.456 mmol) were added to a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid (Compound 40a) (115 mg, 0.304 mmol) in acetonitrile (1 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate/saturated ammonium chloride, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid cyanomethyl ester (Compound 41) (120 mg, 95%).
Reaction SMILES: O1CCCCC1[N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:9]=[N:8]1>CO.Cl>[NH:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:9]=[N:8]1
Reactant: CCOC(=O)Cc1cccc(-c2cnn(C3CCCCO3)c2)c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)Cc1cccc(-c2cn[nH]c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl {3-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenyl}acetate (160 g, 0.50 mol) in MeOH/HCl (800 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and washed with Et2O (300 mL) to afford ethyl [3-(1H-pyrazol-4-yl)phenyl]acetate as a solid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)(=O)=O)=CC=CC=1>>[CH:33]1([CH2:32][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CCCC1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCC2)c1
Yield: 57 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclopentyl)methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound (84 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:62])([F:61])[C:54]1[CH:55]=[C:56]([CH:58]=[CH:59][CH:60]=1)[NH2:57]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:57][C:56]3[CH:58]=[CH:59][CH:60]=[C:54]([C:53]([F:52])([F:61])[F:62])[CH:55]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (162 mg, 0.60 mmol), triethylamine (0.335 mL, 2.4 mmol), and HBTU (250 mg, 0.66 mmol) in 4.0 mL DMF was briefly warmed to approx. 40° C. to dissolve solids. After 3 minutes 3-(trifluoromethyl)aniline (0.149 mL, 1.2 mmol) was added and the reaction stirred at 50° C. for 3 hours, at rt for 16 hours, then an additional 1 hour at 50° C. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oily solid was chromatographed eluting with CHCl3, warm EtOAc, CHCl3:EtOAc (1:1), then 5% MeOH in CHCl3:EtOAc (1:1) giving a pale yellow solid. This solid was recrystallized from EtOAc giving a white solid (100 mg, 40%). 1H NMR (DMSO-d6) δ: 10.46 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.34-7.48 (m, 3H), 7.22-7.27 (m, 1H), 6.41 (s, 2H), 4.30 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1ccccc1CN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-2-methylbenzene. MS 408 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.1 μM.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:7]2[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ncccc1-c1ccccc1
Yield: 79.7 %

Procedure:
To a solution of methyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2-carboxylate (148.6 g, 521 mmol) in anhydrous toluene (550 ml) were added potassium carbonate (148.6 g), tetrakis(triphenylphosphine)palladium(0) (6 g), and phenyl boronic acid (70 g, 574 mmol). The reaction was equipped with a mechanical stirring apparatus and heated to reflux for 2 h. The reaction suspension was filtered through a bed of celite and washed with EtOAc. The filtrate was concentrated in vacuo and purified via flash chromatography (silica, 20% EtOAc/hexanes isocratic) to provide methyl 3-phenylpyridine-2-carboxylate (88.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)cc2)cc1
Agent: [Pt]
Product: Nc1ccc(CCc2ccc(Cl)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36 b), the hydrogenation of (E)-1-chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene using platinum on carbon (5%) as the catalyst but with a reaction time of 18 hours and simultaneous reduction of the double bond yields the 4-[2-(4-chloro-phenyl)-ethyl]-phenylamine as a light yellow solid; MS: m/e=232 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)=O.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].C(OC(=O)C)(=O)C>CCOC(C)=O>[C:19]([O:22][CH2:1][S:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc(-c2ccc(S(C)=O)cc2)cs1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(-c2ccc(SCOC(C)=O)cc2)cs1
Temperature: 25 °C
Yield: 47 %

Procedure:
N-{4-[4-(Methylsulfinyl)phenyl]-1,3-thiazol-2-yl}acetamide (1.5 g), sodium acetate (1.54 g), and acetic anhydride (30 ml) were combined under N2 atmosphere. The reaction mixture was refluxed for 2 hours. After cooled to r.t., the mixture was diluted in AcOEt. The organic solution was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid was washed with ethyl ether/n-hexane to give ({4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl)thio)methyl acetate (811.2 mg) as an off-white solid.