Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[C:25]([CH3:27])([CH3:26])[O:24][C:23]([NH:28][C@H:29]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[F:46])[CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[N:22][S:21]3(=[O:48])=[O:47])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[H][H].Cl>CO.[Pd]>[CH3:26][C:25]1([CH3:27])[O:24][C:23]([NH:28][C@H:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[CH2:30][CH2:31][OH:32])=[N:22][S:21](=[O:48])(=[O:47])[CH:20]1[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c4ccccc4F)=NS3(=O)=O)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 1-Boc-4-(4-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}phenyl)-3,6-dihydro-2H-pyridine (575 mg) in methanol (25 ml) was admixed with palladium on charcoal (10%, 260 mg) and stirred in a hydrogen atmosphere for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in 5 ml of dichloromethane, and 1 ml of trifluoroacetic acid was added. After stirring at room temperature for 1 h, the solvent was removed under reduced pressure and TFA ester formed was cleaved by treatment with 1 N HCl. Extraction with ethyl acetate gave the crude product (91%), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:6]=[O:7])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=[N+]([O-])O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 61 %

Procedure:
After reacting 135 g of 3,4-dimethoxybenzaldehyde and 500 ml of conc. nitric acid at 10° C. for 20 hours, the reaction mixture was poured in 3 l of ice water and the resultant crystals were collected by filtration. The crystals were dissolved in a mixed solvent of 8 l of toluene and 500 ml of ethyl acetate. After washing the resultant solution once with a saturated aqueous solution of sodium bicarbonate, three times with water and then once with saturated saline, the solution was concentrated to about 500 ml under reduced pressure. The concentrate was cooled to room temperature and the resultant yellowish crystals (77.71 g) were then collected by filtration (yield: 61%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](Cl)=[O:42]>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)OCCCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3OCc3ccc4ccccc4c3)cc2)c1

Procedure:
(bb) In an analogous manner to that described in Example 22 (k), by acylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24 (t)] with 3-methoxy-benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-{4-[3-(3-Methoxy-benzoyloxy)-propyl]-phenyl}-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 610 (M+H)+.
Reaction SMILES: C[C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=O)=[CH:17][CH:16]=1>>[CH3:2][C:3]1[C:4](=[O:5])[CH:6]2[CH:11]([C:12](=[O:13])[C:22]=1[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1)[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: CC1=C(Cc2ccc(Cl)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 75 %

Procedure:
As starting materials for the coupling reaction menadione and 4-chlorophenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (cyclohexane:ethyl acetate=3:1, UV), 6.46 g (21.8 mmol, 75% yield) of P_TM30 were isolated as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11](C)[C:10](=O)[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:30].C(N(C(C)C)CC)(C)C>CCOC(C)=O>[Cl:30][C:10]1[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:13]=[C:12]([S:14][CH3:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c(=O)n1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(-c2cccc(C(F)(F)F)c2)c(-c2ccnc(Cl)c2)n1
Temperature: 25 °C

Procedure:
6-(2-chloro-4-pyridyl)-3-methyl-2-methylthio-5-(3-(trifluoromethyl)-phenyl)-(3H)-pyrimidin-4-one (2.05 g, 5 mmol), POCl3 (3.05 g, 20 mmol), and diisopropylethylamine (2.58 g, 20 mmol) in a 50-ml r.b.flask with a stir bar was stirred at 120° C. for 16 h. The reaction was cooled to RT, 20 ml of EtOAc and 5 g of SiO2 gel were added into the cooled solution, then solvents were evaporated in vacuo at 40° C. The brown solid was placed on a cake of SiO2 gel (˜20 g) and washed by 200 ml of 30% EtOAc in hexane. The brown filtrate was evaporated in vacuo to give an oil product; MS m/z (M+H)+ 416.2. The crude intermediate was used in the next step directly.
Reaction SMILES: C(O[CH:4]=[CH2:5])=C.[C:6]1([CH2:11][SH:12])[S:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH2:11][S:12][CH2:11][C:6]2[S:10][CH:5]=[CH:4][CH:7]=2)[S:10][CH:9]=[CH:8][CH:7]=1
Reactant: SCc1cccs1
Reactant: C=COC=C
Product: c1csc(CSCc2cccs2)c1

Procedure:
f. Dithenyl sulfide was prepared by the same method as used for compound (1) b. (diethenyl ether) of Group X above, except that thenylmercaptan was used instead of thenyl alcohol. The product has a b.p. of 118°C./0.04 mm. Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[F-].[Cs+]>COCCOC.O>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1
Reactant: COCCCc1ccccc1B(O)O
Reactant: Cc1cc(Br)ccc1C(C#N)Cc1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cccnc2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution 2-(4-bromo-2-methylphenyl)-3-pyridin-3-ylpropanenitrile (1 eq.) from step 1 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 (1.2 eq.) in DME (0.1M) at room temperature was added palladium tetrakistriphenyl phosphine (Pd(PPh3)4; 0.05 eq.) and CsF (2.4 eq.). The mixture was refluxed for 2 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with water, brine, dried over Na2SO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 65% in 30 min) afforded the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:31][CH:30]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ncnc2cc1OCc1ccccc1
Temperature: 50 °C
Yield: 75.5 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (100 mg, 0.333 mmol), K2CO3 (345 mg, 2.49 mmol) and N-(4-hydroxy-phenyl)-benzamide (106 mg, 0.499 mmol) in DMA was heated at 50° C. for 18 hours. The reaction was cooled and partitioned between ice water and EtOAc. The aqueous was extracted twice with EtOAc and the combine organic washed with water, brine, dried and concentrated. The residue was purified by column chromatography (30-100% EtOAc:Heptane) to provide the title compound as a cream solid (120 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14](O)(=[O:17])[CH2:15][OH:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[OH:17][CH2:14][C:15]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:16]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)CO)C(=O)OCC
Yield: 62.7 %

Procedure:
To a solution of diethyl 2-aminomalonate hydrochloride (4.2 g) and glycolic acid (1.6 g) in dimethylformamide is added triethylamine (2.12 g), and to the mixture are added 1-hydroxybenzotriazole (2.7 g) and N,N'-dicyclohexylcarbodiimide (4.33 g) with stirring under ice cooling. The mixture is reacted at 0° to 5° C. for 2 hours and further reacted at room temperature for 15 hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added ethyl acetate, and the undissolved substance is filtered off. The filtrate is washed with aqueous sodium carbonate solution, dried and then the solvent is distilled off. The residue is purified by silica gel column chromatography [solvent: chloroform-ethyl acetate (2:1)] to give diethyl 2-[(hydroxyacetyl)amino]malonate (2.9 g), m.p. 74°-74.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C.[C:20]([O:24][C:25](=O)[O:26]C(C)(C)C)([CH3:23])([CH3:22])[CH3:21].O>O1CCCC1>[CH2:1]([N:8]1[C@@H:9]([CH3:15])[CH2:10][N:11]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of (2R,5S)-1-benzyl-2,5-dimethylpiperazine (3.52 g, 17.2 mmol) in tetrahydrofuran (50 mL), trimethylamine (2.12 g, 20.9 mmol) and di-tert-butylcarbonate (4.56 g, 20.9 mmol) were added under ice-cold conditions, and the mixture was stirred for 15 minutes. Then, the mixture was stirred at room temperature for 5.5 hours. The reaction solution was added water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (3.16 g, 60%) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[CH:14]=[C:13]([C:15]([O:17]CC)=O)[O:12][N:11]=1.[NH3:20]>CO>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[CH:14]=[C:13]([C:15](=[O:17])[NH2:20])[O:12][N:11]=1
Reactant: CCOC(=O)c1cc(-c2ncc([N+](=O)[O-])n2C)no1
Reactant: N
Solvent: CO
Product: Cn1c([N+](=O)[O-])cnc1-c1cc(C(N)=O)on1

Procedure:
3 g. of the compound prepared in Example 12 is dissolved in hot methanol. The solution is saturated with ammonia. A precipitate is formed and the mixture is cooled by placing in the refrigerator. After filtration and purification, the pure product having a melting point of 235°-238° C. is recovered. This product is identified as 1-methyl-2-(5-carbamoyl-isoxazol-3-yl)-5-nitroimidazole.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15]O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCOc1c(NCCCO)c(=O)c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOc1c(NCCCS(=O)(=O)c2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A solution of 1-butoxy-2-(3-hydroxypropylamino)-1-cyclobutene-3,4-dione [prepared in Example 7] (1.14 g, 5.0 mmol) and pyridine (0.65 mL, 8.0 mmol) in 6.0 mL of dichloromethane cooled to 0° C. was treated dropwise with benzenesulfonyl chloride (0.65 mL, 5.1 mmol). The mixture was stirred at ambient temperature for 3 hours, then washed with water (4 times), dried and evaporated under reduced pressure to give 1.53 g (83% yield) of title compound which was used without purification in the subsequent reaction.