Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][CH2:8][C:9]1[O:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:14]C1OC(CBr)=CC=1>CCOCC>[CH2:8]([O:7][CH2:1][C:2]1[O:6][C:5]([CH3:14])=[CH:4][CH:3]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(CBr)o1
Reactant: c1coc(COCc2ccco2)c1
Solvent: CCOCC
Product: Cc1ccc(COCc2ccco2)o1

Procedure:
d. 5-Methyl-furfuryl furfuryl ether was prepared by the procedure described in J. E. Zanetti in J.Am.Chem.Soc. 49, 1066 (1927) for the difurfuryl ether, starting with 5-methyl-furfuryl bromide (Compt.Rend. 222, 1441 (1946)) instead of furfuryl bromide of Zanetti. The product was isolated by ether extraction of the crude mixture after having diluted with water. For purification the ether extract was distilled twice -- b.p. 68°-70° C. at 0.01 mm/Hg vacuum. The product was a viscous colourless liquid, darkening rapidly on contact with air.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:25]1[CH2:26][C:30]2[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28]1)=[O:6]
Reactant: CCN(CC)Cc1ccccc1
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D36) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with isoindoline (0.08 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound as a white solid (0.08 g). MS electrospray (+ion) 411/413 (MH+). 1H NMR δ (DMSO-d6): 10.55 (1H, s), 7.45 (2H, m), 7.27 (4H, m), 7.11 (1H, m), 4.89-4.68 (3H, m), 4.52 (2H, m), 3.67 (1H, m), 3.46-3.18 (2H, m), 2.90 (2H, m), 2.40-1.63 (10H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14].CC(C)([O-])C.[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:5]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])[CH:6]=1
Reactant: COC(=O)c1cc(Br)c[nH]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cn1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
Methyl 4-bromo-1H-pyrrole-2-carboxylate (250 mg, 1.23 mmol) and 2-bromo-1-(4-chloro-phenyl)-ethanone (315 mg, 1.35 mmol) were dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. before potassium tert-butoxide (125 mg, 1.11 mmol) was added to the reaction mixture in small portions. The resulting suspension was allowed to warm to room temperature then stirred for 10 min. The reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried and concentrated in vacuo to give a residue that was purified using flash chromatography (Biotage SP4, 40 g cartridge, 0-15% EtOAc gradient in n-hexanes) to give the target compound methyl 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (244 mg) contaminated with an impurity. The mixture was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]Cl.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:10]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=3)=[O:18])[C:9]=2[CH:38]=1.C[O-].[Na+].O>CO>[CH2:13]([C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([NH:4][S:2][CH3:1])=[CH:38][C:9]=2[C:10]=1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:24]=1)=[O:18])[CH2:14][CH2:15][CH3:16]
Reactant: CSCl
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccc(NSC)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
1.98 g of methanesulfenyl chloride (II) (0.024 mol, 1.2 eq; freshly prepared as described in the above mentioned literature), 9.57 g of (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone (III) (0.02 mol, 1 eq) and 10 mL of 1.5 M sodium methylate methanolic solution were added into a flask and the mixture was diluted with 50 mL of methanol. The reaction mixture was stirred for 3 hours at room temperature. After the reaction was complete (followed by HPLC) the mixture was poured into 150 mL of water. The product was extracted with 2×60 mL of dichloromethane. The organic phase was washed with 50 mL of aq. NaHCO3 solution and then with 50 mL of water. The solvent was evaporated and the product was purified by column chromatography (column: spheric silica (60 Å); eluent: toluene:MTBE:methanol=50:40:10) to obtain 9.14 g of compound (IV) (87%) as a light yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Methanesulfonyl chloride (364 mg) was added to a solution of 1-t-butoxycarbonyl-4-(2-aminophenyl)piperidine (880 mg) and pyridine (252 mg) in dichloromethane. The mixture was heated under reflux for 30 min., cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between aqueous citric acid (10%) and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (1.15 g), δH (CDCl3) 1.48 (9H, s), 1.60 (2H, m), 1.73 (2H, m), 2.83 (2H, m), 3.04 (3H, s), 3.09 (1H, m), 4.26 (2H, m), 6.21 (1H, br s), 7.21-7.37 (2H, m). m/e (ES+) 355 (MH+).
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=[O:12])[C:7]([CH3:14])=[N:6]1.CC1[C:20]([C:21]([O:23][CH2:24]C)=O)=C(C)NN=1.BrCC(OC)CC>>[CH3:24][O:23][CH2:21][CH2:20][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=[O:12])[C:7]([CH3:14])=[N:6]1
Reactant: COCCn1nc(C)c(C(=O)O)c1C
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Agent: CCC(CBr)OC
Product: COCCCCn1nc(C)c(C(=O)O)c1C
Yield: 41 %

Procedure:
Prepared by following the same method as the preparation of Intermediate 42, ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate (280 mg) was reacted with 1-bromo-2-methoxybutane (367 mg) to afford white solid (185 mg, 41%). ESI-MS m/z 227.4 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(Cl)c(CBr)c1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(Cl)ccc(F)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichloro-4-fluorobenzene and isolated as white solid. MS(m/e): 459.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].O=[C:9]([CH3:15])[CH2:10][C:11](OC)=[O:12].C[O-].[Na+]>CO>[CH3:15][C:9]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[NH:5][C:11](=[O:12])[CH:10]=1
Reactant: COC(=O)CC(C)=O
Reactant: N=C(N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)[nH]c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trifluoroethanimidamide (3.02 g, 22.9 mmol) and 3-oxobutanoic acid, methyl ester (2.60 mL, 24.0 mmol) in methanol (25 mL) was added 25 wt % sodium methoxide (10.5 mL, 45.8 mmol). The reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and diluted with ethyl acetate and 5M HCl. The aqueous layer was extracted with ethyl acetate once. The organic solutions were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column to give the desired product as white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]O)=[CH:6][C:5]([C:13]([NH2:15])=O)=[N:4]1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:13]#[N:15])[CH:6]=1
Reactant: CCn1nc(C(N)=O)cc1CCCCO
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCn1nc(C#N)cc1CCCCCl
Temperature: 0 °C

Procedure:
A modification of the method described in Part E of Examples 1-4 was used to treat 1-ethyl-5-(4-hydroxybutyl)-1H-pyrazole-3-carboxamide (18.2 g, 86.1 mmol) with phosphorous oxychloride (60 mL). The reaction was heated for three hours before cooling to 0° C. and pouring into ice water. The mixture was adjusted to pH 12 with the addition of 2 N aqueous sodium carbonate and extracted with chloroform. The combined extracts were passed through a layer of silica gel (eluting first with chloroform and then with 1:1 hexane/ethyl acetate to provide 10.8 g of 5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile as a dark oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:16]([NH:19][NH:20][C:13]([C:11]1[N:10]=[CH:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:12]=1)=[O:15])(=[O:18])[CH3:17]
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)cn1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1cn(-c2cccc(Br)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5 (0.30 g, 1.1 mmol), acethydrazide (82 mg, 1.1 mmol) diisopropylethyl amine (975 uL, 5.6 mmol), and 1-hydroxy-7-azabenzotriazole (HOAt, 177 mg, 1.3 mmol) in DMF (10 mL) was added and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (EDC HCl; 249 mg, 1.3 mmol). The mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was extracted with hot ethyl acetate. The solvent was evaporated and crystallised from MeOH to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=O)[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([Cl:26])=[O:23])[CH:5]=[C:6]([Br:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)ccc1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)Cl)cc2Br)ccc1O

Procedure:
3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (444 mg) was mixed with 10 ml thionyl chloride and heated at reflux for 3 h. The reaction mixture was co-evaporated with toluene to give the crude 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl chloride. N,O-bis(trimethylsilyl)acetamide (670 mg) was added at 0° C., under nitrogen atmosphere, to a mixture of D-Aspargine (225 mg) and 10 ml acetonitrile. The reaction mixture was further stirred at room temperature and a solution of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl chloride in 10 ml acetonitrile was added. After stirring for 16 h, the reaction mixture was poured into water and the solid filtered off. The solid was dissolved in methanol and the organic phase removed in vacuo. The residue was purified by HPLC to give 76 mg (14%) of D- N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspargine. LC-MS (electrospray): m/z 557 (M−H).