Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 41.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.3 g, 1.8 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.32 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11]O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20]C(C=O)=[CH:16][CH:15]=1.[C:22](O[BH-](OC(=O)C)OC(=O)C)(=[O:24])[CH3:23].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]([OH:24])[CH3:23])[CH2:10][C:11]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Reactant: OCCNCc1ccc(Cl)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCCl
Product: CC(O)N(Cc1ccc(Cl)cc1)Cc1ccc(Cl)nc1
Yield: 94.7 %

Procedure:
This compound was prepared in a manner analogous to that set forth in Step A of Example 1, using 5.0 grams (0.0268 mole) of 2-{[(6-chloro-3-pyridyl)methyl]amino}ethan-1-ol (prepared in Step A of Example 1), 3.8 grams (0.0268 mole) of 4-chlorobenzaldehyde, 8.5 grams (0.040 mole) of sodium triacetoxyborohydride and 6.5 grams (0.053 mole) of magnesium sulfate in 100 mL of 1,2-dichloroethane. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 2% methanol in methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 7.9 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[Li]C(C)(C)C.CCCCC.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]1)[C:20]2=[N:33][S:34]([CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])(=[O:36])=[O:35].C(OC=C[Li])C>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:23]([CH2:22][C:21]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:20]2([NH:33][S:34]([CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])(=[O:36])=[O:35])[C:1]([O:3][CH2:4][CH3:5])=[CH2:2])=[CH:24][CH:25]=1
Reactant: C=COCC
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)(=O)CC[Si](C)(C)C
Agent: [Li]C(C)(C)C
Agent: [Li]C=COCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.17 h

Procedure:
To a solution of ethyl vinyl ether (7 mL, 73 mmol) in THF (10 mL) was added dropwise a solution of 1.7 M t-BuLi in pentane (26 mL, 44 mmol) at −78° C. under nitrogen. After 10 min, the reaction mixture was cooled in an ice bath and stirred for 45 min. To a solution of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-(trimethylsilyl)ethanesulfonamide (2) (1.3508 g, 2.86 mmol) in THF (20 mL) was added a solution of -ethoxyvinyllithium, obtained as described above, at −78° C. under nitrogen via a cannula. After 2 h, LC-MS indicated the disappearance of starting material. The reaction mixture was quenched with saturated NaHCO3 (5 mL) and saturated brine (20 mL) and then vigorously stirred at room temperature for 1 h. The mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product 9 (1.7654 g) was directly used in the next step without further purification. LC-MS tR=2.43 min in 3 min chromatography, m/z 544, 546 (MH+), 480, 482.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:12][C@@H:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[OH:14])([CH3:3])[CH3:2].CO[CH:23](OC)[CH2:24][NH:25][CH:26]=[O:27].B(F)(F)F>C(Cl)Cl>[CH:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:12][C@@H:13]([CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)[O:14][C@H:23]2[CH2:24][NH:25][CH:26]=[O:27])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C[C@H](O)C2CCNCC2)c1OC(C)C
Reactant: COC(CNC=O)OC
Agent: FB(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Reaction time: 15 h

Procedure:
Dissolve (S)-2-(2-Isopropoxy-3-methylphenyl)-1-(4-piperidinyl)ethanol (21.5 g, 78 mmol), N-(2,2,-dimethoxyethyl)formamide (15.5 g, 117 mmol) and BF3□Et2O (66.1 g, 466 mmol) in CH2Cl2 (350 mL). Heat the solution to reflux for 3 hr and then allow to stand 15 hr at room temperature. Evaporate the solvent and dissolve the residue in CH2Cl2. Treat the resulting solution with 50% aqueous NaOH to obtain a pH of 13. Separate the phases and extract the aqueous phase with CH2Cl2. Combine the organic phases, wash with brine and dry over MgSO4. Evaporate the solvent to afford a residue. Purify the residue by chromatography over SiO2 using CHCl3:2M NH3/MeOH (8:2). Evaporate the product-containing fractions and triturate with 1:1 Et2O:heptane to afford a crystalline solid; 1H-NMR (CDCl3) δ 8.2, 7.9 (2s, 1H), 7.0-6.7 (m, 2H), 6.2 (m, 1H), 4.8 (m, 1H). 4.2 (m, 1H), 4.1 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 2.9 (m, 1H), 2.7, (m, 2H), 2.5 (m, 2H), 2.2 (s, 3H), 2.0-1.4 (m, 5H), 1.3-1.2 (2d, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:16])[C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:10].[Cl:17][C:18]1[C:24](Cl)=[CH:23][C:21]([NH2:22])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1>CS(C)=O.CCOC(C)=O>[Cl:17][C:18]1[C:24]([N:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[C:9](=[O:10])[N:8]([CH3:16])[CH3:7])=[CH:23][C:21]([NH2:22])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1
Reactant: CN(C)C(=O)C1CCCN1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)C(=O)C1CCCN1c1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
Potassium carbonate (1.00 g, 7.3 mmol) was added to a mixture of pyrrolidine-2-carboxylic acid dimethylamide (1.00 g, 7.0 mmol) and 4,5-dichloro-2-nitroaniline (1.00 g, 4.8 mmol) in DMSO (6 mL). The reaction mixture was stirred at 120° C. for 2.5 h, diluted with EtOAc and washed with water and sat.aq. NaCl. The organic layer was dried over Na2SO4, concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:28][C:16]1[CH:17]=[CH:18][C:19]([S:22]([C:25](=[CH:12][C:11]2[CH:14]=[CH:15][C:8]([C:4]3[S:5][CH:6]=[CH:7][C:3]=3[S:2][CH3:1])=[CH:9][CH:10]=2)[C:26]#[N:27])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: CSc1ccsc1-c1ccc(C=O)cc1
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CSc1ccsc1-c1ccc(C=C(C#N)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To a stirring solution of 4-(3-methylthio-2-thienyl)benzaldehyde (1.0 mmol, prepared directly above) and p-toluenesulphonylacetonitrile (1.0 mmol) in toluene, add piperidine (0.05 mmol) and acetic acid (0.3 mmol). Heat the reaction mixture to reflux for 2 hours while using a Dean-Stark trap, remove the heat and concentrate the reaction in vacuo. The crude material can be carried on to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].C([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])(C)(C)C.[F:28][CH:29]([F:41])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>>[F:28][C:12]([F:13])([F:14])[C:20]([OH:19])=[O:21].[F:41][CH:29]([F:28])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([O:11][CH:12]([F:14])[F:13])=[C:2]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[CH:7]=1)(=[O:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(OC(F)F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Product: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccc(OC(F)F)c(N2CCNCC2)c1)c1ccccc1OC(F)F

Procedure:
The compound was prepared starting from commercially available 2-bromo-4-nitrophenol, which was reacted with 2-chloro-2,2-difluoroacetophenone (J. Hu et al., J. Org. Chem., 2006, 71, 9845) to yield 2-bromo-1-difluoromethoxy-4-nitro-benzene. Subsequent Buchwald-Hartwig coupling of 2-bromo-1-difluoromethoxy-4-nitro-benzene with tert.butyloxycarbonyl-piperazine by analogy to preparation example 3.1, reduction of the nitro group to the corresponding aniline by analogy to preparation example 3.2, subsequent coupling with commercially available 2-difluoromethoxybenzene-sulfonylchloride by analogy to preparation example 1.4, and final deprotection under acidic conditions by analogy to example 1 yielded the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH2:17])[CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)=[CH:11][C:12]=1[NH2:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)c(N)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@H]1CC[C@H](c2ccc(OCc3ccccc3)c(N)c2)CC1

Procedure:
116.5 g of 4-(trans-4-n-propylcyclohexyl)-2-amino-phenol, 80 g of potassium carbonate and 110 g of benzyl bromide are heated to 100° for 10 seconds in 500 ml of N,N-dimethyl-formamide. Subsequently, the reaction mixture is poured into 1 l of water. From the mixture obtained, the 4-(trans-4-n-propylcyclohexyl)-2-aminophenyl benzyl ether formed is extracted with dichloromethane and, after distilling off of the extraction agent, is recrystallized from isopropanol; yield 120 g.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH3:8])[CH3:2].[C:9](=[O:14])([O:12]C)[O:10][CH3:11].[C:15](=O)=O>CO>[CH3:11][O:10][C:9](=[O:12])[O-:14].[CH2:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH3:15])[C:4]=1[CH3:8])[CH3:2]
Reactant: COC(=O)OC
Reactant: O=C=O
Reactant: CCn1ccnc1C
Solvent: CO
Product: CC[n+]1ccn(C)c1C
Product: COC(=O)[O-]
Temperature: 130 °C
Reaction time: 60 h

Procedure:
110 parts of 1-ethyl-2-methylimidazole, as prepared, 135 parts of dimethyl carbonate and 192 parts of methanol were put into an autoclave made of a stainless steel equipped with a cooling condenser and mixed homogenously. After nitrogen substitution, the temperature was then raised to 130° C. while being sealed, so as to initiate a reaction. At the beginning, the pressure was approximately at 4.5 Kg/cm2, but it was gradually raised due to generation of carbon dioxide, so that the gasses were appropriately released from the upper part of the cooling condenser, adjusted at a pressure of about 7 Kg/cm2 or less. After 60 hours, they were cooled at 30° C., and the result of the reacted solution by means of 1H-NMR showed that 1-ethyl-2-methylimidazole was disappeared and 1-ethyl-2,3-dimethylimidazolium monomethyl carbonate was produced approximately under a quantitative theory. Into 428 parts of the resultant solution of 1-ethyl-2,3-dimethylimidazolium monomethyl carbonate, methanol and dimethyl carbonate, 205 parts of an aqueous solution of fluoroboric acid at a concentration of 42 wt % were gradually put in drops with stirring at a temperature of 25° C. over a period of about 30 minutes. As putting them in drops, bubbles of carbon dioxide were generated. Finishing the dropping and the generation of the bubbles, all the solvents were removed at a pressure of 20 Torr and at a temperature of 150° C., so as to obtain 208 parts of a white solid (1). The examinations of 1H-NMR, 19F-NMR, 13C-NMR and HPLC resulted in showing that 98 mol % of 1-ethyl-2,3-dimethylimidazolium tetrafluoroborate (which is hereinafter shortened as “EDMI.BF4”), 2 mol %, in total, of 1-ethyl-2,3-dimethyl-4-carboxylate imidazolium, 1-ethyl-2,3-dimethyl-5-carboxylate imidazolium, 1-ethyl-2,3-dimethyl-4-carboxylate-5-carboxy imidazolium and 1-ethyl-2,3-dimethyl-4-carboxy-5-carboxylate imidazolium. The HPLC analysis was performed in the conditions as described above. The conditions were the same in the following examples.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7]([N:10]1[CH2:15][CH2:14][N:13]([C@@H:16]([CH2:21][NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([O:30]COCCOC)=[CH:26][CH:25]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]1)(=[O:9])=[O:8].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:21][C@H:16]([N:13]2[CH2:12][CH2:11][N:10]([S:7]([CH3:6])(=[O:9])=[O:8])[CH2:15][CH2:14]2)[C:17]([O:19][CH3:20])=[O:18])=[O:37])=[CH:25][CH:26]=1
Reactant: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
0.5 ml of 98% sulphuric acid are added to a solution of 1.6 g (3.4 mmol) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(2-methoxyethoxymethoxy)benzoyl-amino]propanoate in 15 ml of tetrahydrofuran and 15 ml of methanol. After stirring for 18 h at ambient temperature, the reaction medium is hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate then extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. 1.1 g (85%) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methane-sulphonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.