Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([NH:39][C:40]([CH3:44])([CH3:43])[CH:41]=O)[CH2:38][CH2:37]1>N1CCCCC1.CC#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:41][C:40]([NH:39][CH:36]3[CH2:38][CH2:37]3)([CH3:44])[CH3:43])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)NC1CC1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC1CC1
Reaction time: 0.33 h
Yield: 27.6 %

Procedure:
A solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (118 mg, 0.25 mmol, 1.0 equiv), 2-(cyclopropylamino)-2-methylpropanal (0.16 g, 1.25 mmol, 5.0 equiv) and one drop of piperidine in MeCN (10 mL) was stirred overnight at 40° C. The solvent was removed and the residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 40 mg (27%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 581 (M+H+). H1-NMR (400 MHz, CDCl3+D2O, ppm): 8.33 (s, 1H), 7.54-7.43 (m, 3H), 7.33 (s, 1H), 7.28-7.25 (m, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.94 (dd, J=8.4, 2.0 Hz, 1H), 6.85 (dd, J=11.6, 2.0 Hz, 1H), 4.89-4.64 (m, 3H), 3.65-3.52 (m, 2H), 2.78 (m, 1H), 2.14-1.79 (m, 4H), 1.57-1.55 (d, 6H), 1.20 (m, 2H), 0.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1.I.CS[C:23](=[NH:36])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1>N1C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]2[NH:36][C:13]([C:12]3[CH:17]=[CH:18][C:9]([O:8][C:6]4[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:19])[CH:5]=4)=[CH:10][CH:11]=3)=[N:15][N:16]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Agent: I
Solvent: c1ccncc1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
4-[(2,6-diaminopyrimidin-4-yl)oxy]benzohydrazide (1.48 g, 5.68 mmol) and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (2.33 g, 5.89 mmol) were suspended in 30 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. The formed yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow foamy solid was re-dissolved in 50 mL of 5:1 EtOAc/MeOH; ca. 15 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was packed into ISCO column and the product was purified using ISCO system (80 g pre-packed column, 50 min run, 0% to 10% gradient of solvent B in solvent A [Solvent A—4 mL of MeOH, 4 mL of Et3N in 4 L of CH2Cl2; Solvent B—4 mL of Et3N in 4 L of MeOH]). Solvent was removed in vacuo to give the title product as a white solid (1.33 g). Yield 50.5%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[CH:11]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12]2>>[F:10][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([F:9])[CH:6]=1)[CH2:2][C@@H:14]1[CH2:13][CH2:12][CH2:11][C@H:15]1[OH:16]
Reactant: C1CC2OC2C1
Reactant: Fc1cc(F)cc(CBr)c1
Product: O[C@@H]1CCC[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Reaction of the Grignard reagent prepared from 1-(bromomethyl)-3,5-difluorobenzene with 6-oxabicyclo[3.1.0]hexane gave trans-2-(3,5-difluorobenzyl)cyclopentanol. Conversion to the mesylate, followed by displacement with sodium azide and reduction with triphenylphosphine afforded cis-2-(3,5-difluorobenzyl)cyclopentanamine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH2:25]O)([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[OH:9].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:17]2[C:18](=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[CH2:25][O:9]1
Reactant: N#Cc1ccc(C(O)(CCC2OCCO2)c2ccc(F)cc2)c(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)COC2(CCC1OCCO1)c1ccc(F)cc1
Temperature: 7.5 °C
Reaction time: 0.08 h
Yield: 134.8 %

Procedure:
4-[3-[1, 3]-Dioxolan-2-yl-1-(4-fluorophenyl)-1-hydroxypropyl-]3-hydroxymethylbenzonitrile (15 g) was dissolved in dichloromethane (150 mL) at room temperature, followed by addition of triethylamine (25 mL). The reaction mixture was cooled to 5-10° C. and stirred for 5 min, followed by addition of methane sulfonylchloride (8.4 g). The reaction mixture was warmed to room temperature and stirred for 10 min. It was quenched with 2% NaOH (100 mL) while maintained to 10-20° C. The organic phase was separated and was dissolved in water and concentrated to give 19.2 g crude product. 1H NMR (CDCl3, δ): 1.42-1.57 (m, 1H), 1.63-1.76 (m, 1H), 2.20-2.38 (m, 2H), 3.78-3.96 (m, 4H), 4.84 (t, J=3 Hz, 1H), 5.18 (m, 2H), 7.00 (m, 2H), 7.38-7.50 (m, 4H), 7.60 (m, 1H). The product was separated into its enantiomers by CHIRALCEL OD=column using Methanol as eluent. Enantiomer 6a, 6.67 min; Enantiomer 6b, 8.30 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:22][C:21]([C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1)([F:24])[F:23].[F:24][C:21]([F:22])([F:23])[C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2cccc(C(F)(F)F)c2o1
Reactant: Ic1ccccn1
Product: FC(F)(F)c1cccc2nc(CCC#Cc3ccccn3)oc12
Product: FC(F)(F)c1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 105.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (77 mg, 0.38 mmol) and 2-(but-3-ynyl)-7-(trifluoromethyl)benzo[d]oxazole (90 mg, 0.38 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to DCM/MeOH 99:1) to yield 63 mg (0.20 mmol, 53%) of 7-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH3:12].C([Li])(C)(C)C.[CH3:18][Si:19]([CH3:22])([CH3:21])Cl.O>C1COCC1.CCCCC>[CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([Si:19]([CH3:22])([CH3:21])[CH3:18])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH3:12]
Reactant: C[Si](C)(C)Cl
Reactant: CC1=C(C)C(C)c2ccccc21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C)C(C)c2cccc([Si](C)(C)C)c21
Reaction time: 8 h

Procedure:
1,2,3-Trimethylindene in an amount of 4.09 g (26 mmol) was dissolved in 100 mL of dried THF, and to the resultant solution was added dropwise, under ice-cooling 19 mL of a 1.7M solution of tert-butyllithium in pentane. After 2 hours of reaction at room temperature, the reaction product was incorporated under ice-cooling with 3.25 g (30 mmol, 3.8 mL) of trimethylchlorosilane (TMSCl) that had been subjected to simple distillation, was brought back to room temperature and was allowed to stand overnight. The yellow solution thus obtained was incorporated with 20 mL of water for quenching and THF was removed under reduced pressure. Then, the solution was extracted and separated with 300 mL of hexane, the organic phase thus obtained was dried with magnesium sulfate anhydride as the drying agent, the used drying agent was filtered away, and the volatile components were distilled away under reduced pressure. As the result, there was produced 1,2,3-trimethylindenyltrimethylsilane in the form of yellow oil in a yield of 4.27 g (18.5 mmol) and in a yield rate of 72%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=[O:28])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C:15](=[O:16])[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CCO.ClCCl>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:15]([OH:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:19][CH:18]=3)[C:13](=[O:28])[CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1c1ccc(OC(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: O=C1C2CN(Cc3ccccc3)CC2C(O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a cooled (−35˜−40° C.) solution of 5-Benzyl-2-(4-trifluoromethoxy-phenyl)-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione (0.6 g, 0.5 mmol) and CeCl3.7H2O (0.56 g, 0.5 mmol) in 250 mL EtOH/dichloromethane (1.5:1) were sequentially added NaBH4 (0.057 g, 10 mmol). The temperature was kept at −35˜−40° C. for 2 h, poured into cold water (100 mL) and extracted with dichloromethane (2×80 mL). After washing the organic phase with brine (100 mL) and drying over anhydrous Na2SO4, the solvent was removed and the crude product was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (5:1 to 2:1) to yield the title compound (0.17 g, 29%). 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 2H, J=9.0 Hz), 7.38-7.22 (m, 7H), 5.52 (d, 1H, J=6.9 Hz), 3.69 (q, 2H, J=12.6 Hz), 3.20-3.18 (m, 3H), 3.07 (bs, 1H), 2.52 (t, 1H, J=10.1 Hz), 2.31-2.28 (m, 1H); LC-MS: [M+1]+ 393.0.
Reaction SMILES: [C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O-:15])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:20](#N)[CH3:21].C(N(CC)CC)C.C(OC(OCC)=O)(=O)OCC>C(OCC)(=O)C>[C:1]([C:6]1[C:18]([CH3:19])=[CH:17][C:9]2[N:10]([CH3:16])[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC#N
Reactant: CCCC(=O)c1cc2nc(C(=O)[O-])n(C)c2cc1C
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cc2nc(C(=O)OCC)n(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate acid are introduced, in the course of 15 minutes, into a mixture of 150 ml of acetonitrile, 15 ml of triethylamine and 18.5 g of diethyl pyrocarbonate, while stirring at room temperature. The mixture is left to stand overnight, the acetonitrile is stripped off under reduced pressure, the residue is taken up in ethyl acetate and the resulting solution is washed with water, dried over sodium sulphate and evaporated to dryness. Ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate, which is initially obtained as an oil but soon crystallises, is filtered off. When recrystallised from ethyl acetate/cyclohexane, it melts at 106°-108°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.CN(C)C=O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:5]2[C:6]([C:7]#[N:8])=[CH:9][C:2]([Br:1])=[CH:3][N:4]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2C#N)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a mixture of 5-bromo-2-chloronicotinonitrile (1.00 g), 1-Boc-piperazine (0.94 g) and potassium carbonate (1.27 g) were added toluene (4.5 mL) and N,N-dimethylformamide (10 mL), and the mixture was stirred at 100° C. for 4 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.52 g).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=[O:36]>C1COCC1>[F:44][C:43]([F:45])([F:46])[C:39]1[CH:38]=[C:37]([NH:34][C:35]([N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([O:11][C:12]4[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=4)=[CH:9][CH:8]=3)[CH:4]=[C:5]2[CH3:23])=[O:36])[CH:42]=[CH:41][CH:40]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(F)c(Oc3cc(CS(C)(=O)=O)ncn3)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(F)c(Oc3cc(CS(C)(=O)=O)ncn3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: -78 °C

Procedure:
4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-1H-indole (250 mg, 0.745 mmol) in THF (10 mL) is cooled to −78° C. and a 1 M solution of LiHMDS in THF (1.86 mL, 1.86 mmol) is added. After 12 min 1-isocyanato-3-(trifluoromethyl)-benzene (0.12 mL, 0.895 mmol) is added and the reaction is allowed to stir at −78° C. After 1 h the reaction is quenched with saturated aqueous NH4Cl and then extracted with (3×100 mL) EtOAc, The organic phases are combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified FCC (0-3% MeOH/DCM) to provide 4-fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 523.1 (M+1); 1H NMR (400 MHz, DMSO-d6) ppm 10.99 (s, 1 H), 8.77 (d, J=1.01 Hz, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.66 (s, 1 H), 7.53 (d, J=9.35 Hz, 2 H), 7.36 (d, J=1.01 Hz, 1 H), 7.20 (d, J=7.33 Hz, 1 H), 6.64 (s, 1 H), 4.73 (s, 2 H), 3.13 (s, 3 H), 2.59 (s, 3 H).
Reaction SMILES: [C:1]([O-])(=O)C.[NH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([C:13]#[N:14])=[CH:8][NH+:7]=1.C(O)=O.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[NH2:5][C:6]1[N:7]=[CH:8][C:9]2[CH:13]=[N:14][C:1]([NH:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][C:10]=2[CH:11]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1c[nH+]c(N)cc1N
Reactant: NCc1ccccc1
Solvent: O
Solvent: O=CO
Product: Nc1cc2nc(NCc3ccccc3)ncc2cn1
Temperature: 200 °C
Yield: 73.3 %

Procedure:
A mixture of 2,4-diamino,5-cyanopyridinium acetate (8.78 g, 45 mmol), formic acid (10.66 g, 0.204 mol) and benzylamine (45 mL, 0.41 mol) is heated at 200° C. under N2 for 2 h. Upon cooling, it solidifies. Water (500 mL) is added and the gummy solid/water mixture is stirred for -20 min. at 0° C. The liquid is decanted. The solid is washed with water and then recrystallized from isopropanol (25 mL). After drying in a vacuum oven overnight, 7-amino-2-benzylaminopyrido[4,3-d]pyrimidine (8.29 g, 73%) is obtained as a light yellow solid. 1H NMR (DMSO) δ 9.10 (1H, s), 8.85 (1H, t, J=5.8 Hz), 8.25 (1H, s), 7.21-7.36 (5H, m), 6.46 (2H, brs), 6.35 (1H, s), 4.74 (2H, d, J=6.0 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]2[N:23]3[N:24]=[C:25]([NH2:27])[N:26]=[C:22]3[C:21]3[CH:20]=[CH:19][C:18]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])=[CH:17][C:16]=3[N:15]=2)=[CH:11][C:10]=1[O:35][CH3:36])C1C=CC=CC=1.C(OC1C=CC(CC2N3N=C(N)N=C3C3C=CC(F)=CC=3N=2)=CC=1OC)C1C=CC=CC=1>>[NH2:27][C:25]1[N:26]=[C:22]2[N:23]([C:14]([CH2:13][C:12]3[CH:33]=[CH:34][C:9]([OH:8])=[C:10]([O:35][CH3:36])[CH:11]=3)=[N:15][C:16]3[CH:17]=[C:18]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:19]=[CH:20][C:21]=32)[N:24]=1
Reactant: COc1cc(Cc2nc3cc(NCCCO)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Agent: COc1cc(Cc2nc3cc(F)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Product: COc1cc(Cc2nc3cc(NCCCO)ccc3c3nc(N)nn23)ccc1O
Yield: 91 %

Procedure:
Operating as in Example 83, but employing 5-(4-benzyloxy-3-methoxy-benzyl)-8-(3-hydroxy-propylamino)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 66, instead of 5-(4-benzyloxy-3-methoxy-benzyl)-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, the title compound was obtained in 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=O)=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.Cl.[O:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.[Na]>ClCCl>[O:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:17][C:15]2[S:14][C:13]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=4)[C:9](=[O:22])[N:10]4[N:21]=[CH:20][N:19]=[C:11]4[C:12]=3[CH:16]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)sc32)cc1
Reactant: C1CNCCOC1
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCCOCC4)sc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
8-((1,4-oxazepan-4-yOmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (29). To a mixture of 6-(4-methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde (50 mg, 0.15 mmol) and 1,4-oxazepane hydrochloride (30 mg, 0.22 mmol) in dichloromethane (2 ml) was added triethylamine (25 μl, 0.18 mmol). After 5 minutes of stifling, sodium triacetoxyhydroborate (47 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature. After 4 hours, the mixture was concentrated under reduced pressure. The resulting residue was taken up in DMSO (2 mL), filtered and purified directly by reverse phase chromatography to yield the above product (33 mg, 41%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=O>>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[CH:23]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([O:1][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:3][CH:4]=2)\[C:7]#[N:8])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COCCOCCl
Reactant: N#CCc1ccc(O)cc1
Product: COCCOCOc1ccc(/C(C#N)=C/c2ccc(OC)c(OC)c2)cc1
Yield: 80.6 %

Procedure:
The hydroxyl group of 4-hydroxybenzyl cyanide (26.63 g) was protected by use of 2-methoxyethoxymethyl chloride (24.42 g) in accordance with (production process 1), to thereby produce an MEM form (24.39 g, yield: 55%). The resultant MEM form (22.13 g) and 3,4-dimethoxybenzaldehyde (16.62 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (29.79 g, yield: 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 80.3 %

Procedure:
Under an atmosphere of argon, 4-bromoiodobenzene (7.0 g, 25 mmole), 1-pyreneboronic acid (5.7 g, 23 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (50 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (6.6 g, 80%) were obtained.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3C=[CH:45][C:46](F)=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C[N:64](C=O)C>C1COCC1>[N:41]1[C:42]2[C:43](=[N:64][CH:45]=[CH:46][CH:47]=2)[N:39]([CH:36]2[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:38][CH2:37]2)[CH:40]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: Fc1ccc2c(c1)ncn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(n3cnc4cccnc43)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 60 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5), 60 mg 1-piperidin-4-yl-5-fluoro-1-H-benzoimidazole (from Step D ) and 75 mg of sodium triacetoxyborohydride in 4 mL of THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 48 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:17][C:18]([OH:20])=[O:19])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3]
Reactant: O=C(O)CC(=O)O
Reactant: C=CCOc1ccc(C=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=CCOc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 70.3 %

Procedure:
4-Allyloxy-3-nitrobenzaldehyde (5 g, 24.1 mM) was dissolved in pyridine (100 ml) and malonic acid (5.02 g, 48.3 mM) and piperidine (0.48 ml, 4.8 mM) added. The mixture was heated to reflux with stirring for 2 hours, cooled, and poured onto a mixture of concentrated hydrochloric acid and ice. Organics were extracted into ethyl acetate, the organic layer washed with 2M hydrochloric acid, and product back-extracted into aqueous NaHCO3. The aqueous solution was then re-acidified (concentrated hydrochloric acid), and organics extracted into ethyl acetate, washed with brine, and dried (MgSO4), to give title compound (4.23 g).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[CH2:19]([O:24][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][CH2:21][C:22]#[CH:23]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: C#CCCCO
Product: C#CCCCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 109° C. and MS: m/e=321.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and pent-4-yn-1-ol.