Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:19][CH:18]=2)[CH2:8][CH2:7][C:6]1=[O:40])([OH:3])=[O:2].[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44]O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][O:2][C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:39])[C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:21][CH:22]=2)[CH2:8][CH2:7][C:6]1=[O:40])=[O:3]
Reactant: CN(C)CCO
Reactant: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(=O)N(CC(=O)O)c3ccccc32)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(=O)N(CC(=O)OCCN(C)C)c3ccccc32)cc1
Reaction time: 30 h
Yield: 34.5 %

Procedure:
To a solution of 1-carboxymethyl-5-{4-[2-(2-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (220 mg), 2-dimethylaminoethanol (37 mg) and 4-dimethylaminopyridine (10 mg) in dichloromethane (5 ml) were added dicyclohexylcarbodiimide (102 mg) at ambient temperature and the mixture was stirred at the same temperature for 30 hours. The resulting mixture was washed with saturated sodium bicarbonate aqueous solution. Drying over magnesium sulfate, filtering and the removal of solvents afforded a crude product. The crude product was purified by silica gel column (3% methanol in chloroform). The solvent was evaporated in vacuo and the residue was solidified with diethyl ether to give 1-[(2-dimethylaminoethoxy)carbonylmethyl]-5-{4-[2-(2-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (86 mg) as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 220.3 %

Procedure:
A solution of 150 mg (0.426 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde in 2 ml THF is treated with excess phenylmagnesiumbromide (prepared from 112 μl bromobenzene and 26 mg magnesium in 5 ml diethyl ether). The resulting mixture is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:2) to afford 136 mg of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14]Br)([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][N:27]1[CH2:26][CH2:25][N:24]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=2)[CH2:29][CH2:28]1)([O-:3])=[O:2]
Reactant: O=C(CCBr)Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCN1CCN(c2ccc(F)cc2)CC1)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
A mixture of 14.8 gm of N-(2-nitro-4-fluorophenyl)-3-bromo-propionamide, 9.0 gm of 1 -(4-fluoro-phenyl)-piperazine, 6.46 gm of diisopropylethylamine and 150 ml DMF was kept for 48 hours at 150° C. Water (300 ml) was added at ambient temperature and the mixture was extracted with CHCl3. The CHCl3 extract was collected, washed with 20 ml water and dried over Na2SO4. The crude product obtained after removing the solvents was purified by using chromatography: solid phase (SIO2 ; 40 μm; Baker); eluent CHCI3. A sample of this purified material (12.7 gm) exhibited the following data. M+/z of 405.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>C(O)(=O)C.Cl.O.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)C(=NNc1cccc(C)c1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 3-methylaniline (1000 mg, 9.34 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(3-methylphenyl)hydrazono]pentane-2,4-dione (500 mg, yield 24%). LCMS: m/z=219 [M++H].
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH2:24])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH2:16][C:13]2[N:11]3[N:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=2)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]=[CH:25]1
Reactant: Nc1cnccc1NCc1nnc2ccc(-c3ccccc3)nn12
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1ccc(-c2ccc3nnc(Cn4cnc5cnccc54)n3n2)cc1
Temperature: 60 °C

Procedure:
A mixture of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0650 g, 0.20 mmol), triethyl orthoformate (5.0 ml, 30 mmol), and p-TsOH (0.0039 g, 0.020 mmol) was heated at 60° C. After 2 h reaction is complete. Reaction was concentrated. Took up in DMSO and purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate and volatiles removed. Collected product by filtration. MS m/z=328.1 [M+1]+. Calc'd for C18H13N7: 327.3.
Reaction SMILES: Cl[C:2]1([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:7])[CH:5]=[CH:4][S:3]1.S(=O)(=O)(O)O.[C:17](O)(=O)C>>[OH:7][C:6]1[CH:5]=[C:4]([CH3:17])[S:3][C:2]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)O
Reactant: COC(=O)C1(Cl)SC=CC1=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc(C)cc1O

Procedure:
To a stirred suspension of 2-chloro-2-methoxycarbonylthiophen-3(2H)-one (6.35 g, 33 mmol) in acetic acid (20 ml) was added sulphuric acid (1.8 ml) in acetic acid (20 ml). The mixture was stirred until dissolved then methyl mercaptan was bubbled through for 0.5 hours (total approximately 2 g). The mixture was stirred at room temperature for 18 hours, poured onto ice-water and the oily precipitate extracted into dichloromethane. After evaporation of solvent the crude oil was used in the following preparation.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:6]([O:8]C)=[O:7]>O.CO>[CH3:3][O:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A solution of potassium hydroxide (2.0 g, 35.9 mol) in water (25 ml) was added to a stirred solution of methyl 2-methoxy-3-(3-nitrophenyl)acrylate (8.1 g, 34.2 mmol) in methanol (150 ml) and the resulting mixture was stirred at RT overnight. A further quantity of KOH (0.5 g, 8.9 mmol) in water (10 ml) was added and the mixture heated to 80° C. for 1 hr. The methanol was then evaporated in vacuo and the residue diluted with water (200 ml). The solution was washed with dichloromethane (2×100 ml), filtered through a pad of celite and then acidified by the addition of 3M HCl to pH 3. The mixture was refrigerated for 18 h then the precipitated solid was collected by filtration, washed with water (3×30 ml) and dried in vacuo at 40° C. to give 2-methoxy-3-(3-nitrophenyl)acrylic acid as a yellow solid (6.4 g, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 85.9 %

Procedure:
3-nitrophthalic anhydride (0.79 g, 0.0041 mol) and p-aminobenzoic acid (0.56 g, 0.0041 mol) were refluxed as above overnight. Concentration of the solution under vacuum by rotary evaporator and crystallisation of the product from EtOH/H2O yielded 1.1 g (68%) of 125 as a vibrant light yellow powder: mp=338-340° C.; Rf0.76 (A): Rf0.89 (C): Rf0.66 (D): IR (cm−1): 2750-3125 (OH), 3091 (C═CH), 2671 (C—H), 1782 (C═O), 1736 (C═O), 1693 (C═O), 1610 (C═C), 1585 (C═C), 1529 (N═O), 1513 (C═C), 1433 (C═C), 1378 (C—O), 1360 (N═O), 1291 (C—O), 766 (C═CH); MS m/z (rel intensity) 311 (100), 267 (25), 191 (15).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:31]=2[N:32]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1.FC(F)(F)C([O-])=O>>[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[S:29][C:30]=2[CH:36]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(CCN(C)C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Agent: O=C([O-])C(F)(F)F
Product: CN(C)CCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1)C(=O)O
Yield: 16.3 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-[2-(dimethyl-amino)ethyl]-4-oxobutanoate (60 mg, 0.17 mmol) and 2,6-dichloro-1,3-benzothiazole (51.8 mg, 0.25 mmol) ) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 14.1 mg (13%) of the desired product as the trifluoroacetate salt. 1H NMR (400 MHz, CD3OD) δ 8.10 (d, 2H), 7.70-8.10 (m, 8H), 7.30 (m, 1H), 3.60 (m, 1H), 3.30-3.40 (m, 3H), 3.10 (m, 1H), 2.95 (s, 6H), 2.20 (m, 1H), 2.00 (m, 1H). LC-MS m/z 508.1 (MH+), ret. time 2.66 min.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH3:7])=[CH:3]\[CH2:4][OH:5].[CH3:8][C:9]([CH2:13]CC=CCCC=CC)=[CH:10]CO>>[CH3:1]/[C:2](/[CH2:6]/[CH:7]=[CH:10]/[C:9]([CH3:13])=[CH2:8])=[CH:3]\[CH2:4][OH:5]
Reactant: CC/C(C)=C/CO
Reactant: CC=CCCC=CCCC(C)=CCO
Product: C=C(C)/C=C/C/C(C)=C/CO

Procedure:
(2E, 6E, 10E)-3-methyl-2,6,10-dodecatrien-1-ol;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[C:18](=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](I)[CH3:25]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:24][CH3:25])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: CCI
Reactant: Cc1c(NC2CCCC2)cc(Br)cc1C(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCCC1
Temperature: 80 °C
Yield: 32 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentylamino)-2-methylbenzoate (2 g, 6.43 mmol) in DMF (15 mL), cesium carbonate (4.18 g, 12.8 mmol) and ethyl iodide (5.01 g, 32.15 mmol) were added; the resulting reaction mixture was heated at 80° C. for 18 h. On completion, the reaction mixture was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound, which was purified by column chromatography at afford methyl 5-bromo-3-(cyclopentyl(ethyl)amino)-2-methylbenzoate (0.7 g, 32.1%).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[N:25]1[C:34]2[C:29](=[C:30]([NH:35]N)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:29]=4[CH:28]=[CH:27][CH:26]=[N:25]5)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1cccc2ncccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=432.2 (M+H)+
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:19]=1[C:20]([N:8]1[C:9](=[O:10])[C:4]2=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]1=[O:7])=[O:21]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1cc(Cl)cc(Cl)c1Cl)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(2,3,5-trichlorobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Mg+2].[Cl-].[CH2:15]=[O:16].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]=[O:16])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C=O)c1O
Yield: 90 %

Procedure:
To a stirred suspension of 2-tert-butylphenol (6)(4.55 g, 30 mmol), magnesium chloride (5.71 g, 60 mmol) and paraformaldehyde (2.08 g, 66 mmol) in THF (120 mL) at room temperature, was added triethylamine (8.35 mL, 60 mmol) dropwise. The reaction was heated to reflux for 3 hours to give an orange suspension. The crude was extracted using EtOAc (3×50 mL). A small amount of diluted HCl can be added if a permanent emulsion is formed. The organic layers were dried over MgSO4 and the volatiles evaporated under low pressure to yield a pale yellow oil which did not need any further purification. It can become dark green on storage. Yield: 90%. Pale yellow oil. 1H-NMR δH (CDCl3, 300 MHz): 1.44 (9H, s, 3×CH3), 6.97 (1H, t, J=7.5 Hz, HAr), 7.41 (1H, dd, J=1.5 Hz, J=7.5 Hz, HAr), 7.54 (1H, dd, J=1.2 Hz, J=7.5 Hz, HAr), 9.88 (1H, s, CHO), 11.82 (1H, s, OH).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[O:6]=[C:7]1[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=[C:9]([C:16]([F:19])([F:18])[F:17])[NH:8]1.[ClH:20]>ClCCCl.N1C=CC=CC=1>[Cl:20][C:10]1[CH:11]=[C:12]([C:13]([NH2:15])=[O:14])[C:7](=[O:6])[NH:8][C:9]=1[C:16]([F:17])([F:19])[F:18]
Reactant: NC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Reactant: Cl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: NC(=O)c1cc(Cl)c(C(F)(F)F)[nH]c1=O

Procedure:
At room temperature, 0.39 g (2.9 mmol) of sulfuryl chloride was added to 300 mg (1.46 mmol) of 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide in 5 ml of 1,2-dichloroethane and 2.3 g (0.25 ml) of pyridine, and the mixture was then heated under reflux for 2 h. The mixture was then added to 0.5N hydrochloric acid. The organic phase was removed and then dried and concentrated, which gave 144 mg (41% of theory) of a brownish powder.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]([O:14][CH3:15])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[SH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(Cl)Cl.O>[CH3:15][O:14][C:6]1[C:7]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]=2[C:3]([CH2:2][S:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CO)c2c1OC(C)(C)C2
Reactant: Sc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CSc2ccncc2)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Compound 48a (2.0 g) obtained in Step A was dissolved in methylene chloride (100 ml), and then diisopropylethylamine (5.0 ml) and methanesulfonyl chloride (0.8 ml) were added thereto, followed by stirring at room temperature for one hour. At the same temperature, 4-mercaptopyridine (1.4 g) was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 48 (1.4 g, 48.3%) as colorless crystals.
Reaction SMILES: ClC1C=CC([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.BrC[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:31])([F:32])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[CH:13][N:12]=1
Reactant: Fc1cccc(CBr)c1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2cccc(F)c2)cn1

Procedure:
Compound 3 was prepared in a similar manner to compound 1 from 1-(bromomethyl)-3-fluorobenzene to afford a syrup (0.02 g, 0.04 mmol, 15.5%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.52 (t, J=3.5 Hz, 2H), 7.40-7.26 (m, 3H), 7.17 (d, J=9.5 Hz, 1H), 7.12-7.04 (m, 2H), 6.77-7.6.75 (m, 1H), 6.66 (t, J=9.0 Hz, 1H), 5.56 (d, J=14.0 Hz, 1H), 5.12 (s, 2H), 5.06 (d, J=14.5 Hz, 1H). MS(ESI): m/z 478.2 [M++1]. HPLC: 99.49%.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>O>[O:16]1[CH2:15][CH:14]1[CH2:12][O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9]
Reactant: Cc1occc(=O)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1occc(=O)c1OCC1CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 3-hydroxy-2-methyl-4-oxopyrane (12.6 g), sodium hydroxide (4 g), epichlorohydrin (9.25 g) and water (50 ml) is stirred at room temperature, under nitrogen atmosphere, for 3 hours; then it is extracted four times with chloroform (120 ml) and the organic extracts are combined, washed with water, dried and evaporated to dryness yielding 8.3 g of 3-(2,3-epoxypropoxy)-2-methyl-4-oxopyrane. A mixture of said product and 2-aminotetralin (7.3 g) in absolute ethanol (100 ml) is charged into a sealed vessel, heated to 80° C. for 5 hours, then cooled and evaporated under reduced pressure. The obtained residue is dissolved into ethyl acetate and a solution of fumaric acid in ethyl acetate is then added thereto. The precipitate which forms is recovered by filtration and crystallized from ethanol affording N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-methyl-4-oxopyran-3-yloxy)propanamine hydrogenfumarate ((i): R=H, Ar=radical 10 wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH:2]=[CH2:3].[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)[CH3:19]>>[CH2:1]([C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:18][CH3:19])=[O:34])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)[CH:5]=1)[CH:2]=[CH2:3]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: C=CCc1cc(C=O)cc2c1OC(C)C(=O)N2
Product: C=CCc1cc(CN2CCN(c3ccc(C(=O)NCC)cc3)CC2)cc2c1OC(C)C(=O)N2

Procedure:
Using 356A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.39 (d, J=6.82 Hz, 3H) 2.43-2.49 (m, 4H) 3.18-3.29 (m, 6H) 3.30-3.32 (m, 2H) 3.39 (s, 2H) 4.61 (q, J=6.82 Hz, 1H) 5.01-5.07 (m, 2H) 5.93 (m, J=16.86, 10.17, 6.57, 6.57 Hz, 1H) 6.77 (d, J=2.02 Hz, 1H) 6.73 (d, J=2.02 Hz, 1H) 6.92 (m, 2H) 7.71 (m, 2H) 8.18 (t, J=5.56 Hz, 1H) 10.60 (br. s., 1H). ESI-MS: m/z 449.4 (M+H)+.