Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)c3cccs3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)c1cccs1
Yield: 61.1 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (495 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (166 mg) solution (12 ml) and tetrahydrofuran (12 ml) were added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 289 mg of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CN(C)C=O.ClCCl.O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C#N)cc2OC)cc1
Reaction time: 0.25 h

Procedure:
3.73 g 4-Hydroxy-3-methoxybenzonitrile was dissolved in dimethylformamide and 3.8 g potassium carbonate was added before the mixture was stirred for 15 min. 5 g para-Methoxybenzylbromide was added and stirring was continued for 1 h. The mixture was diluted with dichloromethane and water. The phases were separated and the water phase extracted again with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:11]2)=[CH:7][CH:6]=1>O.C1COCC1.CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Temperature: 60 °C
Yield: 96.5 %

Procedure:
According to Scheme 1 Step 2: A solution of LiOH (358 mmol, 15.3 g) in water (2 M) was added at room temperature to a solution of ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (143 mmol, 37.2 g) in THF/MeOH (1:1, 400 mL) and the reaction mixture was heated at 60° C. overnight. After evaporation of THF and MeOH, a solid was filtered, water (150 mL) was added and the aqueous phase was extracted with Et2O. The aqueous phase was then acidified with a solution of HCl 1 M until pH=1-2 and extracted with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (138 mmol, 32.1 g, 97%) as a pale yellow solid. The crude product was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14](=[O:20])/[CH:15]=[CH:16]/N(C)C)=[C:8]([N+:21]([O-])=O)[CH:7]=1>C(O)(=O)C.[Fe]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:9]([C:14](=[O:20])[CH:15]=[CH:16][NH:21]2)=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)/C=C/N(C)C)c([N+](=O)[O-])cc1OCCCCl
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc2c(=O)cc[nH]c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Intermediate IV (150 g, 0.44 mol) was added to glacial acetic acid (8v/w, 1200 mL). The mixture was warmed up to 40° C. After Intermediate IV was dissolved completely, iron powder (123.1 g, 2.20 mol) was slowly added in batch. The mixture was warmed up to 80° C. and reacted under mechanical stirring for 2 h. After completion of the reaction, the reaction solution was filtered by suction when it is still hot. The filtrate was collected. After cooling the filtrate, a great deal of solid separated out and was filtered by suction to produce a lutescens solid. The filtered cake was dissolved in glacial acetic acid. The mixture was stirred at 80° C. for about 30 min, and was filtered by suction again when it is still hot. The filtrate was collected. After cooling the filtrate, a solid separated out and was filtered by suction to produce a lutescens solid. The solids were combined, and washed with water several times until the filtrate became neutral. The filtered cake was dried to produce a pale yellow solid (79 g) in a yield of 65%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:36]([C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)=[N+:37]=[N-:38].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CCN(C(C)C)C(C)C>CC(O)(C)C.O>[C:11]([O:10][C:9]([N:8]([C:16]1[C:21]([C:22]2[N:38]=[N:37][N:36]([C:39]3[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=3)[CH:23]=2)=[N:20][C:19]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])[CH2:26][CH2:25]2)=[CH:18][N:17]=1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: C#Cc1nc(N2CCN(S(=O)(=O)CC)CC2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Solvent: O
Product: CCS(=O)(=O)N1CCN(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cn(-c4ccc(N)cc4)nn3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-ethylsulfonylpiperazin-1-yl)-3-ethynyl-pyrazin-2-yl]carbamate (50 mg, 0.1009 mmol) and 4-Azidoaniline hydrochloride (17.32 mg, 0.1009 mmol) were suspended in t-BuOH (1 mL)/Water (1.000 mL). The reaction was treated with (+)-Sodium L-ascorbate (1.999 mg, 0.01009 mmol) followed by CuSO4.5H2O (0.2519 mg, 0.1103 μL, 0.001009 mmol) and the mixture allowed to stir at ambient temperature for 16 hours. The reaction was treated with DIPEA (13.04 mg, 17.57 μL, 0.1009 mmol) and allowed to heat to 40° C. for 5 hours and then cooled to ambient temperature. The mixture was partitioned between EtOAc/NaHCO3 and the aqueous layer extracted with EtOAc (2×), dried (MgSO4), filtered and concentrated. The material was used crude in the next step (quantitative yield assumed). MS (ES+) 630.00
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(O[C:17](=[O:19])[CH3:18])(=O)C.C([O:23][CH2:24][CH3:25])(=O)C>N1C=CC=CC=1>[C:2]([O:1][CH:2]1[O:10][C@@H:9]([CH2:11][O:12][C:17](=[O:19])[CH3:18])[C@H:7]([O:8][C:24](=[O:23])[CH3:25])[C@@H:5]([O:6][C:9](=[O:10])[CH3:11])[C@H:3]1[O:4][C:5](=[O:6])[CH3:7])(=[O:1])[CH3:3]
Reactant: O=C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 0.25 h

Procedure:
L-(−)-mannose (9.0 g, 49.96 mmol) was dissolved in pyridine (120 ml), and the resulting solution was cooled in ice. Acetic anhydride (60 ml) was added dropwise thereto over about 15 minutes. The resulting solution was stirred overnight while gradually returning to room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure. Toluene was added to the resulting residue, and an azeotropic distillation procedure was performed twice. Ethyl acetate was added to the residue to dissolve the residue, and the resulting solution was washed sequentially with saturated NaHCO3 solution, water, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dried well under reduced pressure, whereby a target product was obtained (crude yield: 21.04 g (which exceeded the theoretical yield because ethyl acetate and the like were contained, and therefore, the molar amount thereof was taken as 49.96 mmol, and the subsequent reaction was performed)).
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])(=O)C.[Na+].[I:16]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O.O1CCCC1>[I:16][CH2:10][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=C(C)CCC(=O)OCC
Reactant: ClI
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC(C)CI
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 1.0 M tetrahydrofuran solution of borane tetrahydrofuran complex (15.0 mL, 15.0 mmol) was slowly added to a tetrahydrofuran solution (7 mL) of ethyl 4-methyl-4-pentenoate (6.07 g, 42.7 mmol) at 0° C. The solution was heated to 50° C. for one hour then cooled to ambient temperature. Anhydrous methanol (1 mL) was added to quench the excess hydride, followed by sodium acetate (43 mL, 43.0 mmol) in methanol. To this reaction mixture at ambient temperature was added slowly iodine monochloride (1.5 mL, 30 mmol). The reaction mixture was stirred for two hours and poured into water (50 mL). Saturated aqueous sodium thiosulfate was added, and the mixture was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-30% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.00 (d, J=5.5 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H), 1.45-1.60 (m, 2H), 1.70-1.78 (m, 1H), 2.30 (t, J=7.1 Hz, 2H), 3.15 (dd, J=4.7, 9.4 Hz, 1H), 3.21 (dd, J=6.3, 9.4 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H).
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.Cl.[CH3:52][N:53]([CH2:55][C:56](Cl)=[O:57])[CH3:54]>ClCCl.C(N(CC)CC)C>[CH3:52][N:53]([CH3:54])[CH2:55][C:56]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1)=[O:57]
Reactant: CN(C)CC(=O)Cl
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (64 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with dimethylaminoacetyl chloride hydrochloride (100 mg). The mixture was heated with a heat gun, then concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 573.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C2CCOCC2)c1C
Temperature: 80 °C
Yield: 76.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1.0 g, 3.15 mmol) in acetonitrile (15 mL), cesium carbonate (1.97 g, 6.10 mmol) and methyl iodide (2.15 g, 15.27 mmol) were added; resulting solution was heated at 80° C. for 20 h. The solution was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated and the product purified by column chromatography to afford methyl 5-bromo-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzoate (0.82 g, 80%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester.
Reaction SMILES: [C-]#N.[K+].CN([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)C.[CH3:18][N:19](C=O)C>O.C1(C)C=CC=CC=1>[F:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH2:7][C:18]#[N:19])=[CH:9][NH:10]2)=[CH:15][CH:14]=1
Reactant: CN(C)Cc1c[nH]c2cc(F)ccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCc1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine KCN (50.8 g, 0.78 mol), 3-(N,N-dimethylaminomethyl)-6-fluoroindole (100 g, 0.52 mol), DMF (400 mL) and water (200 mL). Heat to reflux. Evolution of gas begins at about 70° C. Maintain the reflux for 4 hours. Cool the reaction mixture to room temperature, dilute with water and toluene and stir for 10 minutes. Decant the organic layer and wash successively with of saturated aqueous sodium bicarbonate and of 2M aqueous hydrochloric acid. Concentrate to dryness the organic layer to give 2-(6-fluoro-1H-indol-3-yl)acetonitrile.
Reaction SMILES: [Br:1]Br.[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=1[C:13]#[N:14].C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:7]1[O:3][C:4]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccco1
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Br)o1
Reaction time: 0.25 h

Procedure:
Bromine (0.71 g, 4.42 mmol) is added to a solution of 2-(2-furyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.00 g, 4.42 mmol) and sodium acetate (0.36 g, 4.42 mmol) in acetic acid. The reation mixture is stirred for 15 minutes and poured into a 1% sodium bisulfite solution. The solids are filtered from the aqueous mixture, dried overnight under high vacuum and recrystallized from ethyl acetate and hexane to obtain the title product as red crystals (1.21 g, 90% mp 224°-226° C.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]1.CCN(CC)CC.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C(Cl)Cl>[C:24]([N:7]1[CH2:6][C:5]2([CH2:1][CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]2)[CH2:9][CH2:8]1)(=[O:27])[CH2:25][CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl 3,7-diazaspiro[4.4]nonane-3-carboxylate (127 mg, 0.56 mmol) in anhydrous DCM (1 mL), cooled in an ice water bath was added Et3N (57 mg, 78 μL, 0.56 mmol), followed by the addition of propanoyl chloride (57 mg, 54 μL, 0.62 mmol) as a solution in DCM (0.2 mL). The reaction mixture was stirred for 20 minutes, diluted with DCM and was washed with 1M HCl (×2) and brine (×1). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl 3-propanoyl-3,7-diazaspiro[4.4]nonane-7-carboxylate (154 mg, 97%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 3.73-3.11 (m, 8H), 2.34-2.17 (m, 2H), 1.97-1.70 (m, 4H), 1.46 (s, 9H), 1.16 (t, J=7.4 Hz, 3H). LC/MS m/z 283.5 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[C:27]([O:33]CC3C=CC=CC=3)=[CH:26][C:25]=2[O:41]CC2C=CC=CC=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[C:27]([OH:33])=[CH:26][C:25]=2[OH:41])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Yield: 68 %

Procedure:
Pd(OH)2/C (0.01 mmol) was added to the intermediate obtained in Step F (0.1 mmol) dissolved in EtOH (5 ml) and the resulting mixture was subjected to hydrogenation under one atmosphere of hydrogen for 1 hour. The catalyst was filtered off through a Celite® pad and the ethanol was removed under reduced pressure. The reaction mixture was purified by column chromatography (DCM/MeOH:90/10) to obtain the title compound as an oil.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:32][CH:31]([CH2:33][CH2:34]O)[CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:34][CH2:33][CH:31]3[CH2:32][O:29][CH2:30]3)=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Reactant: OCCC1COC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3COC3)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Reaction time: 2.5 h
Yield: 53.8 %

Procedure:
To a stirred suspension of Compound 1 (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. Analysis of the reaction mixture after 2.5 h by LCMS showed the presence of starting material and so further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (4) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2; found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10](I)[C:3]=12.[CH3:32][C@@H:33]([OH:36])[C:34]#[CH:35].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:9]=[C:10]([C:35]#[C:34][C@H:33]([OH:36])[CH3:32])[C:3]=12
Reactant: Cc1ccccc1-n1c(Cn2nc(I)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Reactant: C#C[C@@H](C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccccc1-n1c(Cn2nc(C#C[C@@H](C)O)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Yield: 69.7 %

Procedure:
3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1611) (522 mg, 1 mmol) and (R)-but-3-yn-2-ol (84 mg, 1.2 mmol) were dissolved in anhydrous THF (40 mL). The mixture was degassed and back-filled with nitrogen three times. Pd(PPh3)2Cl2 (12 mg, 0.1 mmol), CuI (47 mg 0.25 mmol) and (i-Pr)2NH (505 mg, 5 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon three times and then stirred at reflux for 4 h. The mixture was allowed to cool to RT, filtered through silica gel (10 g) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the product, 3 (R)-3-((4-amino-3-(3-hydroxybut-1-ynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1802) (324 mg, 70% yield) as a slightly yellow solid.