Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=O)(C)(C)C.[ClH:39]>C(O)C>[ClH:39].[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 30.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (218 mg, 0.4 mmol) was added into the reaction flask. A solution of hydrochloric acid in 5 mL of ethanol was then added to the flask. The reaction mixture was reacted at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid hydrochloride 10 (60 mg, yield 30.8%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:12](=[O:17])N(OC)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH:12]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)[C@H](NC(=O)OCc1ccccc1)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C[C@H](NC(=O)OCc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of [(R)-Cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid benzyl ester (27 g, 82 mmol) in THF (400 mL) at −20° C. was slowly added LiAlH4 (4.06 g, 106 mmol, 1.3 equiv). LiAlH4 was freshly ground from pellet purchased from Aldrich. During addition, the internal temperature was carefully monitored and did not rise above 0° C. After addition the mixture was stirred at 0° C. and the reaction was monitored by TLC and LCMS. After 1 hour, the reaction solution was cooled at −10° C. and quenched by slow addition of sat. aq. KHSO4 solution until pH=5. The mixture was partitioned between water and EtOAc. The phases were separated and the organic layer was concentrated. The residue was dissolved in EtOAc and the solution was washed with water, brine, dried over Na2SO4 and concentrated to give product ((R)-1-Cyclohexyl-2-oxo-ethyl)-carbamic acid benzyl ester 22 g (99%). The material was continued to next step with no further purification.
Reaction SMILES: [F:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([O:25][CH3:26])=[C:6]([NH:8][C:9](=[O:24])[O:10][CH:11]([CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH3:12])[CH:7]=1.Br[C:37]1[N:38]=[C:39]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[N:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[C:41]=12>>[F:1][C:2]1[C:3]([C:37]2[N:38]=[C:39]([CH:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[N:40]3[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[C:41]=23)=[CH:4][C:5]([O:25][CH3:26])=[C:6]([NH:8][C:9](=[O:24])[O:10][CH:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH3:12])[CH:7]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)OC(C)CCCO[Si](C)(C)C(C)(C)C
Reactant: Cc1nccn2c(C3CCOCC3)nc(Br)c12
Product: COc1cc(-c2nc(C3CCOCC3)n3ccnc(C)c23)c(F)cc1NC(=O)OC(C)CCCO

Procedure:
Reaction of 5-(tert-butyldimethylsilyloxy)pentan-2-yl 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (prepared according to the procedures described in example 44, 82 mg) and 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (47.5 mg) according to the procedure described in example 4 step 4c and purification using prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid) gave 5-hydroxypentan-2-yl 5-fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2h-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate (14 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=2)=[CH:18][N:17]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH2:30][N:31]([CH3:32])[CH3:33])=[CH:28][CH:29]=2)=[CH:18][N:17]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(CN(C)C)nc2)c(=O)[nH]1

Procedure:
A mixture of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g), 2-nitroamino-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone (2.28 g) in pyridine were heated under reflux for 22 hr. The pyridine (12 ml) was evaporated at reduced pressure yielding [2-(5-methyl-4-imidazolyl-methylthio)ethylamino]-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone as a brown oily residue washed with water by decantation. The residue was dissolved in dilute ethanolic hydrochloric acid and the excess of solvent evaporated at reduced pressure. The residue was recrystallised from methanol/dilute ethanolic hydrochloric acid and then twice from methanol/ethanol to yield the tetrahydrochloride (0.82 g) as a light buff solid m.p. 167°-170° C.
Reaction SMILES: [NH2:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57](O)=[O:58]>C(Cl)Cl.CCOC(C)=O>[CH2:18]([N:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:10][C:6]([NH:5][C:3]([C:2]([NH:1][C:57]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=2)=[O:58])([CH3:26])[CH3:25])=[O:4])=[N:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccccn1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Reaction time: 24 h

Procedure:
2-Amino-N-[1-benzyl-5-(4-fluoro-phenyl)-1H-[1,2,4]triazol-3-yl]-2-methyl-propionamide (137 mg, 0.388 mmol), HATU (295 mg, 0.776 mmol), and picolinic acid (72 mg, 0.582 mmol) were stirred in DCM (6 mL). TEA (108 uL, 0.776 mmol) was added to the reaction mixture and it was stirred for 1 day. It was diluted with EtOAc (65 mL) and extracted with water (15 mL), followed by saturated NaHCO3 (15 mL). The organic layer was dried with a brine wash (10 mL) followed by Na2SO4. The solvents were removed in vacuo and the residue was purified by reverse phase HPLC (C18, 45-100% MeOH/H2O+5 mM NH4OH) followed by silica gel chromatography (0-30% ACN/DCM) to afford the title compound as a white solid: 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.73 (s, 6H) 5.35 (s, 2H) 7.07-7.22 (m, 4H) 7.26-7.39 (m, 3H) 7.49 (ddd, J=7.61, 4.77, 1.14 Hz, 1H) 7.52-7.61 (m, 2H) 7.90 (td, J=7.74, 1.71 Hz, 1H) 8.19 (dt, J=7.77, 1.04 Hz, 1H) 8.47 (br. s., 1H) 8.58 (ddd, J=4.77, 1.61, 0.95 Hz, 1H) 9.45 (br. s., 1H); Rt (method A)=1.22 min, (M+H)+ 459.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.CO[C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH3:27])[CH2:22][CH2:21]1)=O>>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][N:26]([CH3:27])[C@H:23]3[CH2:24][CH2:25][C@H:20]([CH2:18][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:21][CH2:22]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: COC(=O)[C@H]1CC[C@H](N(C)Cc2ccc3c(c2)OCCO3)CC1
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](N(C)Cc4ccc5c(c4)OCCO5)CC3)cc2c1

Procedure:
The title compound is prepared as a yellow oil following Scheme 2 and in analogy to Example 28 using 6-methoxy-quinoline-3-carboxylic acid and trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylic acid methyl ester as starting materials.
Reaction SMILES: OC[C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]([S:11][CH3:12])=[N:5][N:4]=1.[CH:13]([Cl:16])(Cl)[Cl:14]>S(Cl)(Cl)=O>[ClH:14].[Cl:16][CH2:13][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]([S:11][CH3:12])=[N:5][N:4]=1
Reactant: CCCn1c(CO)nnc1SC
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCn1c(CCl)nnc1SC
Product: Cl

Procedure:
A solution of 3-hydroxymethyl-4-propyl-5-mercapto-4H-1,2,4-triazole (2.0 g), iodo methane (1.1 ml) and triethylamine (2.5 ml) in ethanol (20 ml) was stirred for 2 days at 50° C. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), to give 3-hydroxymethyl-5-methylthio-4-propyl-4H-1,2,4-triazole (2.13 g) as pale yellow oil. To a solution of 3-hydroxymethyl-5-methylthio-4-propyl-4H-1,2,4-triazole (2.13 g) in chloroform (6 ml), thionyl chloride (16 ml) was slowly added at 0° C. The mixture was heated to reflux for 2 hours, and concentrated under reduced pressure. To the residue were added small amount of ethanol and ethyl acetate, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and diethylether, to give 3-chloromethyl-5-methylthio-4-propyl-4H-1,2,4-triazole hydrochloride (1.06 g) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[CH3:2].[F:25][C:26]([F:31])([F:30])S([O-])=O.[Na+].ClCCCl.C(OO)(C)(C)C>CS(C)=O.O>[CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[O:15])=[C:12]([C:26]([F:31])([F:30])[F:25])[C:7]=2[NH:6][N:5]=1)[CH3:2]
Reactant: O=S([O-])C(F)(F)F
Reactant: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC(C)(C)OO
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CS(C)=O
Product: CCNc1n[nH]c2c(C(F)(F)F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C

Procedure:
(R)-1-(3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (50 mg, 0.154 mmol) and sodium trifluoromethanesulfinate (72.2 mg, 0.462 mmol) were taken in a solvent mixture containing DCE:water:DMSO in a ratio of 2.5:1:0.5, cooled to 0° C. and added tert-butyl hydroperoxide (0.107 mL, 0.771 mmol) and reaction gradually warmed to room temperature. After two more additions of tert-butyl hydroperoxide in equal concentrations in a span of 36 hours, the reaction was partitioned between DCM and aqueous sodium bicarbonate. The organics were washed with brine, dried with sodium sulfate and concentrated. Purification of residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3-(ethylamino)-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI [M+H]+ calc'd. 393. found 393. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.40-7.30 (m, 4H), 7.20 (m, 1H), 7.10 (s, 1H), 4.97 (m, 1H), 3.29, (m, 2H), 1.38 (d, J=6.5 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:16][C:5]2([CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]2)[O:4][CH2:3]1.OC1CC2(CCN(C(OC(C)(C)C)=O)C2)OC1.C(OC(N1CC(=O)C1)=O)(C)(C)C.[ClH:46]>O1CCOCC1>[ClH:46].[OH:1][CH:2]1[CH2:16][C:5]2([CH2:8][NH2+:7][CH2:6]2)[O:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(O)CO2)C1
Agent: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)(C)OC(=O)N1CCC2(CC(O)CO2)C1
Agent: Cl
Solvent: C1COCCO1
Product: OC1COC2(C[NH2+]C2)C1

Procedure:
In analogy to the procedure described in Example 82 a), tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (which can be prepared in analogy to tert-butyl 3-hydroxy-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (CAN 1331825-50-3) starting from 3-oxoazetidine-1-carboxylic acid tert-butyl ester (CAN 398489-26-4) as described in A. I. Moskalenko et al., Russian Journal of Organic Chemistry, 47(7), 1091-1096; 2011) was treated with a 4 M solution of HCl in dioxane to give the title compound as colorless solid which was sufficiently pure to be used in the next step; MS (EI): m/e=130.2 [(M-Cl)H+].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28](=[O:30])[CH3:29])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1nc(COCc2ccccc2)n(CC(C)(C)O)c1Sc1cc(Cl)cc(Cl)c1
Yield: 73 %

Procedure:
In 5 ml of tetrahydrofuran was dissolved 464 mg (1 mmol) of the ketone (139), followed by addition dropwise of 134 mg (1.1 mmol) of methylmagnesium bromide (tetrahydrofuran;2 ml) under ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride, the mixture was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate:methylene chloride=1:1) to provide 350 mg (yield 73%) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-(2-hydroxy-2-methylpropyl)-4-isopropyl-1H-imidazole (140b) as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[CH:3][C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])=[CH:7][N:6]=1
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)c1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1cnc(C(F)(F)F)nc1
Temperature: 130 °C
Yield: 97.7 %

Procedure:
A mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (900 mg, 3.97 mmol), methyl 2-propenoate (0.533 mL, 5.95 mmol), Pd(OAc)2 (44.5 mg, 0.198 mmol), tri-o-tolylphosphine (241 mg, 0.793 mmol) and TEA (1.105 mL, 7.93 mmol) in DMF (6 mL) under argon was heated at 130° C. for 1 h. After cooling to room temperature, water (40 mL) was added to the reaction mixture and then extracted by EA (3×50 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated in vacuo to afford the title compound (900 mg, 3.88 mmol, 98% yield) as a yellow solid. LCMS: rt=2.67 min, [M+H+]=233
Reaction SMILES: [Cu](C#N)C#N.[C:6]([Mg]Cl)([CH3:9])([CH3:8])[CH3:7].[Br:12][C:13]1[CH:14]=[CH:15][C:16](I)=[N:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:6]([CH3:9])([CH3:8])[CH3:7])=[N:17][CH:18]=1
Reactant: Brc1ccc(I)nc1
Reactant: CC(C)(C)[Mg]Cl
Agent: N#C[Cu]C#N
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a THF (40 ml) suspension of copper cyanide (1.79 g, 20 mmol) which was dried under reduced pressure for 4 hours was added 1.0 M THF solution of tert-butylmagnesium chloride (40 ml, 40 mmol) dropwise at −78° C. over 30 minutes and the mixture was stirred for 1 hour at −78° C. 5-Bromo-2-iodopyridine (2.83 g, 10 mmol) was added at −78° C. and the mixture was stirred for 1 hour at −78° C., followed by additional stirring for 16 hours at room temperature. Then, the reaction was quenched with 25% aqueous ammonia solution (40 ml) and the precipitates were removed by filtration and washed with EtOAc. The filtrate and washings were combined and concentrated in vacuo. Then, filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane/EtOAc (20:1), gave the title compound (1.07 g, 50% yield) as a colorless oil.
Reaction SMILES: C(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].N1CCOCC1.C(O)C.[CH3:16][O:17][C:18]([C:20]1[C:24](=O)O[C:22]2=[CH:26][CH:27]=[C:28]([CH:31]([CH3:33])[CH3:32])[CH:29]=[CH:30][C:21]=12)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]([C:20]1[C:21]2[C:22]([CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)=[C:2]([CH:3]([CH3:5])[CH3:4])[CH:24]=1)=[O:19]
Reactant: COC(=O)c1c2ccc(C(C)C)ccc-2oc1=O
Reactant: CC(C)CC=O
Solvent: CCO
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(C)C)c2ccc(C(C)C)ccc1-2

Procedure:
Isovaleraldehyde (5.16 g) and morpholine (4.36 g) are added to ethanol (14 ml) and then 3-methoxycarbonyl-6-isopropyl-2H-cyclohepta[b]furan-2-one (5) (2.46 g) is added thereto. The obtained mixture is heated under reflux for 16 hours, and then the solvent is distilled off under reduced pressure to give an oily material. The obtained oily material is dissolved in toluene (20 ml), washed twice with water (20 ml) and 4 times with 1N HCl (20 ml), and further, twice with water (40 ml). The obtained toluene layer is passed through silica gel column (1.05 kg), the column is eluted with toluene. From the eluted parts including the product (24), the solvent is distilled off under reduced pressure to give the compound (24) as a purple oily material in a yield of 2.08 g, 76.%.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[C:13]1([C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N+]=[N-])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[C:13]1([CH:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:8][C:7]([CH:5]2[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]2)=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(C(=O)O)C(C(=O)O)O1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)C(C(=O)OC(c2ccccc2)c2ccccc2)O1
Yield: 32 %

Procedure:
262 mg of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid in 5 ml of acetone was stirred with 291 mg of diphenyldiazomethane at room temperature for 20 minutes. The reaction solution was evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography [chloroform/methanol=100/1→10/1] to give 163 mg of the title compound as a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=C(CCCCCl)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 438.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=C)([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[N:8][C:7]=2[N:6]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:27])[CH2:2][CH3:3].[O:28]1CCOCC1>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[O:27]=[C:5]1[N:6]([CH2:24][CH2:25][CH3:26])[C:7]2[N:8]=[C:9]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[O:28])([CH2:18][CH2:19]3)[O:16][CH2:15]4)[NH:10][C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C=CC12CCC(c3nc4c([nH]3)c(=O)n(CCC)c(=O)n4CCC)(CC1)CO2
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)OC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-Dipropyl-8-(1-vinyl-2-oxa-bicyclo[2.2.2]oct-4-yl)-3,7-dihydro-purine-2,6-dione (400 mg, 1.08 mmol) was suspended in 8 ml of dioxane and 1 ml of a 2.5% solution of OsO4 in t-BuOH was added, followed by 3 ml of H2O. After 10 min, NaIO4 was added and the reaction mixture was stirred at rt for 3 h. It was then diluted with H2O and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford the aldehyde intermediate, 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]octane-1-carbaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1>C(OCC)(=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:10]([CH3:9])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: CNc1cccc(C(F)(F)F)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCOC(C)=O
Product: CN(c1cccc(C(F)(F)F)c1)c1cc(Cl)ncn1
Temperature: 126 °C
Yield: 61.9 %

Procedure:
4,6-Dichloropyrimidine (1.55 g, 0.01 mol) and N-metyl-3-trifluoromethylaniline (2.0 g, 0.11 mol) are combined and heated to 126° C. under N2 for 1.5 hours. The resulting oil is taken up in ethyl acetate, is washed with 10% sodium carbonate and dried over sodium sulphate. The organic phase is concentrated under reduced pressure to yield a yellow oil which is purified by column chromatography to give 4-chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (1.78 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][C:23]([CH3:26])=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])[N:10]=2)[CH:7]=1.[Br-].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]([C:21]2[O:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:20])=[CH:12][C:11]=1[C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3cn4cc(Br)cnc4n3)c2)o1
Agent: [Br-]
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3cn4cc(-c5ccccc5)cnc4n3)c2)o1

Procedure:
Compound 31 was synthesized using N-(3-(6-bromoimidazo[1,2-a]pyrimidin-2-yl)-4-chlorophenyl)-5-methylfuran-2-carboxamide (I-14) as the bromide and phenylboronic acid using a suzuki coupling protocol described in the synthesis of I-11. The residue was redissolved in methanol and precipitation yielded the compound 1H NMR (400 MHz, DMSO-D6) δ 10.33 (s, 1H), 9.38 (d, J=2.1, 1H), 8.99 (d, J=2.0, 1H), 8.71 (d, J=2.5, 1H), 8.62 (s, 1H), 7.95 (dd, J=2.4, 8.7, 1H), 7.80 (d, J=7.8, 2H), 7.52 (dt, J=7.8, 14.7, 5H), 7.34 (d, J=3.3, 1H), 6.35 (d, J=3.3, 1H), 2.40 (s, 3H).