Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]([CH:35]2[CH2:38][C:37]([F:40])([F:39])[CH2:36]2)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[Cl:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH:26]([CH:35]2[CH2:36][C:37]([F:40])([F:39])[CH2:38]2)[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:20][C:19]=1[NH:18][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C1CC(F)(F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H]([C@H](C(=O)Nc1cc(C(CC(=O)OC(C)(C)C)C2CC(F)(F)C2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
A solution of 76 mg (0.29 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 45 mg (0.13 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)-propanoate, 119 mg (0.31 mmol) of O-(1H-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and 0.51 ml of pyridine in 1 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was directly, without further work-up, separated into its components by preparative HPLC. This gave 19 mg (25% of theory) of the title compound as a colourless oil.
Reaction SMILES: ClC1C=CC2N=C(N3CCN(C[C:16]4[CH:17]=[C:18]([OH:23])[CH:19]=[C:20](C)[CH:21]=4)CC3)SC=2C=1.[C:26]([O:29][CH2:30][CH2:31]Br)(=[O:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C(OCC)(=O)C>[C:26]([O:29][CH2:30][CH2:31][O:23][C:18]1[CH:17]=[CH:16][CH:21]=[CH:20][CH:19]=1)(=[O:28])[CH3:27]
Reactant: Cc1cc(O)cc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCOc1ccccc1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A mixture of 3-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-5-methylphenol (0.50 g; 1.34 mmol), bromoethyl acetate (0.22 ml; 2.01 mmol) and cesium carbonate (0.65 g; 2.01 mmol) in anhydrous N,N-dimethylformamide (5 ml) was stirred at 50° C. for 17 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]-5-methyl}+phenoxyethyl acetate as pale yellow oil (0.48 g; 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]2[CH2:10][C:9]([CH3:11])([CH3:12])[CH:8]([OH:13])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CC1(C)Cc2c(Br)cncc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2c(Br)cncc2C1O
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-6,6-dimethyl-5H-cyclopenta[c]pyridin-7(6H)-one (1.1 g, 4.58 mmol) in MeOH (25 mL) was added NaBH4 (261.3 mg, 6.88 mmol) portion wise. The resulting mixture was stirred for 1 h before it was quenched with water. The solution was concentrated in vacuo and the residue was extracted between EtOAc and H2O (20 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a crude title product. MS: 243.7 (M+H+, 1 Br).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18](O)=[O:19])=[CH:8]1.O.O.OS(O)(=O)=O>C(OCC)C>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:8]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of lithium aluminum hydride (4.68 g, 126 mmol) in 230 mL anhydrous diethylether was stirred heavily. 3-Indole propionic acid (10.0 g, 53 mmol) dissolved in 460 mL anhydrous diethylether was transferred to a dropping funnel and added at such a rate that gentle reflux was maintained. The reaction mixture was left with stirring at reflux temperature for 2 h, then at room temperature overnight. Then reflux was continued for 2 h before cooling to room temperature. 25 mL H2O was slowly added followed by 70 mL H2O/H2SO4 (1:3H2O/H2SO4). The resulting clear mixture was extracted with 110 mL diethylether three times. The combined organic phases were washed with brine, dried with Na2SO4, filtrated and concentrated to bright oil, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:9][CH:10]=2)[C:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(O)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(O[Si](C)(C)C(C)(C)C)cc12

Procedure:
A mixture of 4-bromo-1-tert-butoxycarbonylaminonaphth-7-ol, as described above in Step C, (1.62 g, 4.80 mmol), tert-butyldimethylsilyl chloride (1.09 g, 7.20 mmol), and imidazole (0.82 g, 12 mmol), was stirred in dry DMF (40 mL) at ambient temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was partitioned between H2O (100 mL) and Et2O (200 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—50% hexane to yield the desired product as a pale solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:12](=[CH2:13])[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=C(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1

Procedure:
A mixture of 5 g of p-bromophenylacetonitrile, 4.6 ml of t-butyl acrylate, 57 mg of palladium diacetate, 310 mg of tri-o-tolylphosphine and 12 ml of triethylamine is refluxed for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 10% HCl and saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo to yield t-butyl p-(cyanomethyl)-phenylacrylate. This material is dissolved in ethanol and hydrogenated over 1.1 g of 10% palladium on carbon catalyst for 3 days at 3 atmospheres pressure of hydrogen. After filtration the solvent is removed in vacuo and the residue is chromatagraphed on silica gel with ether/hexane (1:1) as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-phenyl-acetonitrile; 2.8 g of this material is dissolved in 90 ml of tetrahydrofuran and 50 ml of methanol and to this is added 6.2 g of cobalt chloride in 90 ml of water followed by 2.1 g of sodium borohydride in small portions. After filtration and removal of solvent, the residue is chromatagraphed on silica gel with 7.5% ammonia saturated methanol in methylene chloride as the eluent to afford p-(2-t-butoxy-carbonyl-ethyl)-2-phenethylamine as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]([CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[H][H]>[OH-].[K+].[Pd]>[CH3:1][CH:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]([CH3:13])[CH2:5][C:4](=[O:14])[CH2:3]1
Reactant: [H][H]
Reactant: CC(C)=CCC1C(C)=CC(=O)CC1C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: CC(C)=CCC1C(C)CC(=O)CC1C
Yield: 87.4 %

Procedure:
A solution of 3,5-dimethyl-4-(3-methyl-2-butenyl)-2-cyclohexen-1-one (8.2 g, 0.043 mol) in 0.3 M ethanolic KOH (16 mL) was hydrogenated at room temperature and 1 atmosphere over 5% palladium on carbon (0.8 g). After uptake of 1 equivalent of hydrogen, the solution was filtered through Celite and concentrated. The residue was partitioned between hexane and water; then the hexane layer was dried (Na2SO4) and the solvent removed on a rotary evaporator. Kugelrohr distillation gave 7.3 g of 3,5-dimethyl-4-(3-methyl-2-butenyl) cyclohexanone, bp 115° C./0.5 mm.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C)[CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:38]=[CH:39][N:40]=[C:41]([F:42])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[OH-].[Na+]>C1COCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]5)=[CH:20][CH:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:38]=[CH:39][N:40]=[C:41]([F:42])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCN1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To compound 248 (0.115 g, 0.19 mmol) in THF (1.0 mL) was added tetrabutylammonium fluoride, 1.0 M in THF (0.49 mL, 0.49 mmol). The reaction was stirred at room temperature. After 1 h, the reaction contents were poured into water. The aqueous layer was brought to pH 12 with 5 N NaOH and extracted with 10% methanol in dichloromethane (3×25 mL). The combined organics were dried with Na2SO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 3 to 7.5% 2M methanolic NH3 in DCM) afforded compound 242 (0.070 g, 75% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.68-1.80 (m, 2 H) 1.92-2.05 (m, 2 H) 2.05-2.17 (m, 2 H) 2.25-2.40 (m, 2 H) 2.45 (t, J=6.11 Hz, 2 H) 2.54-2.62 (m, 4 H) 3.00-3.27 (m, 4 H) 3.54 (q, J=5.95 Hz, 2 H) 4.43 (t, J=5.26 Hz, 1 H) 5.45 (quin, J=9.05 Hz, 1 H) 7.47 (dd, J=9.17, 2.81 Hz, 1 H) 7.93-8.07 (m, 3 H) 8.11 (d, J=9.05 Hz, 1 H) 9.32 (s, 1 H) 9.89 (s, 1 H) ppm.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 423.22 g/mol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[N:4][CH:3]=1.O.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)([CH3:16])[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>COCCOC.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:8]([C:6]1[N:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:12]([CH3:16])([CH3:11])[C:13]([OH:15])=[O:14])=[CH:18][CH:19]=2)[CH:3]=[N:4][CH:5]=1)#[N:9]
Reactant: N#Cc1cncc(Cl)n1
Reactant: CC(C)(C(=O)O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: COCCOC
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Temperature: 80 °C
Yield: 70.2 %

Procedure:
6-Chloropyrazine-2-carbonitrile (example 20b) (890 mg, 6.4 mmol) was dissolved in DME (24 mL) and water (6 mL) followed by 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (1.86 g, 6.4 mmol) and K2CO3 (1.76 g, 12.7 mmol). The mixture was degassed using an argon stream, Pd(PPh3)4 (369 mg, 0.32 mmol) was added and the mixture was heated (80° C.) overnight. The solvents were removed under reduced pressure and a residue was suspended in 1M aq. NaOH (10 mL) and washed with EtOAc. The aqueous phase was then acidified to pH 4-5 using 6N aq. HCl and extracted with EtOAc (3×60 mL). The organic extracts were combined, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (5% MeOH in DCM) to give 1.2 g (70%) of the pure intermediate 2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid. 1H NMR (400 MHz, dMSO): δ 1.50 (s, 6H), 1.69 (m, 1H), 7.54-7.56 (d, 2H), 8.13-8.15 (d, 2H), 9.17 (s, 1H), 9.56 (s, 1H), 12.50 (s, 1H).
Reaction SMILES: [Mg].II.C(Br)C.Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH2:15](Cl)[CH:16]=[C:17]([CH3:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:9][CH:10]=1
Reactant: CC(C)=CCCl
Reactant: Clc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CC(C)=CCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Under nitrogen atmosphere, 55.1 g of magnesium turnings, 800 ml of tetrahydrofuran, and about 0.1 g of several pieces of iodine were put in a flask. With stirring, 2 ml of ethyl bromide was added, whereupon coloration by iodine disappeared. Then, a solution of 361.7 g of p-bromochlorobenzene in 2 liters of tetrahydrofuran was added dropwise at such a speed that the reaction temperature was maintained at 25° C. to 30° C. After the addition, the mixture was further stirred for 1 hour, and cooled to about 20° C. A solution of 256.8 g of prenyl chloride in 800 ml of tetrahydrofuran was added dropwise at 15° C. to 20° C. over the course of about 4 hours. After the addition, the mixture was left to stand overnight at room temperature. Two liters of a 10% by weight aqueous solution of ammonium chloride were added, and the mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with 300 ml of diethyl ether. The diethyl ether layer was combined with the organic layer previously separated, and washed with water, dried, concentrated, and distilled to give 218.3 g (yield 64.0%) of p-chloroprenylbenzene.
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1.[CH3:12][C:13]1[N:14]=[C:15]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH:8]1([CH2:7][N:25]2[CH2:26][CH2:27][N:23]([C:15]3[S:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:12])[N:14]=3)[C:24]2=[O:28])[CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCC1CCC1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCC3)C2=O)nc1C
Yield: 88 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl)cyclobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 88% yield: 1NMR (300 MHZ, CDCl3) δ 4.29-3.96 (m, 4H), 3.60-3.23 (m, 4H), 2.63-2.48 (m, 4H), 2.09-2.02 (m, 2H), 1.93-1.83 (m, 2H), 1.77-1.68 (m, 2H), 1.26 (t, J=7.3 Hz, 3H); MS (ES+) m/z 324.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Reactant: Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccc(F)cc2)nc1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 39.5 mg (0.39 mmol) of 2-aminothiazole. Yield: 20 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([O:35][CH3:36])[C:33]=1[CH3:34])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7].Br[CH2:38][C:39]([O:41]C)=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([O:35][CH3:36])[C:33]=1[CH3:34])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[N:22]([CH2:38][C:39]([OH:41])=[O:40])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:7]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCc2ccccc2)cc(OC)c1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(CCc2ccccc2)CC(=O)O)cc(OC)c1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A solution of compound 9a (45 mg, 0.092 mmol), methyl bromoacetate (0.053 mL, 0.56 mmol), and potassium carbonate (38 mg, 0.27 mmol) in DMF (1 mL) was sealed in a pressure tube and heated at 80° C. overnight and at rt for two days. Additional methyl bromoacetate (0.060 mL) and potassium carbonate (42 mg) was added and the reaction was heated at 100° C. for 5 h. The reaction mixture was filtered and concentrated on a rotary evaporator. The residue was purified by preparative tlc. This compound was dissolved in a mixture of THF (1 mL) containing several drops of MeOH and 10% LiOH (1 mL). The reaction mixture was stirred at rt for 4 h, neutralized, and concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with water, dried, and concentrated to give compound 22a (31 mg, 62%). ESI-MS m/e 545.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[C:12][Si](C)(C)C)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[CH:12])=[CH:4][N:3]=1
Reactant: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(N)c(C#N)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.8 grams (0.012 mole) of 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl)pyridine and 1.8 grams (0.012 mole) of potassium carbonate in 100 mL of methanol is stirred at ambient temperature for one hour. The reaction mixture is then concentrated under reduced pressure to a residue. The residue is taken up in about 150 mL of water, and the solution is extracted with two 250 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-ethynylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][N:3]=1.N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Nc1ccccc1
Product: Clc1cc(Nc2ccccc2)ccn1
Yield: 92 %

Procedure:
The title compound (3.8 g) was prepared by the same procedure as the preparation 4 except for using 2-chloro-4-nitropyridine (3.2 g) and aniline (5.7 g).
Reaction SMILES: ClC1N(CC2C=CC=CC=2C#N)C(=O)NC(=O)C=1.C(O)(=O)C1C=CC=CC=1.[NH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]2[N:40]([CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44]#[N:45])[C:39](=[O:50])[N:38](C)[C:37](=[O:52])[CH:36]=2)[CH2:30]1>>[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]2[N:40]([CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44]#[N:45])[C:39](=[O:50])[NH:38][C:37](=[O:52])[CH:36]=2)[CH2:30]1
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Agent: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Agent: O=C(O)c1ccccc1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)[nH]c1=O

Procedure:
The title compound 6 was prepared from compound 2 by the procedure used in preparation of compound 4. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.65 (d, J=7.5 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 5.32 (s, 1H), 5.13-5.13 (ABq, 2H, J=30.0, 15.0 Hz), 3.39 (m, 2H), 2.95 (m, 2H), 2.69 (m, 1H), 2.12 (m, 1H), 1.85 (m, 1H), 1.64 (m, 2H). MS (ES) [m+H] calc'd for C17H20N5O2, 326.2; found, 326.2.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][S:6]([C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=2[CH:10]=1)(=[O:8])=[O:7])C.[CH:26]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([CH2:31][NH:32][C:4]([NH:5][S:6]([C:9]2[CH:24]=[CH:23][C:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:20])[CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)(=[O:7])=[O:8])=[O:3])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NCC1CCCC1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NCC3CCCC3)cc2CC1

Procedure:
By the reaction of [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]carbamic acid ethyl ester with cyclopentylmethylamine in a manner analogous to that described in Example 12, there is obtained 1-cyclopentylmethyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-sulfonyl]urea, m.p. 165°-166° C.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:22]#[N:23])([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:24])=O.[Cl-].[Na+].O.CS(C)=O>>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([C:9]2([C:22]#[N:23])[CH2:8][CH2:7][C:6](=[O:24])[CH2:5][CH2:10]2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: COC(=O)C1CC(C#N)(c2ccc([N+](=O)[O-])c(OC)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C2(C#N)CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 165 °C

Procedure:
Into a 8-dram vial, 5-Cyano-5-(3-methoxy-4-nitro-phenyl)-2-oxo-cyclohexanecarboxylic acid methyl ester (2.00 g, 6.02 mmol), Sodium chloride (1.00 g, 17.1 mmol), Water (1.00 mL, 55.5 mmol) and Dimethyl sulfoxide (5.00 g, 64.0 mmol) were added. The reaction mixture was heated at 165° C. for 6 hours. HPLC suggested no SM. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 1-(3-Methoxy-4-nitro-phenyl)-4-oxo-cyclohexanecarbonitrile a white solid (0.80 g, 48%).