Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]3[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=3[CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][C:25]5[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=5[CH:27]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cc3c(s2)CCCC3)n1
Product: c1cn(CCCc2ccc(OCc3coc(-c4cc5c(s4)CCCC5)n3)cc2)cn1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 83-84° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:14]#[C:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CCC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC[C@H](CC(=O)OC)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
To a stirred solution of 25.1 (0.067 g, 0.3 mmol) in EtOAc (3 mL) at 23° C. was added palladium on carbon (0.03 g, 0.3 mmol). The reaction was placed under an atmosphere of hydrogen and then stirred at room temperature. After 5 hours, the reaction mixture was filtered through a pad of silica gel and then concentrated. After concentration, the residue was purified on silica gel (0%-20% EtOAc/hexane) to give 37.1 (0.065 g, 95%). MS ESI (pos.) m/e: 237.1 (M+H)+.
Reaction SMILES: C([SiH](CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[CH:14][NH:15]2)([O-:10])=[O:9]>C(O)(C(F)(F)F)=O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:14][NH:15]2)([O-:10])=[O:9]
Reactant: COC(=O)C(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1CNc2cccc([N+](=O)[O-])c21
Reaction time: 3 h

Procedure:
Triethylsilane (13 mL, 80.6 mmol) was added to a solution of methyl (4-nitro-1H-indol-3-yl)(oxo)acetate from Step A (1.00 g, 4.03 mmol) in TFA (15 mL). After 3 h, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of CHCl3:MeOH—100:0 to 98:2, to give the title compound. MS: m/z=237 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:15]2[C:6](=[CH:7][C:8]3[C:9]([CH3:19])([CH3:18])[CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]=3[CH:14]=2)[CH2:5][CH2:4][CH2:3]1.CC(O)=[O:23]>[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1([CH3:20])[C:15]2[C:6](=[CH:7][C:8]3[C:9]([CH3:19])([CH3:18])[CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]=3[CH:14]=2)[C:5](=[O:23])[CH2:4][CH2:3]1
Reactant: CC1(C)CCCc2cc3c(cc21)C(C)(C)CCC3(C)C
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Product: CC1(C)CCC(=O)c2cc3c(cc21)C(C)(C)CCC3(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of chromium trioxide (13.55 mL of a 10% CrO3 /AcOH solution) was slowly added to a solution of finely ground 1,1,5,5,8,8-hexamethyl-1,2,3,4,5,6,7,8-octahydroanthracene (861 mg, 3.18 mmol) in AcOH (12 mL) at 25° C. The mixture was stirred for 30 min. Ice water (100 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The organic extracts were combined and twice treated with Et3N (10 mL), and washed and with sat. NaHCO3 (20 mL), water (2×20 mL) and brine (2×20 mL). The solvent was evaporated and the crude residue was purified by silica gel chromatography (hexanes:EtOAc 9:1) to give 831 mg of pure 3,4,5,6,7,8-hexahydro-4,4,5,5,8,8-hexamethyl-2H-anthracen-1-one (structure 1 where R1, R2, R3, and R4 are methyl, R5, R6, R7, R8, R9, and R10 are hydrogen, X and Y are carbon, Z is C(CH3)2 and m=n=1): 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H, Ar), 7.31 (s, 1H, Ar), 2.68 (t, J=8.0 Hz, 2H), 1.98 (t, J=6.0 Hz, 2H), 1.68 (s, 4H) 1.37 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H). The above ketone was transformed to the title compound as outlined in Scheme II.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl[CH2:17][CH:18]([OH:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:20][CH:18]([CH3:19])[CH2:17][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1
Reactant: CC(O)CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
18.30 g (172.6 mmol) of sodium carbonate are added to a solution of 7.03 g (57.5 mmol) of p-hydroxybenzaldehyde and 6.80 g (71.9 mmol) of 1-chloro-2-propanol (technical grade, about 70% pure, isomer mixture with 2-chloro-1-propanol) in 125 ml of dry DMF, and the mixture is stirred at +130° C. for 20 h. After cooling to RT, 100 ml of saturated sodium bicarbonate solution are added and the mixture is extracted with ethyl acetate (three times, 100 ml each). The combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane/ethyl acetate 5:1→2:1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[C:22]([O-:25])(=[S:24])[CH3:23].[K+]>C(#N)C.C(OC(=O)C)C>[C:22](=[O:25])([S:24][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)[CH3:23]
Reactant: CC([O-])=S
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)SCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 140 °C
Yield: 13.5 %

Procedure:
A mixture of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (300 mg, 0.876 mmol) and potassium thioacetate (400 mg, 3.5 mmol) in acetonitrile (15 mL) was heated in microwave at 140° C. for 10 min. The dark red solution was diluted with ethylacetate (50 mL), washed with brine (2×50 mL), dried over sodium sulphate, the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (Flash Master, 20 g Isolute Silica column, gradient 0 to 5 min hexane, then ethyl acetate up to 50% over 20 min) to afford S-2-oxo-2-(3-(quinoxalin-2-yl)phenylamino)ethyl ethanethioate (40 mg, 13% yield). LCMS calculated for C18H15N3O2S (M+H): 338.40. found 338. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.45 (1H, br.), 9.50 (1H, s), 8.51 (1H, m), 8.11-8.18 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 3.90 (2H, s), 2.41 (3H, s).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 174.1) and pyrimidin-5-ylboronic acid to afford a white solid. HPLC (Condition 4) tR=4.93 min, UPLC-MS (Condition 3) tR=0.97 min, m/z=476.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.57 (m, J=12.10, 7.80 Hz, 1H) 1.84 (m, J=11.90, 6.10 Hz, 1H) 2.12-2.31 (m, 1H) 2.95 (dd, J=10.56, 7.04 Hz, 1H) 3.08-3.44 (m, 5H) 4.60 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.21 Hz, 2H) 7.84 (d, J=9.38 Hz, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.88 (s, 2H) 9.17 (s, 1H) 10.16 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:8]([Cl:9])=[C:7]([C:10]([O:12]C)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2].[OH-].[Li+].S(=O)(=O)(O)[O-].[K+]>C1COCC1.O>[C:1]([C:4]1[C:8]([Cl:9])=[C:7]([C:10]([OH:12])=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1[nH]nc(C(C)=O)c1Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1n[nH]c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a mixture containing methyl 3-acetyl-4-chloro-1H-pyrazole-5-carboxylate (1.3 g, 0.0064 mol) in THF (30 ml), lithium hydroxide (1.35 g, 0.032 mol) in water (15 ml) was added dropwise at 5-10° C. The reaction mixture was stirred at RT for 18 h. Cold water (15 ml) was added and the pH was adjusted to ˜4 with 1N potassium bisulfate. The product was extracted with ethyl acetate, the organic layer dried with anhydrous Na2SO4 and concentrated. The crude product was purified by recrystallization from diethyl ether/n-hexane. Yield 56%. 1H-NMR (400 MHz; DMSO-d6): δ 2.57 (s, 3H), 13.91 (bs, 1H), 14.69 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17]([CH2:30]Br)=[C:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[O:21])[O:19][C:15]=2[CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17]([CH2:30][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[O:21])[O:19][C:15]=2[CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(Br)ccc2c1CBr
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCNCc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a solution of 2-methoxyethylamine (118 mg, 1.57 mmol) in THF (6 mL) at 0° C. was added potassium carbonate followed by slow addition of (6-bromo-3-bromomethyl-benzofuran-2-yl)-(2,4-dichlorophenyl)-methanone (660 mg, 1.43 mmol) in several portions. The reaction mixture was stirred at rt for 2 h, and the resulting precipitate was removed by filtration and the filtrate was concentrated. The crude residue was purified by column chromatography (30-50% ethyl acetate in hexanes) giving the desired product (315 mg, 44% yield) as a light yellow viscous oil. 1H-NMR (acetone): δ 8.05 (d, 1H), 7.78 (d, 1H), 7.66 (m, 2H), 7.56 (dd, 1H), 7.50 (dd, 1H), 4.25 (s, 2H), 3.41 (t, 2H), 3.25 (s, 3H), 2.74 (t, 2H). LC-MS RT=2.71 min; [M+H]+=456.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.CC1(C)C(C)(C)[O:29][B:28](B2OC(C)(C)C(C)(C)O2)[O:27]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)=[CH:3][C:2]([B:28]([OH:29])[OH:27])=[N:7]1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cn1nc(B(O)O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 258a (2.0 g, 5.73 mmol, 1.0 eq.), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (7.56 g, 28.6 mmol, 5.0 eq.), Pd(dppf)Cl2 (465 mg, 0.57 mmol, 0.1 eq.), X-Phos (461 mg, 1.14 mmol, 0.2 eq.), potassium acetate (1.11 g, 11.4 mmol, 2.0 eq.), and dioxane (50 mL). After three cycles of vacuum/argon flush, the mixture was heated at 50° C. for 6 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with 1:3 ethyl acetate/petroleum ether to afford 258b (1.70 g, 83%) as a yellow solid, which was used in the next step without further purification. MS: [M+H]+ 360.1
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[C:6]([Cl:19])([Cl:18])[C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2.Cl>CO>[Cl:18][C:6]([Cl:19])([C:7]12[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][C:9]([OH:17])([CH2:15]3)[CH2:8]1)[CH2:16]2)[C:5]([OH:20])=[O:4]
Reactant: COC(=O)C(Cl)(Cl)C12CC3CC(CC(O)(C3)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cl)(Cl)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C

Procedure:
A 500 ml round-bottomed flask was charged with methanol (200 ml) and 1 N NaOH (194 ml, 194 mmol, approximately 1.36 equivalents relative to input dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid methyl ester (Formula VIII)). The resulting solution was cooled in an ice bath until the temperature was <9° C. The cold bath was removed and dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid methyl ester (Formula VIII)(41.68 g, 142.1 mmol) was added. The resulting suspension was allowed to stir at ambient temperature under argon. After stirring for approximately 6 hours, an additional portion of methanol (10 ml) was used to rinse down the vessel walls. After stirring for approximately 17 hours, the reaction mixture was filtered to remove a small amount of particulate material. The resulting solution was transferred to a 2-liter three-necked flask equipped with a mechanical stirrer. Water (900 ml) was used to dilute the reaction mixture and to compete the transfer. The resulting solution was acidified by the addition of concentrated HCl (38 ml, approximately 456 mmol). A white solid quickly formed. The mixture was gently stirred for approximately 20 minutes and then placed in an ice bath. After gently stirring for approximately 90 minutes, the stirrer was stopped and the mixture was allowed to stand in the ice bath for an additional 2 hours. The resulting suspension was filtered and the filtercake was washed with ice cold water. The bulk of the water was removed from the solid by pulling air through the filtercake. The material was then dried under vacuum at ambient temperature for 22 hours to give dichloro-(3-hydroxy-adamantan-1-yl) -acetic acid (Formula IX) as a colorless powdery solid: 39.19 grams (98.7% yield); mp 238° C. (dec).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([NH:15]C(=O)C)=[C:8]([CH3:19])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.C([O-])(O)=O.[Na+]>C(O)C>[N:1]1([C:6]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([NH2:15])=[C:8]([CH3:19])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1c(C)cc(-n2ccnc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(-n2ccnc2)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a suspension of N-(4-imidazol-1-yl-2-methyl-6-nitro-phenyl)-acetamide (279 mg, 1.07 mmol) in ethanol (3 mL) was added 2 N HCl (2 mL). The reaction mixture was heated to reflux for 14 h, cooled to room temperature, and neutralized with saturated NaHCO3. The resulting bright orange solid was filtered and dried under vacuum. The title compound (179 mg, 76%) was obtained as an orange solid. 1H NMR (300 MHz, CD3OD) δ 8.78 (1H, s), 8.24 (1H, s), 7.78 (1H, s), 7.64 (1H, s), 7.46 (1H, s), 2.36 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CCO.[H][H].[OH-].[OH-].[Pd+2]>[NH:1]1[CH2:6][CH2:5][NH:4][CH:3]=[C:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnccn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=CNCCN1
Yield: 102 %

Procedure:
A solution of ethyl pyrazine-2-carboxylate (60 g) in EtOH (500 ml) was subjected to catalytic reduction using palladium hydroxide on carbon (5.0 g), in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 62.8 g of ethyl 1,4,5,6-tetrahydropyrazine-2-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C:9]([NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:11])=[S:10]
Reactant: Nc1nc2ccccc2s1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1ccc(Cl)cc1NC(=S)Nc1nc2ccccc2s1
Yield: 31.1 %

Procedure:
Prepared using Method A from 5.0 g (27.2 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 3.90 g (26 mmol) of 2-aminobenzothiazole to give 2.7 g of title compound as a white fluffy solid (30% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.I[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+].C(OC)(C)(C)C>CN(C)C=O>[CH3:18][C:10]([CH3:19])([CH2:9][CH2:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([O:1][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH2:3]1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Cc1ccc(-c2nc(CI)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)CC[C@H]1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CCC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
365 mg of tert-butyl 4-(cis-3-hydroxycyclohexyl)-2,2-dimethylbutyrate are, together with 850 mg of 4-iodomethyl-5-methyl-2-(4 methylphenyl)oxazole, dissolved in 5 ml of dimethylformamide, and 110 mg of sodium hydride (60% strength in paraffin) are added. After 1 hour of stirring at room temperature, 100 ml of methyl tert-butyl ether are added and the reaction mixture is washed three times with water. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 330 mg of tert-butyl 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyrate as a white solid. C28H41NO4 (455.64), MS(ESI): 456 (M+H+).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:18]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118°C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118°C. (0.07 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](O)=[O:14])=[CH:5][CH:4]=1.B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C(=O)O)c2c1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2cccc(CO)c2c1
Temperature: -2 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To 1 equivalent of 7-methoxy-1-naphthoic acid (100 g) in THF (3.8 ml/g) there are slowly added 2.5 equivalents of 1M BH3-THF (1.235 litres). During the addition, the temperature of the reaction mixture is maintained at 5° C. (+/−2° C.) and then the mixture is left at ambient temperature for 3 hours. After evaporation under reduced pressure, the residue is taken up in dichloromethane and washed with water. The organic phase is dried over MgSO4 and then the solvents are evaporated off under reduced pressure to yield the title compound in the form of a light-brown solid in a yield of 91%.
Reaction SMILES: [ClH:1].Cl.C[CH:4]([C:23](=[O:25])[OH:24])[CH2:5][C@H:6]([C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[NH2:7].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1.[Li+].[OH-].Cl>>[ClH:1].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:7][C@@H:6]([C:8]([N:10]3[CH2:11][CH2:12][CH:13]([CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[CH2:14][CH2:15]3)=[O:9])[CH2:5][CH2:4][C:23](=[O:25])[OH:24])=[O:36])[CH:33]=2)[CH:28]=[CH:27]1
Reactant: CC(C[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1)C(=O)O
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CN1CCC(C2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Prepared from 1-[(γ-methyl)-D-glutamyl]-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride and indole-6-carboxylic acid using methods substantially equivalent to General Coupling Method 1. Ester deprotection with 2 eq LiOH and final purification and HCl salt formation via prep HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:16]1[C:12]2[N:13]=[CH:14][N:15]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[NH2:1])[C:11]=2[CH:18]=[CH:17]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cccc(N)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (12.0 g, 32.4 mmol) in methanol (200 mL), was added Pd/C (2.00 g, 10 wt. %). The reaction was then purged with hydrogen gas and stirred overnight at room temperature under hydrogen atmosphere (1 atm) before being filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 50% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline as a yellow oil. LRMS (ESI) calc'd for C18H25N4OSi [M+H]+: 341, found 341.