Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=4)[C:20](=[O:39])[C:19]=3[C:18]=2[O:40][CH3:41])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C1COCC1.C(=O)([O-])O.[Na+]>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=4)[C:20](=[O:39])[C:19]=3[C:18]=2[O:40][CH3:41])=[O:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(Cc1cccc(C)n1)c1ccccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(Cc1cccc(C)n1)c1ccccc21
Yield: 50 %

Procedure:
A solution of 2-{4-[({3-methoxy-1-methyl-5-[(6-methylpyridin-2-yl)methyl]-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl}carbonyl)amino]piperidin-1-yl}-2-oxoethyl acetate (80 mg) and potassium carbonate (100 mg, 0.71 mmol) in THF (2 mL)-methanol (1 mL)-water (1 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (37 mg, 11%) as white crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Br:21][CH2:22][CH2:23][CH2:24]Br.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:21][CH2:22][CH2:23][CH2:24][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)CCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran being stirred, 126 ml of a 1.6 M solution of n-butyl lithium in hexane wasadded at -5° to 0° C., followed by stirring for 30 minutes. After the reaction mixture was cooled to -78° C. and 26.7 ml of ethyl isobutyrate was added dropwise to the mixture and stirred for 1 hour. 41.8 g of 1,3-dibromopropane was added dropwise to the reaction mixture. After stirring at -78° C. for 1 hour and then at room temperature (15° to 20° C.) for 2 hours, the reaction mixture was added to an aqueous solution of ammonium chloride and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off, and the residue was distilled under reduced pressure, to yield 40.3 g of the title compound in the form of a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C:24]1([C:39](O)=[O:40])[CH2:29][CH2:28][N:27]([C:30]2[C:31]3[CH:38]=[CH:37][NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:15][C:39]([C:24]2([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:25][CH2:26][N:27]([C:30]3[C:31]4[CH:38]=[CH:37][NH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:28][CH2:29]2)=[O:40])[CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=1
Reactant: CN(C)CCCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
1-(4-Chlorophenyl)-N4,N4-dimethylbutane-1,4-diamine (Intermediate 57) (330 mg, 1.46 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (526 mg, 1.46 mmol) and DIPEA (0.763 mL, 4.37 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (609 mg, 1.60 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 51.0%) as a colourless gum. tert-Butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 0.74 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford 4-amino-N-(1-(4-chlorophenyl)-4-(dimethylamino)butyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (245 mg, 35.8%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[CH:10][CH:11]=2)[C:6](=O)[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl.CC(OC)(C)C>[Cl:14][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc(=O)n2nccc2[nH]1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Nc1cc(Cl)n2nccc2n1
Temperature: 25 °C

Procedure:
A solution of 5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2) (1.5 g, 10 mmol) in phosphoryl chloride (45 mL) is stirred at reflux overnight. The reaction mixture is allowed to cool to RT and concentrated in vacuo. The residue is then dissolved in ice-water (25 mL) and the resulting mixture is neutralized with aqueous NaOH solution (20%) to adjust the pH to 9-10. The mixture is extracted with ethyl acetate (3×50 mL) after which the combined organic layers are washed with brine (500 mL), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the crude product which is slurried in a mixture of DCM/MTBE (3 mL/15 mL). The resulting solid is then collected by filtration to afford 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (Z-3).
Reaction SMILES: CCCCCC.C([Li])CCC.C(NC(C)C)(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl[CH2:34][C:35]1[CH:43]=[CH:42][C:38]2[O:39][CH2:40][O:41][C:37]=2[CH:36]=1.[Cl-].[NH4+]>O1CCCC1>[O:39]1[C:38]2[CH:42]=[CH:43][C:35]([CH2:34][CH:27]3[C:28](=[O:32])[NH:29][CH2:30][CH2:31][N:26]3[C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])=[CH:36][C:37]=2[O:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Under argon atmosphere, 17.5 ml of 1.58M n-butyl lithium-n-hexane solution was dropped into a mixture of 25 ml of tetrahydrofuran and 2.78 g of diisopropylamine under cooling ice, followed by 30 minutes' stirring under the same condition. Thereafter a solution of 2.50 g of 1-tert-butoxycarbonyl-3-oxopiperazine (which was prepared by following Tetrahedron Lett., 1980, 21, 3019-3020) in 60 ml of tetrahydrofuran was added by dropping under cooling with ice, followed by 3 hours' stirring under the same condition, further dropping of a solution of 2.30 g of 5-chloromethyl-benzo[1,3]dioxole in 20 ml of tetrahydrofuran under cooling with ice, and an hour's stirring under the same condition. The solution was warmed to room temperature and stirred for 18 hours. After addition of saturated aqueous ammonium chloride solution, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was distilled therefrom under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate) to provide 2.84 g (68%) of 2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine.
Reaction SMILES: C(Br)C.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:42]2[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:41]=2[N:40](CC)[C:39](=[O:52])[C:38]([CH3:54])([CH3:53])[N:37]=1>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:42]2[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:41]=2[NH:40][C:39](=[O:52])[C:38]([CH3:54])([CH3:53])[N:37]=1
Reactant: CCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCBr
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 1.7 g (0.005 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and ethyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 36 hours, 5-(o-chlorophenyl)-1-ethyl-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 174° (ether).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21](O)=[O:22])[CH:9]=2)[C:5]([I:24])=[CH:4][N:3]=1.CC[N:27](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([NH2:27])=[O:22])[CH:9]=2)[C:5]([I:24])=[CH:4][N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2nc(N)ncc2I)cc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2nc(N)ncc2I)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
Crude 5-(2-amino-5-iodo-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxylic acid (691 mg, 1.52 mmol) in DMF (5 mL) and DIPEA (1.06 mL, 6.08 mmol) was stirred at 0° C. EDCl (582 mg, 3.04 mmol) and HOBT.NH3 (469 mg, 3.04 mmol) were added and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured into saturated solution of sodium hydrogen carbonate. The solid was filtered with suction and the panel washed thoroughly with water and dried under vacuum in an oven at 50° C. The crude compound may be purified by flash chromatography (DCM/MeOH 95/5) to give the title compound (518 mg, 75%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([F:42])=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[C:25][CH2:26][C@@:27]3([NH:34]C(=O)OC(C)(C)C)[CH2:31][CH2:30][N:29]([CH3:32])[C:28]3=[O:33])[N:18]=2)[CH:16]=1)[CH3:9].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:34][C@:27]1([CH2:26][C:25]#[C:24][C:19]2[N:18]=[C:17]([C:15]3[CH:16]=[C:11]([O:10][CH2:8][CH3:9])[CH:12]=[CH:13][C:14]=3[F:42])[CH:22]=[C:21]([CH3:23])[N:20]=2)[CH2:31][CH2:30][N:29]([CH3:32])[C:28]1=[O:33]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(NC(=O)OC(C)(C)C)CCN(C)C3=O)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(N)CCN(C)C3=O)n2)c1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Trifluoroacetic acid (3 mL, 40.39 mmol) was added to a solution of tert-butyl N-[(3R)-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-2-oxo-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 18) (605 mg, 1.25 mmol) in DCM (15 mL) at 20° C. and the reaction was stirred for 1 hour. Solid K2CO3 was added to quench the TFA present (care: gas evolved) and the resultant solid was filtered off and washed five times with DCM. The solvent was evaporated to give the (3R)-3-amino-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-pyrrolidin-2-one (D19) (447 mg, 1.1688 mmol, 93.2% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])O.[Na+].[Br:19]Br>CO>[Br:19][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([F:12])([F:13])[F:1]
Reactant: BrBr
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and a sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN1CCCC1=O>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:7]=3)[N:9]=2)[NH:14][CH:15]=1)=[O:22]
Reactant: C1CCNC1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccnc(Cl)c3)nc12
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccnc(N4CCCC4)c3)nc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of 1-[2-(2-chloro-pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.030 g, 0.095 mmol), 0.100 mL of pyrrolidine and 1.5 mL of N-methylpyrollidinone was stirred at 150° C. in a pressure tube for 3 h. The resulting black solution was partitioned between 30 mL of ethyl acetate and 40 mL of water. The organic layer was washed with three 30 mL portions of water, dried over MgSO4, filtered and concentrated to a residue. Silica gel chromatography (0->60% EtOAc/hexanes) afforded 0.020 g (61%) of 2,2-dimethyl-1-[2-(2-pyrrolidin-1-yl-pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow solid.
Reaction SMILES: CI.[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([OH:14])=[CH:11]2)=[CH:6][CH:5]=1.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2ccc(Br)cc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2ccc(Br)cc2c1
Reaction time: 72 h
Yield: 96.6 %

Procedure:
Methyl iodide (2 mL, 32.1 mmol) was added to a mixture of 7-bromonaphthalen-2-ol (6.26 g, 28.0 mmol) and K2CO3 (4.62 g, 33.4 mmol) in DMF (21 mL). After stirring for 3 days, the mixture was partitioned between ethyl acetate/H2O and the organic solution was further washed with H2O (5×60 mL). The organic solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (6.41 g, 96%).