Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH3:14])[CH:7]=1)=[O:5].[Br:19]Br>C(Cl)Cl.N1C=CC=CC=1>[Br:19][C:10]1[CH:11]=[C:6]([C:4](=[O:5])[C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])[CH:7]=[C:8]([CH2:13][CH3:14])[C:9]=1[OH:12]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)ccc1O
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1O
Reaction time: 48 h
Yield: 93 %

Procedure:
At ambient temperature, to a stirred solution containing 4-(2-chlorobenzoyl)-2-ethylphenol (13.62 g, 52.24 mmol) and pyridine (0.25 mL, 3.23 mmol) in CH2Cl2 (870 mL) was added dropwise bromine (3.3 mL, 62.29 mmol). After 48 h, the reaction was washed with 10% aq. Na2SO4 (1×180 mL), H2O (2×350 mL), brine (1×300 mL), dried (Na2SO4) and concentrated to give 16.50 g (93%) of the title compound. 1H NMR: consistent.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([OH:27])=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([O:27][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(OCc3ccccc3)cc12
Reaction time: 24 h
Yield: 51.2 %

Procedure:
A solution of benzyl bromide (230 μl, 1.9 mMol) in acetone (6 ml) is added at room temperature, over 15 minutes, to a mixture containing 1-chloro-9-hydroxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 10) (490 mg, 1.73 mMol), acetone (7 ml), DMF (2 ml) and K2CO3 (400 mg). The assembly is left stirring for 24 h, then the solvents are subsequently evaporated under vacuum. Water is then added (30 ml). The assembly is again left stirring for 24 h. The solid form is recovered by filtration, washed with water, then dried at room temperature for 18 h. An inter-mediate, 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole (330 mg, 51% yield) is obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99%/1% to 95%/5%) as eluent. The product obtained is identical to that obtained according to the method described in J. Chem. Soc. Perkin Trans. 1, 1979, 1706. The mixture of 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole obtained above (320 mg, 0.86 mMol), DMF (7 ml) and sodium methoxide (30% solution in methanol, 10 ml) is heated under reflux for 20 h. The reaction mixture is poured into 60 ml of water, then left stirring for 2 h. The solid formed, recovered by filtration, is washed with water then dried. 280 mg (88% yield) of the expected compound 9-benzyloxy-1-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 7) are then obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99.5%/0.5% to 99%/1%) as eluent. The proton NMR spectrum of Compound 7 is the following:
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].[H][H].[1HH]>CO>[CH3:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: [H][H]
Agent: [1HH]
Solvent: CO
Product: COC(=O)CC(C)C(=O)OC
Reaction time: 0.25 h

Procedure:
4.73 mg (0.0126 mmol) of [Rh(NBD)2]BF4 and 8.55 mg (0.0133 mmol) of B2a are placed in a flask provided with a magnetic stirrer and blanketed with argon by repeatedly evacuating the flask and flushing it with argon. 5 ml of degassed methanol are then added and the mixture is stirred for 15 minutes. 0.4 g (2.53 mmol) of dimethyl itaconate and 5 ml of degassed methanol are subsequently introduced into a 10 ml Schlenk flask filled with an argon atmosphere. Stirring is continued until a homogeneous solution is formed. The solution is injected by means of a steel capillary into a 180 ml glass reactor filled with argon. Finally, 1.05 bar of hydrogen are introduced in three flushing cycles (argon 1 bar/hydrogen 1 bar). The hydrogenation is started by switching on the stirrer and is carried out at 25° C. The course of the reaction is followed via the hydrogen consumption (pressure decrease in the hydrogen reservoir). After a reaction time of 20 hours, the conversion is found to be complete. The enantiomeric purity of dimethyl 2-methyl succinate is 94.6% of (R).
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[C:29]1([S:43]([OH:46])(=[O:45])=[O:44])[C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:39]([OH:42])(=[O:41])=[O:40])[C:33]=2[CH:32]=[CH:31][CH:30]=1>C(#N)C.CC(C)=O>[C:29]1([S:43]([OH:46])(=[O:45])=[O:44])[C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:39]([OH:42])(=[O:41])=[O:40])[C:33]=2[CH:32]=[CH:31][CH:30]=1.[Cl:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3](=[O:9])[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CCl)C(=O)C(Br)Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC(C)=O
Solvent: CC#N
Product: CC(C)(CCl)C(=O)C(Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
20.8 g (0.05 mol) of crude 1-bromo-4-chloro-1-[4-(4-chlorophenyl)-phenoxy]-3,3-dimethyl-butan-2-one were dissolved in 120 ml of absolute acetonitrile. 12 g (0.175 mol) of imidazole were added and the mixture was heated for 40 hours under reflux. It was then concentrated by distilling off the solvent in vacuo and the residue was taken up in 300 ml of methylene chloride. The solution was washed three times with 100 ml of water at a time and was dried over sodium sulphate and again concentrated in vacuo. The residue was taken up in 100 ml of acetone and a solution of 9 g (0.038 mol) of 1,5-naphthalenedisulphonic acid in 50 ml of acetone was added. After 2 hours, the precipitate formed was filtered off and dried. 19.6 g (72% of theory) of 4-chloro-1-[4-(4-chlorophenyl)-phenoxy]-3,3-dimethyl-1(imidazol-1-yl)-butan-2-one naphthalene-1,5-disulphonate of melting point 246° C. were obtained.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([F:27])[C:14]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:15]([F:21])[C:16]=2[F:20])[N:11]([CH2:28][CH3:29])[C:10]1=[O:30])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>FC(F)(F)C(O)=O>[CH2:28]([N:11]1[C:12]2[C:17](=[C:16]([F:20])[C:15]([F:21])=[C:14]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:13]=2[F:27])[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:30])[CH3:29]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2c(F)c(F)c(N3CCCC3)c(F)c21
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)n(O)c(=O)c2c(F)c(F)c(N3CCCC3)c(F)c21
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 3-benzyloxy-1-ethyl-5,6,8-trifluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example X-3, 0.15 g, 0.36 mmol) in trifluoroacetic acid (5.0 mL) was reacted with a 1.0 M solution of boron tris(trifluoroacetate) (1.8 mL, 1.8 mmol) in TFA and allowed to stir for 1 hour. The mixture was then concentrated and the residue dissolved in methanol and concentrated. This process was repeated three times. The residue was then triturated from dietbyl ether and filtered to provide 0.11 g of the title compound as a solid, mp 223-225° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (14 g, 31.1 mmol) in THF (150 mL) was added TEA (6.3 g, 62.1 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.77 g, 46.6 mmol). The mixture was stirred at r.t. for 4 h. The mixture was diluted with EtOAc (400 mL) and washed with 3% HCl, water and brine. Evaporation of solvent gave 18.2 g of product. LC/MS (APCI): m/z 580.9 (M+H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 4 h

Procedure:
3,5-Dichlorobenzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (step 1) (3.53 g, 8.75 mmol) was dissolved in DCM (20 ml). 4M HCl in dioxane (22 ml, 88 mmol) was added which resulted in the formation of a white solid. After gas evolution ceased, DCM (20 ml) was added and the reaction mixture was stirred vigorously for 4 hrs. The resulting mixture was filtered and the white solid was dried in a vacuum oven under reduced pressure to afford the title compound as a hydrochloride salt;
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH:16]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH:16]=[N:19][OH:20])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1onc(-c2ccccc2)c1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 80 °C
Yield: 86.7 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbaldehyde (Intermediate I-12B, 0.38 g, 1.576 mmol) in ethanol (5 mL) were sequentially added hydroxylamine hydrochloride (0.131 g, 1.891 mmol) and sodium acetate (0.155 g, 1.891 mmol) at room temperature. The reaction mixture was heated at 80° C. for 20 min. The reaction mixture was concentrated and water (10 ml) was added. A pale yellow solid separated out from solution, and was filtered, washed with water (2×5 mL) and dried overnight to yield 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbaldehyde oxime (0.35 g, 1.366 mmol, 87% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (br. s., 1H) 8.32 (s, 1H) 7.62-7.67 (m, 2H) 7.47-7.57 (m, 3H).
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][O:10][C:11](=[O:16])[C@H:12]([CH2:14][OH:15])[NH2:13].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:16])[CH:12]([NH:13][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][OH:15]
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of Et3N (13.4 mL, 96.78 mmol) in CH2Cl2 (40 mL) was added to a solution of L-serine methyl ester hydrochloride (5.0 g, 32.26 mmol) and Ph3CCl (13.5 g, 48.39 mmol) in CH2Cl2 (129 mL) at 0° C. under N2 atmosphere. The reaction was then allowed to warm to room temperature and was stirred overnight. The reaction was quenched with saturated NaHCO3, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried and concentrated, the residue was purified by silica gel column chromatography which gave the title compound as a colourless solid (11.41 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:15]=1[NH:16][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:12]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: COc1ccc(O)c(C(=O)O)c1
Product: COc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)ccc2Cl)c1
Yield: 56.4 %

Procedure:
Using 5-methoxysalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1Br.[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: NC(=O)c1ccc(N)c(Br)c1
Reactant: OB(O)C1=CCCCC1
Product: NC(=O)c1ccc(N)c(C2=CCCCC2)c1
Yield: 76 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 4-amino-3-bromo-benzamide (as prepared in the previous step, 500 mg, 2.32 mmol), and cyclohexane-1-enyl boronic acid (322 mg, 2.56 mmol). The mixture was purified by trituration with DCM to afford the title compound (382 mg, 76%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H16N2O, 217.1 (M+H), found 217.2.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([CH3:16])[CH:9]2[O:14][CH3:15].[C:17]([OH:20])(=O)[CH3:18]>C1COCC1>[CH3:15][O:14][CH:9]1[C:10]2[C:6](=[C:5]([CH2:4][CH2:3][C:17]3([OH:20])[CH2:18][C:13]4[C:5](=[CH:6][CH:10]=[CH:11][CH:12]=4)[CH2:4]3)[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH:8]1[CH3:16]
Reactant: COC1c2cccc(CCBr)c2CC1C
Reactant: CC(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: COC1c2cccc(CCC3(O)Cc4ccccc4C3)c2CC1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2.26 g (93.0 mmol) of magnesium turnings in 20 ml of THF a solution of 16.7 g (62.0 mmol) of 4-(2-bromoethyl)-1-methoxy-2-methylindane in 80 ml of THF was added dropwise at reflux. The resulting mixture was additionally refluxed for 1 h, and then this Grignard reagent was titrated. To a suspension of 10.9 g (44.1 mmol) of anhydrous CeCl3 in 160 ml of THF 100 ml (44.1 mmol) of 0.441 M solution of the Grignard reagent was added at vigorous stirring for 15 min at 0° C., and then the reaction mixture was stirred at this temperature for 1.5 h. Further on, 5.83 g (44.1 mmol) of indanone-2 was added at 0° C. This mixture was stirred overnight at room temperature, and then 300 ml of 10% acetic acid was added. The product was extracted by 3×100 ml of ether. The combined extract was washed by brain and aqueous Na2CO3. The organic layer was separated, dried over Na2SO4, and evaporated to dryness. The title product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 50 mm, l 300 mm, eluent: hexanes/ether=3/1). Yield 10.7 g (75%) of a one diastereomer (as the starting material was one pure diastereomer).