Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:26][C:27]([O:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)=[O:28].O>CN(C)C=O.C(OCC)(=O)C>[NH:26]([C:27]([O:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:11][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[O:12])=[CH:36][CH:37]=1)=[O:28])[NH:25][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]
Reactant: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc(O)cc1
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C(=O)Oc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
To a suspension of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (466.2 mg, 2.504 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added 1,1′-carbonyldiimidazole (405.7 mg, 2.502 mmol), and the mixture was stirred at 50° C. for 2.5 hr. tert-Butyl 2-(4-hydroxyphenyl)ethyl hydrazine-1,2-dicarboxylate (594.8 mg, 2.001 mmol) was added, and the mixture was stirred at 50° C. for 18 hr. Water (40 ml) and ethyl acetate (40 ml) were added to the reaction mixture and the mixture was stirred, stood still and then partitioned. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 40 g, hexane:ethyl acetate=6:4→5:5). The fractions containing the object product were concentrated under reduced pressure and the obtained solid was suspended in a mixture of hexane (40 ml) and tert-butyl methyl ether (20 ml). The suspension was filtered and dried under reduced pressure to give 2-[4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}oxy)phenyl]ethyl tert-butyl hydrazine-1,2-dicarboxylate (539.2 mg, 1.161 mmol, yield 58.0%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(SCCCCl)cc1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
To a stirred suspension of 5.62 g (0.025 mole) of 3-(4'-acetamidophenylthio)propanol in 25 ml of methylene chloride and 2.03 ml of pyridine (0.025 mole) is added 3.7 g of thionyl chloride (0.031 mole) in 10 ml of methylene chloride. After the exothermic reaction subsides, the mixture is heated at reflux for 0.5 hr. The reaction mixture is poured into 100 ml of ice-water with stirring. The organic layer is separated, dried and concentrated to a dark red solid. Extraction of the latter with ether in a Soxlet apparatus yields 3.5 g of 3-(p-acetamidophenylthio)propyl chloride having the correct IR and NMR spectra.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:15]2[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[CH:30]1([N:14]([C:15]2[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)[C:12](=[O:13])[NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:36])=[O:3])=[CH:10][CH:9]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-benzoic acid ethyl ester (10 mg, 21 μmol in THF/MeOH 2/1 (150 μl) was a added a 1 N aqueous lithium hydroxide solution (120 μl, 120 μmmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred for 12 h at ambient temperature, poured onto ice water/1 N aqueous HCl solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (10 mg, 22 umol; quant.) as yellow solid. MS: m/e=455.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([OH:15])=O)[N:7]2[CH3:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([CH:47]=1)[NH2:46]>ClCCl.N1C=CC=CC=1>[F:40][C:41]1[C:42]([B:50]2[O:54][C:53]([CH3:56])([CH3:55])[C:52]([CH3:58])([CH3:57])[O:51]2)=[CH:43][C:44]([O:48][CH3:49])=[C:45]([NH:46][C:13]([C:6]2[N:7]([CH3:12])[C:8]3[C:4]([CH:5]=2)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)=[O:15])[CH:47]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1N
Reactant: COc1cccc2c1cc(C(=O)O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
4-Methoxy-1-methyl-1H-indole-2-carboxylic acid (0.225 mmol, 46.1 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.247 mmol, 94 mg) were added to a solution of 5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.225 mmol, 60 mg) in dichloromethane (2.5 mL) and pyridine (0.5 mL) at 0° C. After stirring the reaction mixture overnight at room temperature it was concentrated in vacuo. Water was added to the residue and extracted with dichloromethane. The organic extracts were washed with water. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptanes/ethyl acetate) to give impure N-(5-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (45 mg). The latter compound and 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (35 mg) were reacted using the procedures described in example 4 step 4c and purification using column chromatography (silica gel, heptanes/ethyl acetate) gave N-(5-fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (9.7 mg)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:18]([N:20]([CH:34]([CH3:36])[CH3:35])[C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[O:19])[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[O:7][C:6]([CH3:38])([CH3:37])[C:5]1=[O:39].[F:40][C:41]([F:47])([F:46])[C:42](=O)[CH2:43][CH3:44].C(N(C(C)C)CC)(C)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.CO>[CH3:38][C:6]1([CH3:37])[C:5](=[O:39])[N:4]([CH2:3][CH2:2][NH:1][CH:42]([C:41]([F:47])([F:46])[F:40])[CH2:43][CH3:44])[C:9]2[CH:10]=[C:11]([C:18]([N:20]([CH:34]([CH3:35])[CH3:36])[C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]3)=[O:19])[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]=2[O:7]1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCC(=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (278 mg) in methylene chloride (2 ml) were added 1,1,1-trifluoro-2-butanone (0.1 ml), diisopropylethylamine (0.34 ml), and titanium tetrachloride (0.05 ml), and the mixture was stirred at room temperature for 3 hours. Then, to the reaction solution were added sodium cyanoborohydride (110 mg) and methanol (10 ml), and the mixture was stirred at room temperature for one hour. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (100 mg) as amorphous.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH2:25])[C:22]([Cl:26])=[CH:21][C:17]=1[C:18]([OH:20])=O.[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[C:23]([NH2:25])=[CH:24][C:16]=3[O:15][CH3:14])[CH2:36][CH2:35]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NC1CCN(CC2CCCCC2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml; 0.04 moles) were added successively to a stirred suspension of 2-methoxy-4-amino-5-chlorobenzoic acid (8 g; 0.04 moles) in anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature beween -5° and -10° C. After stirring at this temperature for 0.5 hours, a solution of 1-cyclohexylmethyl-4-aminopiperidine (7.85 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at -5° to -10° C. for 1 hour and then allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layer washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether. N-(1-Cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (8 g) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:26]1([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2F)[CH:32]=[O:33])[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:36]3[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][C:29]=3[CH:26]3[CH2:27][CH2:28]3)=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)c(C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
N-(4-Chlorophenethyl)-4-hydroxybenzamide (504 mg, 1.83 mmol) was diluted with DMSO (8 mL) and K2CO3 (379 mg, 2.74 mmol) and 3-cyclopropyl-4-fluorobenzaldehyde (300 mg, 1.83 mmol) were added. The reaction was stirred 85° C. overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (3:1) to provide N-(4-chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 20.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[N:24]([CH3:30])[C:23]=2[CH:31]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:19]4[CH:20]=[CH:21][C:22]5[N:26]=[C:25]([CH:27]6[CH2:28][CH2:29]6)[N:24]([CH3:30])[C:23]=5[CH:31]=4)[C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ccc2oc(-c3ccc(Cl)cc3)cc12
Reactant: Cn1c(C2CC2)nc2ccc(Br)cc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)cc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A mixture of 2-(4-chlorophenyl)furo[3,2-c]pyridin-4(5H)-one (100 mg), 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (123 mg), N,N′-dimethylethylenediamine (0.043 mL), copper(I) iodide (78.0 mg), potassium carbonate (169 mg) and DMSO (3.0 mL) was stirred at 190° C. for 1 hr under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate to give the title compound (37.3 mg) as a pale red solid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16].[I:42]I.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C.O>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([I:42])=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)=[O:24])=[O:16]
Reactant: II
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Reaction time: 0.5 h

Procedure:
n-BuLi (2 eq.) is added dropwise for 10 min to a cold (−40° C.) solution of diisopropylamine (1 eq.) in dry THF. The reaction mixture is stirred at the same temperature for 30 min. Then a solution of 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1 eq.) in THF is added dropwise (35 min) keeping the internal temperature around −40° C. The reaction mixture is stirred for 30 min and a solution of iodine (2 eq.) in THF is added dropwise, stirred for 30 min at the same temperature before being added a sat. solution of NH4Cl. The reaction mixture is diluted with ethyl acetate and water. The organic layer is separated and washed with 5% sodium thiosulfate solution. The organic layer is separated, dried (Na2SO4) and evaporated to a suspension and then added heptane. The suspension is stirred at 0° C. for 30 min, filtered and washed with heptane to obtain 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclo-hexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][NH:27][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
1H-NMR (300 MHz, CDCl3): δ 7.27 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=9 Hz), 6.01 (s, 2H), 3.81 (s, 3H), 3.78 (d, 1H, J=14 Hz), 3.62 (d, 1H, J=14 Hz), 3.46 (m, 1H), 3.12-2.70 (m, 5H), 2.60 (m, 1H), 1.55 (s, 9H). 2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (70% pure, 0.2 g, 0.347 mmol) was dissolved in a mixture of anhydrous dichloromethane (5 ml) and triethylamine (72 μl) and cooled in an ice-bath and stirred under nitrogen. Benzoyl chloride (40 μl, 1.0 eq) was added dropwise and the reaction was stirred for 5 minutes, then warmed to ambient temperature and stirred for an additional 16 hours. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 ml) and washed with 0.5 N hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo, which afforded 0.15 g of crude 7-(benzoylamino-methyl)-2-amino-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.BrC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C3CC3)C=NC=2C=1.[O:45]1[CH2:48][CH:47]([N:49]2[CH2:54][CH2:53][CH:52]([C:55]3[CH:60]=[CH:59][C:58](B4OC(C)(C)C(C)(C)O4)=[CH:57][CH:56]=3)[CH2:51][CH2:50]2)[CH2:46]1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:58]4[CH:57]=[CH:56][C:55]([CH:52]5[CH2:53][CH2:54][N:49]([CH:47]6[CH2:46][O:45][CH2:48]6)[CH2:50][CH2:51]5)=[CH:60][CH:59]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc(C3CCN(C4COC4)CC3)cc2)OC1(C)C
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: C[C@@H](Oc1nc(-c2ccc(C3CCN(C4COC4)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 48 %

Procedure:
In a round-bottomed, 100-mL, single-necked flask equipped with a reflux condenser were placed a mixture of (R)-4-((R)-1-((6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: and (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (85.0 mg, 0.23 mmol), 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (103.9 mg, 0.30 mmol), and tetrakis(triphenylphosphine)palladium (10.3 mg, 0.010 mmol) in DME (3 mL) and 2N Na2CO3 (2 mL). The reaction mixture was sonicated for 30 sec, degassed with nitrogen gas for 30 sec, and heated at 100° C. for 3 h. Then, it was cooled to room temperature, quenched with water, and the organic layers extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane) to afford 55.9 mg (48%) of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.28 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.74 (s, 1H), 7.57 (s, 1H), 7.34 (s, 1H), 5.57 (m, 1H), 4.50 (m, 4H), 3.71 (m, 1H), 3.42 (m, 2H), 3.21 (m, 1H), 2.82 (m, 3H), 2.51 (m, 1H), 2.32 (m, 2H), 1.79 (m, 6H), 1.41 (d, J=6.3 Hz, 3H), 1.18 (m, 4H). MS (ESI+) m/z 502.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]2[C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)C(C)C)(C)C>C(O)C.C(Cl)(Cl)Cl.[Pd]>[C:15]1([N:13]2[C:12](=[O:21])[N:11]3[CH2:2][NH:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]3=[N:14]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=c1n(-c2ccccc2)nc2n1CNc1ccccc1-2
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-phenyl-1,2,4triazolo[4,3-c]-quinazolin-3-one (1g, 3.4 mmol), N,N-diisopropylethylamine (1 ml, 6.7 mmol) and 10% Pd-C (200 mg) in ethanol was shaken under hydrogen at 50 psi overnight. The reaction was diluted with CHCl3 and filtered through Celite. The filtrate was evaporated under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with water, dried over Na2SO4 and evaporated under reduced pressure to yield 2-phenyl-5,6-dihydro-1,2,4-triazolo[4,3-c]quinazolin-3-one (Compound 2) as a white solid. m.p. 202-204° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C[Mg+].[Br-].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)CBr
Reactant: Cc1cc2ccccc2[nH]1
Agent: C[Mg+]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To 2-methyl indole (1.69 g; 12.9 mmol) in 10 mL of THF at 0° C. was added MeMgBr 1.4M (12.9 mmol). After 30 min at 0° C. ZnCl2 1M (12.9 mL; 12.9 mmol) in THF was added and the reaction stirred for an other 30 min at r.t. Methyl bromoacetate (1.4 mL; 14.7 mmol) was added dropwise and left stirring for 48 h. The mixture was poured into aqueous NaHCO3, extracted with EtOAc (3×25 mL) and the combined organic extracts were washed with brine. The solution was dried over Na2SO4 and the solvent removed. Chromatography on silica gel (eluted with 5% EtOAc in hexane) yielded 1.13g (43%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:35]1[C:36]2[C@H:43]([CH3:44])[CH2:42][CH2:41][C:37]=2[N:38]=[CH:39][N:40]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:15]([C:35]3[C:36]4[C@H:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Temperature: 90 °C
Yield: 23.5 %

Procedure:
A mixture of (R)-tert-butyl 2-(1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (50 mg, 0.11 mmol), (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (19 mg, 0.11 mmol), Cs2CO3 (40 mg, 0.12 mmol), Pd(OAc)2 (3.0 mg, 0.01 mmol), Xantphos (7.0 mg, 0.01 mmol) in toluene (5 mL) was degassed by a nitrogen balloon, and the mixture was heated to 90° C. for 12 hours. The reaction mixture was filtered by a pad of celite and eluted with EtOAc. The filtrate was concentrated, and the residue was purified by flash chromatography to afford the product (R)-tert-butyl 2-(1′-benzyl-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (15 mg, 23%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 7.20-7.40 (m, 5H), 7.09-7.12 (m, 1H), 6.84-6.90 (m, 1H), 6.70-6.74 (m, 1H), 5.25-5.32 (m, 1H), 4.10-4.20 (m, 1H), 3.80-3.90 (m, 1H), 3.70-3.80 (m, 1H), 3.50-3.60 (m, 2H), 3.30-3.40 (m, 1H), 2.95-3.00 (m, 2H), 2.85-2.95 (m, 2H), 2.20-2.60 (m, 4H), 1.95-2.05 (m, 2H), 1.80-1.95 (m, 2H), 1.60-1.80 (m, 4H), 1.30 (s, 4H), 1.20 (s, 5H), 0.80-0.90 (m, 3H). MS (APCI+) [M+H]+ 580.