Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][N:19]1[C:23]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=2)=[O:27])=[CH:22][CH:21]=[N:20]1.O>CN(C)C=O>[CH3:18][N:19]1[C:23]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][N:36]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:34])=[CH:31][CH:32]=2)=[O:27])=[CH:22][CH:21]=[N:20]1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: Cn1nccc1CNC(=O)c1ccc(C(=O)NN)s1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccnn2C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 70 °C
Yield: 76 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic Acid (1-methyl-1H-pyrazol-5-ylmethyl)amide (49 mg, 0.17 mmol) prepared in Reference Synthetic Example 18 were dissolved in N,N-dimethylformamide (0.50 mL) and heated at 70° C. for 24 hours and cooled to room temperature. After addition of water, the precipitated crystals were recovered by filtration, washed with water and chloroform and dried to give the desired product (yield 76%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[N:13][C:12]=1[CH2:24][Br:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)NCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1nc(CBr)c(C(=O)NCc2ccccc2)s1
Yield: 58.3 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid benzylamide (0.108 g, 0.31 mmol) in acetonitrile (10 mL) was added N-bromosuccinimide (0.071 g, 0.40 mmol). The resultant mixture was stirred at ambient temperature until the reaction was completed. The reaction mixture was concentrated in vacuo and the crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford 2-(tert-butoxycarbonylamino)-4-bromomethylthiazole-5-carboxylic acid benzylamide (0.077 g, 58% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)(=O)C.C(=O)(O)[O-].[Na+].O.[Cl-].[Na+]>CO>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:11](=[O:20])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])=[CH:18][CH:17]=1
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-aminophenylcarbamoyl)phenyl acetate (580 mg) in methanol (10 mL) is added saturated sodium bicarbonate (2 mL) and water (3 mL). The mixture is heated at 80° C. for 30 minutes, then poured into half-saturated aqueous sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which is then triturated with diethyl ether to provide the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:25]#[N:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:25]#[N:26])([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=2[Br:35])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(C#N)c2ccc(C(F)(F)F)cc2)CC1
Reactant: BrCc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C#N)(Cc2ccccc2Br)c2ccc(C(F)(F)F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of the above nitrile (280 mg, 0.76 mmol) in THF at −78° C. was added freshly prepared LDA (0.32M, 2.6 mL, 0.83 mmol). The resulting mixture was stirred for 30 min. at −78° C. and 2-bromobenzyl bromide (570 mg, 2.28 mmol) in THF (1 mL) was added. The reaction was stirred for 3 hours at 0° C. and quenched with saturated aqueous NH4Cl (20 mL) to give 4-[2-(2-bromo-phenyl)-1-cyano-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (264 mg, 65%) as a white foam after work-up and purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dibromopyridine (1.0 g) and tert-butyl piperazine-1-carboxylate (870 mg) are dissolved in N,N-dimethylformamide (10 ml) and stirred at 80° C. in the presence of potassium carbonate (1.17 g) for 5 hours. To the reaction mixture is added tert-butyl piperazine-1-carboxylate (200 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1-carboxylate (900 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:16][CH2:15][CH2:14][C@@H:13]3[N:9]2[C:10](=[O:17])[CH:11]=[CH:12]3)=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:16][CH2:15][CH2:14][C@@H:13]3[N:9]2[C:10](=[O:17])[CH2:11][CH2:12]3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1C=C[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Yield: 82.1 %

Procedure:
Platinum oxide (10 mg) was added to a solution of (5R*,8aS*)-5-(4-fluorophenyl)-6,7,8,8a-tetrahydro-5H-indolizin-3-one (105 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 87 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[NH:18][CH2:17][CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:31]CCl.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH3:31])[CH2:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCNc1ccccc1-3
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCN(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 14-cyclohexyl-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate in DCE (0.05 M) 1 eq of formaldehyde (37 wt. % sol. in H2O) and 2 eq of NaBH(OAc)3 were added and the solution stirred at RT for 1 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with NaHCO3 (s.s.) and brine. The organic phase was dried over Na2SO4 filtered and concentrated in vacuo. The title compound was used directly in the next step; MS (ES+) m/z 403 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:28][CH3:29])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([CH3:27])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:30].[OH-].[Li+]>O1CCOCC1.O>[CH2:11]([C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([CH3:30])[CH:6]=1)([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH3:27])[CH:14]=1)[CH2:28][CH3:29])[CH3:12]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)O)c(C)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
To an ambient temperature solution of 4-{1-Ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid methyl ester (2.40 g, 5.73 mmol) in dioxane/water (30/30 ml) is added lithium hydroxide (412 mg, 17.20 mmol) and heated to 60° C. for 1 h. The reaction is concentrated and partitioned between Et2O/EtOAc (150/150 ml) and 1N HCl (50 ml). The aqueous phase is extracted with a second portion of EtOAc (100 ml) and the combined organic phases are washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated to yield the title compound (1.57 g, 68%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][NH:28][C:29](=[O:33])[CH:30](Cl)[CH3:31])[CH2:10]1)(C(C)(C)C)(C)C.[O-:34][C:35]#[N:36].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([CH2:27][N:28]2[C:29](=[O:33])[CH:30]([CH3:31])[NH:36][C:35]2=[O:34])[CH2:10]1
Reactant: CC(Cl)C(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: N#C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(=O)N(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A solution of (2S,4R)-4-(t-butyldimethylsilyloxy)-2-(2-chloropropionyl)aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (18.4 g), potassium cyanate (14.9 g) and tetrabutylammonium iodide (13.6 g) in N,N-dimethylformamide (180 ml) was stirred at 100°-110° C. for 3 hours. The reaction mixture was poured into water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (150 ml) and conc. hydrochloric acid (6.1 ml). The solution was stirred at ambient temperature for 2 hours and evaporated in vacuo. The resulting residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(4-methyl-2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.16 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: NC1CCCC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(NC2CCCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of (±)-cis-4-(-2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.53 g, 2 mmol) from Example 4, triethylamine (2.00 g, 20 mmol), cyclopentylamine (267 mg, 3.1 mmol) and ethanol (10 mL) was stirred at reflux for 9 hours. The solution was allowed to cool to room temperature before the addition of 2 mL of 1.0N NaOH. Concentration of the solution afforded the crude product which was purified by elution from a silica gel column using 5% methanol in chloroform (0.430 g, 68.4%). Crystallization of such a sample from ethanol-acetonitrile gave an off-white powder, m.p. 143°-146° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[C:2]#[C:1][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccccc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: COC(=O)c1ccccc1C#Cc1c(-c2ccccc2)noc1C
Yield: 82 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using methyl 2-iodobenzoate instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=100:0 to 80:20, 166 mg, 82%) which was obtained as an off-white solid. MS: m/e=318.1 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C1COCC1>[C:19]([O:18][C:8]1([CH3:7])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Yield: 39 %

Procedure:
The procedure of Comparative Example 1 was repeated with the proviso that under the cooling conditions, 24 ml of pyridine was slowly dropwise added to a mixture of 22.6 g (0.136 mole) of 2-methyl-2-adamantanol, 130 ml of THF and 26.6 g of methacrylic chloride. The raw product was purified on a column of silica gel to obtain 12.1 g of the target product, i.e., 2-methyl-2-adamantyl methacrylate, (yield: 39.0%). It was confirmed that the product contained a remarkable amount of impurities.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]1([CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: OCCCCCCCCCCCCBr
Product: O=C(CCCc1ccccc1)OCCCCCCCCCCCCBr
Yield: 85 %

Procedure:
From 12-bromo-1-dodecanol and 4-phenylbutyric acid. Yield: 85% (oil).
Reaction SMILES: [C:1](Cl)(=O)C.[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:9]=[C:10]([F:12])[CH:11]=1>CO>[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]([O:16][CH3:1])=[O:15])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Solvent: CO
Product: COC(=O)Cc1cc(F)cc(F)c1

Procedure:
A solution comprising 25 ml of acetyl chloride in 250 ml of methanol is prepared at 0° C., then, at ambient temperature, 25.5 g of 3,5-difluorophenylacetic acid are dissolved in this solution and the solution is left stirring at AT. The reaction is monitored by thin layer chromatography. After the starting material has disappeared, the medium is evaporated under reduced pressure and then the residue is dissolved in 250 ml of MTBE. The organic phase is washed three times with 100 ml of water, dried over MgSO4 and then evaporated to dryness under reduced pressure. 26.9 g of the expected compound are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]4[N:27](C5CCCCO5)[N:28]=[CH:29][C:24]4=[C:23]([C:36]4[CH:37]=[C:38]([NH:42][C:43](=[O:46])[CH:44]=[CH2:45])[CH:39]=[CH:40][CH:41]=4)[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>C(Cl)Cl>[O:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:26]=[C:25]4[NH:27][N:28]=[CH:29][C:24]4=[C:23]([C:36]4[CH:37]=[C:38]([NH:42][C:43](=[O:46])[CH:44]=[CH2:45])[CH:39]=[CH:40][CH:41]=4)[N:22]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)nc3c2cnn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoroacetic acid (0.220 mL, 2.85 mmol) was added to a solution of N-(3-(6-((4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (15 mg, 0.029 mmol) in CH2Cl2 (5 mL) and the reaction mixture was stirred overnight at room temperature, after which the solvent was removed in vacuo. The residue was purified by flash column chromatography (5% CH3OH/CH2Cl2) to yield the title compound as a solid. 1H NMR (400 MHz, CD3OD): δ 8.71 (s, 1H), 7.32 (s, 1H), 7.99 (m, 1H), 7.74 (m, 3H), 7.54 (m, 1H), 7.00 (m, 2H), 6.48-6.43 (m, 2H), 5.82 (dd, 1H, J=2.4 and 9.6 Hz), 3.85 (m, 4H), 3.12 (m, 4H): ESI-MS: 442.27 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4.53 g, 19.8 mmol) and K2CO3 (4.146 g, 30 mmol) in THF (30 mL) was added phenyl chloroformate (4.071 g, 26 mmol). It was stirred at room temperature overnight. The reaction was quenched by adding water and extracted with DCM. Extracts were dried over MgSO4 and concentrated. The crude product was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate as solid (5.12 g, 74%). 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 2.43 (s, 3H), 6.5 (s, 1H), 7.0 (s, 1H), 7.15 (d, 2H), 7.36 (m, 7H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[C@@H:26]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[N:38][N:39]2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:35][CH:34]=1)[CH2:27]OS(C)(=O)=O)(=O)=O>C1COCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C@:12]2([CH2:27][C@H:26]2[C:33]2[CH:41]=[C:40]3[C:36]([CH:37]=[N:38][N:39]3[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:35][CH:34]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cnn(Cc4ccccc4)c3c1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
To a 250 mL round bottom flask charged with 60% NaH (1.20 g, 30 mmol) was added anhydr. THF (20 mL) and the resulting mixture was cooled to 0° C. A solution of 1-benzyl-5-methylindolin-2-one (2.37 g, 10 mmol) in dry THF (25 mL) was added over 2 min, followed by rinsing with THF (5 mL). After stirring for 20 min at 0° C., a solution of (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (4.24 g, 10 mmol) in dry THF (45 mL) was added dropwise through dropping funnel over 40 min, followed by rinsing with THF (5 mL). After addition, the resulting mixture was stirred for 30 min at 0° C. (TLC showed completion) then left O/N at rt. After cooling to 0° C., the reaction mixture was poured into an Erlenmeyer flask containing ice (100 mL) and sat. NH4Cl (30 mL) and extracted with EtOAc (150 mL×2), dried (Na2SO4). After removal of solvents, the residue was transferred to a 100 mL RBF using 30 mL of EtOAc and crystals formed. Suction filtration gave the title compound as a beige solid (1.537 g). The filtrate was concentrated and purified by Biotage Isolera (20-30% EtOAc in hexane) and triturated with EtOAc/hexane to give 2nd crop as off white solid (1.560 g). The filtrate was purified using the above procedure to give 3rd crop as a beige solid (115 mg). Total 3.212 g (68%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.36-7.20 (m, 9H), 7.14 (d, J=6.0 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.64 (d, J=7.2 Hz, 1H), 5.62 (d, J=16.8 Hz, 1H, partially overlapping with s at 5.59), 5.59 (s, 1H, partially overlapping with d at 5.62), 5.55 (d, J=16.8 Hz, 1H), 5.08 (d, J=16.0 Hz, 1H), 4.97 (d, J=15.6 Hz, 1H), 3.48 (t, J=8.4 Hz, 1H), 2.30-2.25 (m, 1H), 2.02-1.96 (m, 1H), 1.85 (s, 3H); MS ESI 470.3 [M+H]+, calcd for [C32H27N3O+H]+ 470.2.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([NH:34][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:14][CH2:15]3)=[N:20][CH:21]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87 mg, 0.213 mmol) and cyclopropanamine (18.24 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-cyclopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (70.3 mg, 0.157 mmol, 73.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 0.49-0.56 (m, 2 H) 0.62-0.70 (m, 2H) 1.82-2.02 (m, 3 H) 2.11-2.22 (m, 1 H) 2.40 (t, J=4.93 Hz, 4 H) 2.78 (tq, J=7.34, 3.86 Hz, 1H) 3.34 (br. s., 2 H) 3.36-3.44 (m, 1 H) 3.49-3.64 (m, 5 H) 3.94-4.03 (m, 1 H) 6.81 (d, J=8.59 Hz, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.90 (dd, J=9.09, 2.53 Hz, 1H) 8.20 (d, J=4.04 Hz, 1 H) 8.54 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H29N7O2, 448; found, 448.