Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O.[CH3:9][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11]>>[C:4]1(=[O:6])[O:8][C:1](=[O:7])[CH:2]=[CH:3]1.[CH3:11][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:9]
Reactant: O=C(O)/C=C\C(=O)O
Agent: C=C(C)CC(C)(C)C
Product: O=C1C=CC(=O)O1

Procedure:
Type A is the ammonium salt of a copolymer of maleic acid and 2,4,4-trimethylpent-1-ene obtained by ammoniacal hydrolysis of a copolymer of maleic anhydride and 2,4,4-trimethylpent-1-ene. Latter copolymer is obtainable in accordance with Example 3 of EP-A 9169. Instead of isolating the unhydrolyzed copolymer by spray drying as in Example 3 of EP-A 9169, 325 parts of water are added to the suspension and excess diisobutene is distilled off by steam distillation (bath temperature 80° C.). When an internal temperature of 98° C. is reached, steam is passed in for a further 1 h. Following the addition of a further 200 parts of water and 170 parts of 25% strength by weight ammonia, the mixture is stirred at 60° C. until a virtually clear aqueous solution is obtained (about 1 h). The solids content is then adjusted to 22% using water. The pH of the solution is 9. The K value of the copolymer (determined in accordance with Fikentscher as a 1% strength by weight solution in dimethylformamide) is in the range of 30-40.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.Cl>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Product: COc1ccc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)cn1
Yield: 94.7 %

Procedure:
A solution of 6-methoxy-N-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (95.3 mg, 228 μmol) in 2 N aqueous HCl (2.0 mL, 4 mmol) was heated briefly at 100° C. in an oil bath, and then the heater was turned off and the mixture allowed to slowly cool. The solution was concentrated and purified by SCX ion exchange chromatography washing with MeOH and eluting off with 2 N NH3/MeOH to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (72 mg, 95% yield) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 13.60 (br. s., 1H); 12.68 (s, 1H); 9.80 (dd, J=7.82, 1.96 Hz, 1H); 8.60 (s, 1H); 8.54 (d, J=2.69 Hz, 1H); 8.31 (dd, J=4.65, 1.96 Hz, 1H); 8.20 (dd, J=8.92, 2.81 Hz, 1H); 7.00 (dd, J=7.95, 4.77 Hz, 1H); 6.85 (d, J=8.80 Hz, 1H); 3.85 (s, 3H); 2.86 (s, 3H). m/z (ESI, +ve) 334.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:28](=[O:30])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:28]([OH:30])=[O:29]
Reactant: O=C=O
Reactant: Clc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of 3-chloropyridine (1.00 mL, 10.5 mmol) in THF at −78° C. was treated dropwise with a solution of lithium diisopropylamide in THF [freshly prepared by addition of butyllithium (7.21 mL, 11.5 mmol) to diisopropylamine (11.5 mmol)]. After 0.25 h, the mixture was treated with carbon dioxide (g) and slowly warmed to ambient temperature. The mixture was concentrated, partitioned between EtOAc and water, and the aqueous layer was washed with EtOAc (2×). The pH of the aqueous layer was adjusted (˜3) by addition of 1 N HCl and then washed with EtOAc (3×). The combined extracts were dried with magnesium sulfate and concentrated. The residue was recrystallized from EtOAC yielding 200 mg (12%) of 3-chloroisonicotinic acid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[C:7]([Br:23])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:33](O)C>CO.O>[Br:23][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:24])[CH:10]=[C:9]([Br:11])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]=[CH:33][NH:20][C:15]=2[CH:14]=1
Reactant: CCO
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c([N+](=O)[O-])c2)c(Br)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cc(Br)c(Oc2ccc3nc[nH]c3c2)c(Br)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
Methyl[3,5-dibromo-4-(4-amino-3-nitrophenoxy)phenyl]acetate (1 g) was dissolved in methanol (10 mL) and hot solution of sodium dithionite (6.1 g) in water (30 mL) was added. The reaction mixture was refluxed for 26 hours, ethanol (255 mL) was added and the formed precipitate filtered off through a pad of celite. The filtrate was concentrated to a constant volyme of 20 mL to which formic acid (16 mL) was added. After reflux for 4 hours, the reaction mixture was cooled down to room temperature, the formed yellow precipitate filtered off and washed with methanol. Recrystallisation from ethanol gave 0.4 g (42%) of 3,5-dibromo-4-(5-benzimidazolyloxy)phenylacetic acid. 1H-NMR (300 MHz, DMSO-d6): δ 12.55 (br s, 1H), 9.47 (s, 1H), 8.27 (s, 1H), 7.88 (d, J=3.0 Hz, 1H), 7.70 (s, 2H), 6.97 (d, J=9 Hz, 1H), 6.34 (dd, J=8.9 Hz, J=3.1 Hz, 1H), 3.68 (s, 2H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.[OH-].[Na+].O>C(Cl)Cl>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:7][C:6]2[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:4]([O:3][CH3:2])[CH:5]=2)=[CH:35][CH:34]=1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=Cc2ccc(F)cc2)cc(OC)c1
Reaction time: 5 h

Procedure:
To a solution of (3,5-dimethoxybenzyl)triphenylphosphonium bromide (300 mg, 0.6 mM), 4-fluorobenzaldehyde (133 mg, 1.07 mM), catalytic amounts of 18 crown-6 in DCM was added 1.5 mL of 50% solution of NaOH. The reaction was stirred for 5 h and water was added. The water phase was extracted with ethyl acetate and the organic phase was combined. The crude product was purified through flash chromatography eluting with hexanes/ethyl acetate (98:2).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]([CH3:7])[CH2:4][CH:3]([CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:16]1([S:22]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[C:16]1([S:22][N:1]2[CH2:6][CH:5]([CH3:7])[CH2:4][CH:3]([CH3:8])[CH2:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1CNCC(C)C1
Reactant: ClSc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1CC(C)CN(Sc2ccccc2)C1

Procedure:
In a flask, 3,5-lupetidine (22.9 parts), triethylamine (20.4 parts) and ether (200 parts) are charged, and phenylsulfenyl chloride (27.7 parts) is dropwise added thereto. The resultant mixture is stirred at 30°C for 6 hours. The reaction mixture is filtered to separate the precipitate and the filtrate is distilled to give N-phenylthio-3,5-lupetidine (36 parts by weight). B.P.; 134°C/4 mmHg. nD25 1.5511.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@@H:7]([CH3:25])[CH2:6]1)=[O:4].[OH-].[Li+].CO.Cl>O1CCCC1.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH:7]2[CH3:25])=[O:24])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OC)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2c3ccccc3C(C(=O)O)CC2C)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A round bottom flask with magnetic stirrer was charged with cis-1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (3.00 g, 8.8 mmol) in anhydrous tetrahydrofuran (70 mL). To the reaction was added a solution of lithium hydroxide (423 mg, 18 mmol) in water (24 mL), followed by methanol (24 mL). The reaction was stirred at room temperature for 18-20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (3×35 mL) and the combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and diethyl ether (50 mL) added to the resulting residue. The precipitated solid was collected via suction filtration to afford 1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid as a mixture of cis and trans-isomers (2.71 g, 95%). 1H-NMR (d6-DMSO) δ: 1.22 (d, 3H), 1.63 (ddd, 1H), 2.94 (ddd, 1H), 3.76 (s, 3H), 3.89 (dd, 1H), 4.83-4.91 (m, 1H), 6.51 (d, 1H), 6.72-6.76 (m, 2H), 6.95 (ddd, 1H), 7.11 (ddd, 1H), 7.26-7.35 (m, 3H). MS m/z=326 (M+1).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[CH2:23]([I:25])[CH3:24]>C1(C)C=CC=CC=1>[I-:25].[CH2:23]([P+:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:22])[CH3:24]
Reactant: CCI
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: CC[P+](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Product: [I-]
Temperature: 27 °C
Yield: 21.2 %

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, are charge 5 gms (0.0164 mole) of tri-o-tolylphosphine and 23 gms of toluene. The slurry is heated to 27° C. then 3.08 gms (0.0197 mole) of ethyl iodide is added. This reaction mass is heated to 70° C. and maintained for 17 hours, then heated to 100° C. and maintained for 9 hours, then cooled to 70° C. and maintained for 15 hours, then cooled to 26° C. This mixture is filtered and washed with 6 gms of toluene. After vacuum drying, 1.6 gms of ethyltri(o-tolyl)phosphonium iodide is obtained which has a melting point of 247° C. to 250° C.
Reaction SMILES: C[O-].[Na+].[C:4]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C=O)C>[CH2:11]([O:10][C:4]([C:5]1([C:6](=[O:7])[CH3:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C)=O)CCCC1
Temperature: 90 °C
Yield: 78.7 %

Procedure:
27.2 g (0.4 mol) of sodium methoxide are initially introduced into 300 ml of DMF at approx. 40° C. and stirred. A mixture of 26 g (0.2 mol) of ethyl acetoacetate and 43 g (0.2 mol) of 1,4-dibromobutane is slowly added dropwise to this suspension and the reaction mixture is stirred for approx. 24 hours at this temperature. Towards the end of the reaction, the temperature may optionally be raised to 90° C. for a further hour. The precipitated sodium bromide is filtered out, the DMF removed and the residue fractionated. 29 g (78%) of 1-acetyl-1-cyclopentanecarboxylic acid ethyl ester are obtained. Bp.: 136° C. (1500 Pa); IR: 1745 cm−1 (C═O, ester), 1713 cm−1 (C═O, ketone); MS: m/e=142 (M−42), 114, 101, 96, 86, 67, 43.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([Mg]Br)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[CH:15][CH:14]=1>O1CCCC1>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([OH:23])([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:18](=[O:22])[NH:19]2)=[CH:15][CH:14]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: CC(C)c1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: -25 °C
Reaction time: 3 h

Procedure:
A solution of 4-isopropyl-phenyl magnesium bromide in tetrahydrofuran (0.5 M, 3.3 mL, 1.65 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.2 g, 1.1 mmol) in tetrahydrofuran (5 mL) with cooling in a −25° C. bath. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 3 hours, 15% aqueous ammonium chloride solution was added and mixture extracted with ethyl acetate. The combined organic layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one as a pale yellow solid. This was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[H-].[Na+].CS(O[CH2:18][CH2:19][C:20]1([CH3:31])[O:24][C:23]2=[N:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][N:22]2[CH2:21]1)(=O)=O>CN(C=O)C>[CH3:31][C:20]1([CH2:19][CH2:18][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][C:2]2=[O:10])[O:24][C:23]2=[N:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][N:22]2[CH2:21]1
Reactant: CC1(CCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=c1[nH]c2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CCn2c(=O)oc3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A mixture of 2-benzoxazolinone (240 mg, 1.8 mmol), sodium hydride (67 mg, 1.95 mmol) and DMF (10 ml) was stirred at room temperature for 30 minutes. To the reaction mixture, 2-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-yl)ethyl methanesulfonate prepared in Example 42 (500 mg, 1.7 mmol) was added followed by stirring at 50-60° C. for 4 hours. The reaction mixture was allowed to return to room temperature and poured into ice-water. The precipitates were filtered off and recrystallized from ethanol to afford 3-[2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl]-3H-benzoxazol-2-one (320 mg, yield 56%) as a light brown powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(N(CC)CC)C>ClCCl>[CH2:14]([O:13][C:11]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl 3-aminopropionate hydrochloride (2.00 g, 13.0 mmol) was dissolved in dichloromethane (40 ml), and benzyl chloroformate (2.00 ml, 14.1 mmol) was added. With cooling with ice, triethylamine (4.00 ml, 28.9 mmol) was added, followed by stirring at room temperature for 15 hours, then the reaction, liquid was concentrated. Ethyl acetate and water were added, the organic layer was collected, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a pale yellow oil (3.26 g, quant).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:15]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCCl
Product: COc1ccc(C(=O)CCCCCl)cc1

Procedure:
Using anisole (15.0 g) and 5-chlorovaleryl chloride (18.0 ml) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (27.3 g) having a melting point of 67 to 68° C.
Reaction SMILES: COC1C=C(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])C=CC=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.C(#N)CC#N.O.[NH2:31][NH2:32]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:24][N:10]=[C:11]2[C:12]([NH2:13])=[N:32][N:31]=[C:14]2[NH2:15])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cccc(NN=C(C#N)C#N)c1
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: COc1cccc(NN=C2C(N)=NN=C2N)c1

Procedure:
4-[(3-methoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 100 mg (0.5 mmol) of 2-[(3-methoxyphenyl)hydrazono]malononitrile, which was derived from m-anisidine (112 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, recrystallized from ethanol, and dried to yield 25 mg (22%) of the compound as a brownish orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]1[CH2:15][O:14]1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:13]([C:3]1[C:4]([CH3:12])=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])(=[O:14])[CH3:15]
Reactant: Cc1cc2c(c(C)c1C1CO1)COC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)cc2c(c1C)COC2=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 20 mL microwave tube containing a stir bar were added 4,6-dimethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (from the synthesis of INTERMEDIATE 9, 1.0 g, 4.2 mmol), tetrakis(triphenylphosphine)palladium (0) (0.240 g, 0.207 mmol), and tributyl(1-ethoxy-vinyl)tin (2.20 g, 6.22 mmol); to the mixture was added anhydrous toluene (18 mL) and the tube was capped, degassed and purged with N2. The tube was then placed in an oil bath and heated at 110° C. for 12 h; LC indicated some product formation. The tube was taken out of the oil bath and cooled to room temperature. The solution was concentrated to dryness under reduced pressure and the resulting residue was then treated with 4M HCl (10 mL); the resulting solution was stirred at room temperature for 1 h; LC analysis indicated completion of the reaction. The solution was concentrated to dryness and the residue was re-dissolved in DCM, was absorbed in silica gel and was then loaded into silica column for separation with the solvent systems of Hexanes/EtOAc (1/1); this yielded 5-acetyl-4,6-dimethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5](OC)=[O:6].[CH2:11]([Mg]Br)[CH:12]=[CH2:13].C(OCC)C.[CH2:21]1[CH2:25]OC[CH2:22]1>>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][C:5]([OH:6])([CH2:25][CH:21]=[CH2:22])[CH2:11][CH:12]=[CH2:13]
Reactant: COC(=O)CC(OC)OC
Reactant: C=CC[Mg]Br
Reactant: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)(CC=C)CC(OC)OC
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In a 2 liter round bottom flask equipped with a stir bar, methyl 3,3-dimethoxypropanoate (24 g, 162 mmol) was dissolved in THF (1L). Under nitrogen, the solution was chilled to −78° C. Allyl Magnesium bromide, 1.0 M solution in diethyl ether (405 mL, 405 mmol) was added dropwise in such a way that the internal temperature remained lower than −75° C. After addition, the reaction was allowed to stir for 3 hours at −78° C. before being quenched with saturated ammonium chloride solution (300 mL). The ice bath was removed and the reaction allowed to come to RT. Water was added (200 mL) and the reaction was concentrated on a rotary evaporator to remove as much THF as possible. The product was extracted from the resulting aqueous with diethyl ether (3×200 mL). The organics were then washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to afford the product.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][C:3]1[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=[N:1][CH:2]=1
Reactant: c1cn2c(n1)CCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cnc2n1CCCC2
Yield: 25.1 %

Procedure:
375 mg of the 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-1] was dissolved in 10 mL of carbon tetrachloride, then 546 mg of N-bromosuccinimide was added, and the mixture was heated for 30 minutes under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and then by preparative thin-layer chromatography sequentially, to obtain 155 mg of 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-2] as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:14]([CH:15]([OH:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1.CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33].CN(C1C=CC=CN=1)C>C(Cl)Cl.CCOC(C)=O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[C:14]([CH:15]([O:24][C:32](=[O:34])[CH3:33])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC(CCc1ccccc1)c1cc2c(cc1C1OCCO1)OCO2
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(CCc1ccccc1)c1cc2c(cc1C1OCCO1)OCO2
Yield: 81.4 %

Procedure:
A solution of (±)-5-(1,3-dioxolanyl)-[6-(1-hydroxy-3-phenylpropyl)]-1,3-benzodioxole (Compound 12, 182 mg, 0.554 mmol), Et3N ) (0.23 mL, 1.66 mmol), acetic anhydride (78 μl, 0.832 mmol) and dimethylaminopyridine (DMAP, 33.8 mg, 0.277 mmol) in CH2Cl2 (1.0 mL) was stirred at 23° C. for 16 hours. The reaction was diluted with EtOAc and washed with 1N HCl saturated ag. Na HCO3, brine. The organic portion was dried (MgSo4), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 6:1 hex(EtOAc) gave 167 mg (82%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5]([NH2:7])=[O:6].O=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([OH:13])=[O:12].C(OC)(=O)CC(C)C>O>[CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5]([NH:7]/[C:10](=[CH:14]\[CH2:15][CH2:16][C:17]([OH:19])=[O:18])/[C:11]([OH:13])=[O:12])=[O:6]
Reactant: O=C(O)CCCC(=O)C(=O)O
Reactant: CC1(C)CC1C(N)=O
Agent: COC(=O)CC(C)C
Solvent: O
Product: CC1(C)CC1C(=O)N/C(=C\CCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of 2,2-dimethylcyclopropanecarboxamide, 2.4 g. of 2-ketoadipic acid and 25 ml. of methyl isovalerate was heated under reflux for 4 hrs, with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). After standing at room temperature overnight, the crystalline precipitate was filtered, washed with ether and recrystallized from ethyl acetate to give 0.23 g. of product, m.p. 163°-165°. The NMR spectrum was consistent with the desired structure.
Reaction SMILES: Cl[CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3].C[O-].[Na+].C[CH2:17][O:18]C(C)=O>CO>[CH3:17][O:18][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3]
Reactant: CC(Cl)c1nc2ccccc2[nH]1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)c1nc2ccccc2[nH]1

Procedure:
2-(1-chloroethyl)-1H-benzo[d]imidazole (0.39 g) and 25 wt % solution of Sodium Methoxide in Methanol (0.96 mL) in 10 mL of Methanol was heated for 20 minutes at 150° C. in a microwave synthesizer. The reaction mixture was extrated with EtOAc and sat NH4 chloride. The organic layer was dried, filtered and concentrated to afford crude 2-(1-methoxyethyl)-1H-benzo[d]imidazole in quantitative yield.