Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][OH:34].O1CCCC1>O>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][O:34][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:4][N:3]=1
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2ccccn2)cc1Cl
Reactant: OCc1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2nc(OCc3ccccn3)ncc2C(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine (prepared in Example 90-(3)) 110 mg, 2-pyridinemethanol 34 mg, 10% sodium hydride 12 mg and tetrahydrofuran 3 ml is stirred at room temperature for 5 minutes. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent: ethyl acetate) and triturated with ethyl ether to give 2-(2-pyridylmethoxy)-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine, 104 mg. mp 81–84° C., MS(m/z): 462(M+H)+
Reaction SMILES: C([S:8][CH2:9][C:10]1([CH3:21])[CH2:14][CH2:13][N:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:11]1=[O:20])C1C=CC=CC=1.O1CCCC1.N.[Na]>CO>[SH:8][CH2:9][C:10]1([CH3:21])[CH2:14][CH2:13][N:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:11]1=[O:20]
Reactant: C[C@@H](C(=O)O)N1CCC(C)(CSCc2ccccc2)C1=O
Agent: N
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)N1CCC(C)(CS)C1=O

Procedure:
Two grams of (αS)-3-(benzylmercaptomethyl)α,3-dimethyl-2-oxo-1-pyrrolidineacetic acid were dissolved in about 15 ml. of tetrahydrofuran. This solution was then added to liquid ammonia. Small pieces of sodium metal were added until a blue color persisted. The reaction was then quenched by the addition of about two grams of ammonium chloride. The ammonia was evaporated and water was added to the residue. The slurry was made acidic with hydrochloric acid, saturated with sodium chloride and the acidic solution was extracted with chloroform. The chloroform extract was washed with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. Two crystallizations of the resulting solid from diethylether/Skelly B gave 0.5 g. of the desired title product, m.p. about 132°-133° C. [α]D25 =-23.78° (c=1, methanol).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([NH:21][C:22]2[O:23][CH:24]=[C:25]([C:27]([N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]3[CH2:42][O:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[O:28])[N:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[ClH:1].[ClH:1].[C:15]1([NH:21][C:22]2[O:23][CH:24]=[C:25]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH:30]3[CH2:42][O:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[O:28])[N:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Nc3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1coc(Nc2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 83 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-(phenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (64.8 mg, 0.109 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 41 mg (83%) of the title compound as a white solid. LC-MS: RT=3.29 min, [M+H]+=380.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Mg].Br[C:14]1[O:18][CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=1.C([Li])(C)(C)C.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1.CCCCC>[OH:20][CH:19]([C:16]1[CH:15]=[C:14]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: C[Si](C)(C)Cl
Reactant: O=Cc1coc(Br)c1
Agent: [Li]C(C)(C)C
Agent: [Mg]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
A mixture of 1-bromodecane (2.83 g, 13 mmol) and magnesium turnings (322 mg, 13.5 mmol) in THF (10 ml) was refluxed under argon for 60 min. After cooling to 0°, a solution of 5-bromo-3-furaldehyde (2.24 g, 13 mmol) in tetrahydrofuran (3 ml) was added and conditions maintained for 20 min. The mixture was further cooled to -78° and tert-butyl lithium (a 1.7M solution in pentane; 9.04 ml, 15.4 mmol) was added dropwise, followed by chlorotrimethylsilane (4.88 ml, 38.4 mmol) after 20 min. Stirring was continued overnight (12h) while the cooling bath attained room temperature. The mixture was quenched with saturated aqueous ammonium chloride, diluted with water (15 ml) and extracted with ether. Evaporation of the dried (magnesium sulfate) extract gave a brown oil, which was flash chromatographed on silica using 15% ethyl ether/petroleum ether. Fractions with about Rf 0.22 on evaporation gave the title compound as a yellow oil.
Reaction SMILES: O1CCN(CC[N+]#[C-])CC1.[C:11]([C@H:14]([C@@H:26]([CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[CH2:15][N:16]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH3:24])[C:17]1=[O:25])([OH:13])=O.[OH:41][N:42]1C=CC=CC1=O.C[Si](C)(C)ON>C(Cl)Cl>[CH:36]1([CH2:35][C@H:26]([C@@H:14]([C:11](=[O:13])[NH:42][OH:41])[CH2:15][N:16]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[N:18]([CH3:24])[C:17]2=[O:25])[C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:28])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reactant: O=c1ccccn1O
Agent: C[Si](C)(C)ON
Agent: [C-]#[N+]CCN1CCOCC1
Solvent: ClCCl
Product: CN1C(=O)N(C[C@H](C(=O)NO)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
0.78 g of 2-morpholino-ethyl isocyanide was added to a suspension of 2.11 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX) from Example 5 or 6 and 0.61 g of N-hydroxy-2-pyridone in 21 ml of methylene chloride at 22° and the mixture was stirred for 3 hrs. The solution was treated with 0.58 g of O-trimethylsilyl-hydroxylamine and stirred for 2 hrs. The reaction mixture was washed with saturated NaHCO3 solution and with water and evaporated. The residue was dissolved in 20 ml of tert-butyl methyl ether and 0.23 ml of water, stirred at 22° for 11/2 hrs., the suspension was diluted with 10 ml of hexane, filtered and the residue was dried at 22°/11 mbar, there being obtained 1.82 g (83%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (X), MS (EI): 436 (40%).
Reaction SMILES: Cl.[CH3:2][N:3](C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2C=NN1.CN>O1CCCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:3][CH3:2])=[O:24])=[CH:17][CH:16]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CN
Agent: Cl
Agent: ON1NN=Cc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.60 g) was added to a stirred suspension of (4-methoxyphenyl)acetic acid (0.50 g) and 1-hydroxybenzotriazine hydrate (0.40 g) in 10 mL tetrahydrofuran. The mixture was stirred for 30 min, then methylamine (2.0 M in THF, 6.0 mL) was added. Stirring was continued for 12 h and the volatile material was subsequently evaporated. The crude residue was dissolved in 50 mL of EtOAc and washed twice with 50 mL of 1 M hydrochloric acid, twice with 50 mL of saturated sodium bicarbonate, and twice with 50 mL of saturated sodium chloride. Evaporation of the ethyl acetate gives 0.45 g of 2-(4-methoxyphenyl)-N-methylacetamide.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.S(Cl)(Cl)=O>O>[NH2:6][C:7]1[N:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][N:8]=1
Reactant: Nc1ncccn1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: Nc1ncc(S(=O)(=O)Cl)cn1
Temperature: 0 °C
Yield: 27.4 %

Procedure:
21 ml (0.316 mol) of chlorosulfonic acid was cooled in ice-water and 3 g (0.032 mol) of 2-aminopyrimidine was added thereto little by little under stirring. 9.2 ml (0.126 mol) of thionyl chloride was further added thereto, followed by stirring at 150° C. for 70 hours. The reaction solution was returned to room temperature, poured into water and extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated to dryness, to give 1.7 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and (3R,4S)-pyrrolidine-3,4-diol (313 mg, 3.03 mmol) in a mixture of DIPEA (0.883 mL, 5.06 mmol) and iPrOH (2.53 mL) was subjected to MW irradiation at 140° C. for 30 min. The RM was treated with 0.5 M aq. HCl (30 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3, brine and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=462.1-464.0 [M+H]+, m/z=460.1-462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.61 (dd, J=11.13, 4.28 Hz, 2H) 3.84 (dd, J=10.76, 4.89 Hz, 2H) 4.10 (d, J=3.42 Hz, 2H) 4.96 (d, J=3.91 Hz, 2H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=8.80 Hz, 2H) 8.34 (s, 1H) 8.67 (s, 1H) 10.21 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][C:12](Cl)=[O:13].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>O1CCCC1>[Br:9][CH2:10][CH2:11][C:12]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH:5]1[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)=[O:13]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COc1ccncc1
Reactant: O=C(Cl)CCBr
Agent: Cl
Solvent: C1CCOC1
Product: O=C1C=CN(C(=O)CCBr)C(c2ccc(F)cc2)C1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxypyridine (3.0 g) in tetrahydrofuran (50 mL), 4-fluorophenylmagnesium bromide (1 M solution in tetrahydrofuran; 27.5 mL) was added dropwise at −40° C. to −20° C. over 10 minutes. To this solution, 3-bromopropionyl chloride (2.77 mL) was added dropwise at −40° C. to −20° C., and the reaction solution was stirred at −20° C. for 30 minutes. The reaction solution was poured into a 10% hydrochloric acid solution, and the mixture was stirred for 20 minutes, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 2.9 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:4][CH:3]=1.S1C=CC=[CH:25]1.[H][H]>CO.[Pt]>[CH3:1][C:2]1[O:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: [H][H]
Reactant: Cc1ccc(Cn2c(NC3CCNCC3)nc3cccnc32)o1
Agent: [Pt]
Agent: *CO*
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCN(C)CC3)nc3cccnc32)o1
Yield: 14.3 %

Procedure:
A mixture of 2 parts of poly(oxymethylene), 4.5 parts of 3-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 1 part of a solution of thiophene in methanol 4% and 120 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 0.7 parts (14.3%) of 3-[(5-methyl-2-furanyl)methyl]-N-(1-methyl-4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine; mp. 131.0° C. (compound 1).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=2)[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18].C([O-])(O)=O.[Na+]>CO>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=2)[C:9]([NH:17][OH:18])=[NH:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NO
Reactant: COc1cc(C#N)cc(C2CCCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=N)NO)cc(C2CCCC2)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 113.1 %

Procedure:
To a solution of 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g, 10.3 mmol) in methanol (100 mL), hydroxylamine hydrochloride (2.15 g, 31.0 mmol) and NaHCO3 (3.04 g, 36.2 mmol) are added. The mixture is stirred at 60° C. for 18 h before it is filtered and the filtrate is concentrated. The residue is dissolved in EA (300 mL) and washed with water (30 mL). The washings are extracted back with EA (4×100 mL) and DCM (4×100 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried under HV to give the title compound (2.74 g) as a white solid; LC-MS**: tR=0.47 min, [M+1]+=236.24; 1H NMR (D6-DMSO): δ 1.61-1.82 (m, 6H), 1.92-2.01 (m, 2H), 3.04-3.13 (m, 1H), 3.84 (s, 3H), 5.90 (s, 2H), 6.86 (s, 1H), 7.13 (s, 1H), 9.91 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[CH2:28][C:29](=[O:31])[CH3:30]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:28][C:29](=[O:31])[CH3:30])[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c([N+](=O)[O-])cc23)C1
Yield: 35.6 %

Procedure:
Prepared by the method described for example 26 from 1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.008 moles), triethylamine (2.3 ml, 0.017 moles), and 1-chloro-2-propanone (0.7 g, 0.008 moles). Recrystallization from methanol gave the product (0.9 g), mp 166°-168° C.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8](O)=[C:9]([C:11]2(C3C=CC=CC=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])[CH:10]=1)(C)(C)C.C1([Mg]Br)C=CC=CC=1.N1C2C(=CC=CC=2)C(=O)C1=[O:38]>C1COCC1>[OH:38][C:11]1([C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:10]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)(C)c1ccc(O)c(C2(c3ccccc3)C(=O)Nc3ccccc32)c1
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
As another non-limiting example, 3-(5-tert-butyl-2-hydroxy-phenyl)-3-phenyl-1,3-dihydro-indol-2-one (compound 1181) was synthesized by adding dropwise a 1M solution of phenylmagnesiumbromide (0.33 mole) to isatin (15 g, 0.1 mole) in 60 mL THF at 0° C. The resulting mixture was allowed to warm to room temperature and let stir at room temperature for 12 hours. The reaction mixture was quenched with a saturated solution of NH4Cl (100 mL) and diluted with 100 mL of dichloromethane. The layers were separated, the organic layer was washed with water followed by brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to yield 20.1 g (90%) of 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one. A mixture of the above solid (2.5 g, 10 mmole), p-t-Bu-phenol (1.5 g, 10 mmol), p-toluenesulfonic acid (3 g) in 40 mL dichloroethane, was heated to 95° C. for six hours. The mixture was cooled and filtered. The filtrate was concentrated in vacuo to yield 2.4 g (66%) of the desired product (compound 1181).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.Cl([O-])(=O)(=O)=O.[CH2:22]1[C:29]2[CH2:28][CH2:27][CH2:26][N+:25]=2[CH2:24][CH2:23]1.Cl>C1COCC1.CCOC(C)=O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:29]23[CH2:28][CH2:27][CH2:26][N:25]2[CH2:24][CH2:23][CH2:22]3)[CH:8]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Brc1cnc2ccccc2c1
Agent: Cl
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc2ncc(C34CCCN3CCC4)cc2c1
Temperature: -100 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A solution of 2.5M nBuLi (1.2 mL, 2.8 mmol) in hexanes was added to 3-bromoquinoline (386 μL, 2.8 mmol) in THF (10 mL) at -100° C. followed immediately by 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (200 mg, 0.9 mmol). The reaction mixture was allowed to stir for 2 hours at -100° C. and then 2N HCl was added at 0° C. After warming to ambient temperature, the mixture was poured over EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (3×). The organic fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; EtOAc) to afford a pale solid (104 mg, 46%). mp 80°-83° C. MS (CI/NH3) m/e: 239 (M+H)+. 1 H NMR (CDCl3, 300 MHz) δ1.61-1.75 (m, 2H), 1.83-1.94 (m, 2H), 2.03-2.17 (m, 4H), 2.71-2.80 (m, 2H), 3.20-3.27 (m, 2H), 7.52 (ddd, J=7.0, 7.0, 1.1 Hz, 1H), 7.65 (ddd, J=7.0, 7.0, 1.5 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.32 (d, J=2.2, Hz, 1H), 8.97 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:34])[N:10]([CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:11]2=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:34])[N:10]([CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:11]2=[O:16])(=[O:4])=[O:3]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)ccc1OC
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (0.3 g, 2.62 mmol) was added to a stirred suspension of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl]isoindoline-1,3-dione (0.55 g, 1.31 mmol) and triethylamine (0.4 g, 3.93 mmol) in methylene chloride (60 mL) and the resulting mixture stirred for 24 hours. The mixture was then washed with sat. Sodium bicarbonate (25 mL), 1N hydrogen chloride (25 mL), H2O (25 mL), brine (25 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was slurried in methanol:tetrahydrofuran (2:1) to give after isolation by filtration 4-[bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione (0.53 g, 70%) as a white solid: mp 277-279° C.; 1H NMR (DMSO-d6) δ 8.05-7.95 (m, 3H), 7.11-6.92 (m, 3H), 5.78-5.74 (dd, J=5.5, 9.1 Hz, 1H), 4.31-4.22 (m, 2H), 3.99 (q, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.55 (s, 6H), 2.95 (s, 3H), 1.31 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 166.11, 165.35, 148.96, 147.88, 138.63, 136.05, 132.60, 129.64, 129.31, 129.27, 125.26, 119.89, 112.33, 111.76, 63.73, 55.46, 53.38, 47.92, 43.50, 43.44, 41.15, 14.61; Anal. Calcd. for C22H26N2O10S3: C, 45.95; H, 4.56; N, 4.87; S, 16.74. Found: C, 45.90; H, 4.40; N, 4.75; S, 16.55.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:6]=1[CH2:7][N:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[N:10]=[CH:9]1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:29]=1[CH2:30]Br.CN(C)C=[O:41]>>[CH3:3][O:4][C:5]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:6]=1[CH2:7][N:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([O:19][CH2:30][C:29]3[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:28]=3[O:27][CH3:26])=[CH:15]2)=[N:10][C:9]1=[O:41]
Reactant: COc1cccc(OC)c1Cn1cnc2ccc(O)cc2c1=O
Reactant: CN(C)C=O
Reactant: COc1ccc(OC)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(OC)c(COc2ccc3nc(=O)n(Cc4c(OC)cccc4OC)cc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
12 mg of sodium hydride (80% in mineral oil) are added to a solution of 115 mg of 3-(2,6-dimethoxybenzyl)-6-hydroxy-3H-quinazolin-4-one in 10 ml of dry dimethylformamide. After stirring for 30 minutes at room temperature, 85 mg of 2,5-dimethoxybenzylbromide are added, and stirring is continued overnight. The solvent is distilled off in vacuo, and the residue partitioned between aqueous pH7-buffer solution and ethyl acetate. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo. The pure title compound is obtained after silica gel chromatography (toluene/ethyl acetate=2/1) as colourless crystals. mp: 148-150°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C1(C)C=CC=CC=1.N1CCCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:12](\[C:10]#[N:11])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(C#N)=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 4-bromobenzaldehyde (106 g, 573 mmol) in toluene (1000 mL) were added ethyl 2-cyanoacetate (71.3 g, 630 mmol) and piperidine (976 mg, 11.5 mmol) and the clear, light brown solution was heated at reflux for 5 h in a 4-neck flask equipped with a Dean-Stark trap, then stirred overnight at room temperature. After cooling the reaction mixture was evaporated, the residue suspended in heptane (500 mL), homogenized in an ultrasound bath for min, stirred for 20 min at 50° C., then the precipitate was collected by filtration. This was dissolved in ethyl acetate (1000 mL) and heptane (500 mL), then slowly concentrated at 50° C. to a volume of approximately 300 mL of solvent. This solution started to crystallize upon standing. The precipitate (96 g) was collected by filtration and washed with heptane/ethyl acetate 9:1 (300 mL). The mother liquor was concentrated at 50° C. until crystallization started. The product was allowed to precipitate over 1 h at room temperature, then collected by filtration to produce a second crop of product (44 g). Total yield: 140 g (87%). Light yellow solid, MS: 299.1 [M+H]+.