Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:5])#[N:2]>[Pd].C(O)C>[C:1]([CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:5])#[N:2]
Reactant: COc1ccc(C(C)=CC#N)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(C)CC#N)cc1

Procedure:
A suspension of the 1-cyano compound of Step 1. (53.2 g) and 5% palladium on carbon (5.3 g) in ethanol (530 ml) is stirred under an atmosphere of H2 for four hours. The reaction mixture is filtered, and the filtrate evaporated in vacuo affording the crude product as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])=[C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 463.4 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.40-6.55 (m, 9H), 4.85-2.70 (m, 5H), 1.85-0.65 (m, 8H).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](F)=[O:21])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](=[O:21])[NH:7][CH2:8][CH2:9][SH:10])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: NCCS
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (148.1 mg, 1.76 mmol) in 8.6 mL water was added 2-aminoethanethiol hydrochloride (107.5 mg, 0.95 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25c (163.5 mg, 0.86 mmol) in 8.6 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 108.0 mg (51% from 24c) of clean 26c as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([C:23]1[O:27][N:26]=[C:25]([NH2:28])[N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[O:27][N:26]=[C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1noc(Cc2ccccc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3noc(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 5-benzyl-[1,2,4]oxadiazol-3-ylamine (Zeitschrift für Chemie 14, 94 (1974)). The title compound was obtained as a light yellow solid (Yield=41%). MS ISP (m/e): 357.1 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:30]=[CH:29][C:15]([C:16]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)=[O:17])=[CH:14][C:13]=1[O:31]CC1C=CC=CC=1)=[CH:5]2.CCO.CC#N>Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:30]=[CH:29][C:15]([C:16]([NH:18][CH:19]3[CH2:20][C:21]([CH3:27])([CH3:28])[NH:22][C:23]([CH3:25])([CH3:26])[CH2:24]3)=[O:17])=[CH:14][C:13]=1[OH:31])=[CH:5]2
Reactant: CC1(C)CC(NC(=O)c2ccc(-c3cc4cc(Cl)c(Cl)cc4[nH]3)c(OCc3ccccc3)c2)CC(C)(C)N1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: CC1(C)CC(NC(=O)c2ccc(-c3cc4cc(Cl)c(Cl)cc4[nH]3)c(O)c2)CC(C)(C)N1
Yield: 30 %

Procedure:
A mixture of 4-(5,6-dichloro-1H-indol-2-yl)-3-benzyloxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)-benzamide (0.08 g, 0.145 mmol), prepared as described in Example 2, in 37% HCl (5 ml) and EtOH (5 ml) was refluxed for 3 h. After cooling the solvent was removed under vacuum. The resulting solid was purified by column chromatography over silica gel (CH2Cl2/MeOH/NH4OH 86:10:0.6) to yield, after trituration with CH3CN, 0.02 g (yield 39%) of the title compound as a white solid, mp>270° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C:9]([CH:11]=[O:12])=[CH:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].[BH4-].[Na+].CO>C(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C:9]([CH2:11][OH:12])=[CH:8][N:7]1[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:5]
Reactant: CCOC(=O)[C@@H]1CC(C=O)=CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H]1CC(CO)=CN1C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
A solution of (S)-4-formyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (3.32 g, 12.3 mmol) in CH2Cl2 (51.4 mL) was cooled at −78° C. under nitrogen atmosphere, solid NaBH4 (1 g, 24.7 mmol) was added portionwise maintaining the temperature at −78° C. MeOH (25.7 mL) was added dropwise and the reaction mixture was allowed to reach 0° C. and was stirred 1 h30 at 0° C. The reaction was quenched with an aqueous saturated solution of NH4Cl and extracted with CH2Cl2 (×3). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1 to EtOAc) to give the desired material as a yellow oil. Rf, TLC (c-hexane/EtOAc 1:1)=0.30; MS (UPLC-MS): 272.2 [M+H]+, 316 [M+HCOO]−; tR (HPLC conditions f): 1.74 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH2:13][CH3:14])[CH:9]([C:11]#[N:12])[OH:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18]>CO.C[O-].[Na+]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH:9]([OH:10])[C:11](=[NH:12])[NH:17][OH:18])[CH2:13][CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: NO
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.2 %

Procedure:
A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (9.53 g, 44 mmol) in methanol (80 ml) was cooled to 0° C. and treated successively with hydroxylamine hydrochloride (3.05, 44 mmol) in methanol (80 ml) and 25% sodium methoxide solution in methanol (10.2 ml). Stirred at 0° C. for 5 minutes, cold bath removed and the reaction mixture stirred at room temperature for 5 hours. Methanol evaporated off under reduced pressure, crude partitioned between ethyl acetate and water. Organic layer separated, dried (MgSO4) and evaporated under reduced pressure to give yellow oil. Purified by mplc, eluting with a mixture of ethyl acetate-heptane to give the title compound as white solid (3.5 g); MS: M(H+) 248.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13](=[O:21])[C:12]([CH3:23])([CH3:22])[C:11](=[O:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:21])[C:12]([CH3:22])([CH3:23])[C:11](=[O:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CN1C(=O)C(C)(C)C(=O)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetate from Step A (170 mg, 0.501 mmol) in THF (2 mL) and H2O (1 mL) was added LiOH monohydrate (36 mg, 0.858 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 1 N HCl (1 mL, 1 mmol), concentrated in vacuo and dried to afford the title compound. MS: m/z=312 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[C:3]=1F.[Br:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:19][C:3]1[C:4]([C:8]#[N:9])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: N#Cc1nccc(Cl)c1F
Reactant: Oc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1nccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Temperature: 55 °C

Procedure:
To a solution of 4-chloro-3-fluoropyridine-2-carbonitrile (2.18 g, 9.03 mmol) in DMF (10 mL) was added 3-bromo-5-chlorophenol (1.96 g, 9.48 mmol) and potassium carbonate (1.25 g, 9.03 mmol) and the mixture was heated to 55° C. for 10 minutes. The mixture was cooled to room temperature and partitioned between water (200 mL) and ethyl acetate (2×100 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent evaporated in vacuo to provide the title compound. LRMS (M+1): 344.8
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:22]
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Cc1ccnc(N)c1
Product: Cc1ccnc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)c1
Yield: 91 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-pyridyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 6 from methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-4-methyl-pyridine with a yield of 91% of theory; M.p.: 250°-251° C. (decomposition).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[C:22]([CH2:33][C:34]([O:36]C)=[O:35])([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:21][CH2:20]4)=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[C:22]([CH2:33][C:34]([OH:36])=[O:35])([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:21][CH2:20]4)=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CC1(CC(F)(F)F)CCc2cc(-c3ccc(Nc4cccc(Cl)c4)nn3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC1(CC(F)(F)F)CCc2cc(-c3ccc(Nc4cccc(Cl)c4)nn3)ccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
Lithium hydroxide (0.063 g, 1.49 mmol) was added to a solution of 21E1 (0.15 g, 0.298 mmol) in 6 mL of ethanol-water (3:1) mixture, and the reaction mixture was stirred at room temperature for 4 h. After the solvent was removed in vacuo, the residue was diluted with water. The aqueous layer was acidified by addition of saturated citric acid solution until pH 2 was attained. The resulting solution was cooled to 0° C., and solids obtained were filtered off and dried under vacuum to afford the title compound 21 (0.118 g, 78%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (bs, 1H), 9.78 (s, 1H), 8.19 (s, 1H), 8.13 (d, J=9.6 Hz, 1H), 8.07-7.95 (m, 3H), 7.58 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 3.24-2.87 (m, 5H), 2.68 (d, J=15.2 Hz, 1H), 2.34 (d, J=14.4 Hz, 1H), 2.14 (m, 1H). ESI-MS m/z: 490 (M+H)+; HPLC purity: 97%.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[CH:7][N:6]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Product: Cc1onc(-c2ccccc2)c1CNc1cnc(C(=O)NC2CCOCC2)cn1
Yield: 81 %

Procedure:
As described for example 9b, 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester (650 mg, 2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (640 mg, 81%) which was obtained as a white solid. MS: m/e=350.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C>C(Cl)Cl>[O:1]=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3ccccc3)cc2)S1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3ccccc3)cc2)S1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
To a stirring solution of 5-[4-(2-hydroxy-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione (1.00 g, 2.91 mmol) in DCM (35 mL) was added DMSO (2 mL) and the solution was cooled to 0° C. Phosphorus pentoxide (0.83 g, 2.91 mmol) was added followed by triethylamine (1.8 mL, 13.1 mmol). The reaction was allowed to slowly warm to RT. After 2 hours, the reaction mixture was partitioned between DCM and water and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on silica gel eluting with 25-35% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 0.40 g (40%) of the title compound as a white solid. Trituration with ether afforded 245 mg of clean product. MS (ESI−) for C18H15NO4S m/z 340.1 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: CC1(C)OB(c2cnccc2Cl)OC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2cnccc2Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
A mixture of 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (506 mg, 2.004 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (480 mg, 2.004 mmol, Combi-Blocks, Inc., San Diego, Calif.), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (164 mg, 0.200 mmol), and cesium carbonate (0.321 mL, 4.01 mmol) in dioxane (4 mL) and water (0.5 mL) was stirred at 100° C. for 30 min. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×30 mL), The organic extract was washed with saturated NaCl (2 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a plug of silica gel and purified by flash chromatography eluting with 10% MeOH in CH2Cl2 to provide 6-(4-chloropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (98 mg, 15% yield) as light-yellow glass. 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H); 8.61 (d, J=5.41 Hz, 1H); 8.27 (s, 1H); 7.50 (d, J=5.41 Hz, 1H); 5.87 (d, J=10.08 Hz, 1H); 4.20 (d, J=11.25 Hz, 1H); 3.84 (t, J=11.33 Hz, 1H); 3.48 (d, J=5.41 Hz, 1H); 2.90 (s, 3H); 1.99-2.29 (m, 3H); 1.64-1.95 (m, 3H). m/z (ESI, +ve ion) 330 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:50]1[C:55]([F:56])=[C:54]([F:57])[C:53]([F:58])=[C:52]([F:59])[C:51]=1[F:60])=O>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29]([O:31][C:50]3[C:51]([F:60])=[C:52]([F:59])[C:53]([F:58])=[C:54]([F:57])[C:55]=3[F:56])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of #@5 (19.43 g, 37.03 mmol, 1 eq.) in dichloromethane (100 mL) and pyridine (5.86 g, 74.1 mmol, 2 eq.) was added pentafluorophenyl trifluoroacetate (20.7 g, 74.1 mmol, 2 eq.) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 to 52% ethyl acetate in heptane) to afford #174 (23.58 g, 92%) as a yellow oil. LC-MS (Protocol Q1): m/z 691.2 [M+H+], retention time=1.23 minutes.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li]CCCC.CON(C)[C:20]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH3:33])=[O:21]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]#[C:11][C:20]([C:22]1[O:26][C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:24][C:23]=1[CH3:33])=[O:21])([CH3:5])([CH3:6])[CH3:7]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CON(C)C(=O)c1oc(-c2ccccc2)nc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)oc1C(=O)C#CCNC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A −15° C. solution of N-BOC propargyl amine (651 mg, 4.2 mmole, 3.5 eq) in dry THF (12 ml) was treated dropwise with a 1.6M n-BuLi in hexanes solution (5.25 ml, 8.4 mmole, 7.0 eq) and the pale yellow dianion solution was stirred at −15° C. for 30 minutes under nitrogen. A dry THF solution (3 ml) of the above-prepared 4-methyl-2-phenyl-oxazole-5-carboxylic acid methoxy-methyl-amide (296 mg, 1.2 mmole, 1.0 eq) was added dropwise to the dianion solution at −15° C. and the mixture stirred at 0° C. for 2 hours under nitrogen. The mixture was quenched by adding a solution of 2M NaH2PO4 (5 ml), warmed to room temperature, and then extracted with ethyl acetate. The organic phase was washed with water and brine then dried over anhydrous sodium sulfate and concentrated in vacuo to provide the title compound as a crude brown oil. The crude oil was used immediately in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[CH3:19])/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C/C(=C\c1ccc(C#N)c(N)c1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(C#N)c(N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1370 mg (5.3 mmol) of tert-butyl (2E)-3-(3-amino-4-cyanophenyl)-2-methylacrylate were dissolved in 30 ml of ethyl acetate, 282 mg of palladium on carbon (10%) were added and the mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure for three days. The reaction mixture was then filtered off through celite, the filter residue was washed with ethyl acetate and the combined filtrate was concentrated. The crude product was purified by preparative HPLC (mobile phase acetonitrile/water). This gave 870 mg of the title compound (63% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([S:8][C:9]2[CH:22]=[CH:21][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:23]2([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([S:8][C:9]2[CH:22]=[CH:21][C:12]([C:13](=[N:32][OH:33])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)c4ccccc4)cc3)c2)CCOCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC1(c2cc(F)cc(Sc3ccc(C(=NO)c4ccccc4)cc3)c2)CCOCC1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A mixture of 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzophenone (0.22 g), hydroxylamine hydrochloride (0.042 g) and pyridine (4 ml) was stirred and heated to reflux for 3 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with brine. dried (MgSO4) and evaporated. There was thus obtained, as a mixture of (E)- and (Z)-isomers, 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzophenone oxime as a foam (0.12 g, 53%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[CH:23]=[N:22][CH:21]=[N:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[N:20]=[CH:21][N:22]=[CH:23][C:24]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ncncc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cncnc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine to provide the title compound in moderate yield.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]([F:20])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1>CO>[F:20][CH:4]([F:3])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:14][CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: O=Cc1ccc(OC(F)F)c(OC2CCOC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
A sodium borohydride solution (0.0177 mol) was added portionwise to a solution of intermediate 1 (0.0532 mol) in methanol (100 ml), and the reaction mixture was stirred for 1 hour at RT. The solvent was evaporated, the residue was washed with water, and extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by open column chromatography over silica gel (eluent: CH2Cl2 /2-propanone 96/4 and 90/10; CH2Cl2 /CH3OH 96/4). The pure fractions were collected and the solvent was evaporated, yielding 11.3 g (81%) of (±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzenemethanol (intermediate 2).