Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[N:31]=[CH:32][C:33]([C:36](OC)=[O:37])=[N:34][CH:35]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:36]([C:33]3[CH:32]=[N:31][C:30]([C:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH:26]=4)=[CH:35][N:34]=3)=[O:37])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(C2=CCN(C)CC2)cn1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(C4=CCN(C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
Trimethylaluminium (2M in toluene, 1.74 ml, 3.48 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (343 mg, 1.39 mmol) and methyl 5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate (324 mg, 1.39 mmol) in anhydrous toluene (6.94 ml) at ambient temperature. The resulting solution was then stirred at 60° C. for 18 h. The reaction mixture was quenched into methanol (100 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (152 mg, 24%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH2:33][C:34](Cl)=O)=[CH:28][CH:27]=3)[CH:20]=[N:19]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:34]([CH2:33][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)=[CH:32]4)=[N:9][N:8]=2)[N:7]=1
Reactant: Cn1cc(-c2cnc3ccc(CC(=O)Cl)cc3c2)cn1
Reactant: NNc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
(6-Chloro-pyridazin-3-yl)-hydrazine (190 mg, 1.315 mmol) was dissolved in dimethylformamide followed by the addition of triethylamine (3 eq). This mixture was stirred for 5 minutes. The mixture became dark green and then was cooled 0° C. A solution of [3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl]acetyl chloride (375 mg, 1.315 mmol) in dimethylformamide was added dropwise and the reaction mixture turned dark yellow, and stirred for one hour. After such time mixture was concentrated to dryness then taken up in acetic acid (10 mL) and stirred at 60° C. for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water, and the aqueous phase further extracted with ethyl acetate. The combined organics purified via flash column chromatography (SiO2, CH2Cl2, methanol gradient 0 to 10%) to return the title compound (217 mg, 42% yield). Analytical data presented in Table 2.
Reaction SMILES: Cl.C(OC([NH:12][C@@H:13]1[CH2:17][CH2:16][C@@:15]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:18])[C:14]1([CH3:29])[CH3:28])=O)C1C=CC=CC=1>CO>[NH2:12][C@@H:13]1[CH2:17][CH2:16][C@@:15]([CH2:19][NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:18])[C:14]1([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@@H](NC(=O)OCc2ccccc2)C1(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@@H](N)C1(C)C
Reaction time: 14 h
Yield: 67.6 %

Procedure:
A pressure bottle was flushed with nitrogen. The bottle was charged with 10% palladium on carbon-Degussa Type (51.2 mg, 0.481 mmol). The catalyst was wet with methanol (1 ml) while under a gentle stream of nitrogen. A premixed methanol (14.6 ml) and 1.0 N hydrochloric acid (1.459 ml) solution of the title compound of Step 7 of Example 345 (940 mg, 2.407 mmol) was added. The suspension was flushed with nitrogen. The reaction evacuated and pressurized to 50 psi with hydrogen at room temperature, and continued stirring for 14 hrs. The reaction was evacuated and backfilled with nitrogen, and filtered over a pad of celite. The filtrate was concentrated under reduced pressure to afford tert-butyl (((1S,3R)-3-amino-1,2,2-trimethylcyclopentyl)methyl)-carbamate (417.4 mg, 1.628 mmol, 67.6% yield) as a colorless oil. ESI-MS m/z 257.3 ([M+H]+).
Reaction SMILES: [O-2].[Mg+2].[CH:3]1([CH3:16])[CH2:8][CH2:7][CH:6]([CH:9]([CH3:11])[CH3:10])[CH:5]([O:12][C:13](Cl)=[O:14])[CH2:4]1.[CH3:17][N:18]1[C:24]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:21][CH2:20][C:19]1=[O:36]>CC(C)=O>[CH3:17][N:18]1[C:24]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:21]([C:13]([O:12][CH:5]2[CH:6]([CH:9]([CH3:11])[CH3:10])[CH2:7][CH2:8][CH:3]([CH3:16])[CH2:4]2)=[O:14])[CH2:20][C:19]1=[O:36]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC1CCC(C(C)C)C(OC(=O)N2CC(=O)N(C)c3ccc(Cl)cc3C2c2ccccc2)C1

Procedure:
0.2 g. of magnesium oxide and 1.21 g. (0.0055 moles) of menthyloxycarbonyl chloride are added to a solution of 1.34 g. (0.005 moles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 20 ml. of acetone, and the mixture is stirred overnight. Next day carbon is added to the mixture, the suspension is filtered, and the filtrate is evaporated to dryness. The oily residue is dissolved in 20 ml. of ethyl acetate, the solution is shaken with 3×5 ml. of 0.1 N hydrochloric acid, the organic phase is washed with water until neutral, then dried over sodium sulfate. The drying agent is filtered off, and the filtrate is evaporated. The residue is admixed with hexane, and the solids are filtered off. 0.82 g. of 1methyl-4-menthyloxycarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one, melting at 144°- 144.5° C., are obtained. The obtained substance is recrystallized from a mixture of ethanol and water. Rf2 = 0.8.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][C:19]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:13]([F:34])[CH:12]=1)[C:2]1C=CC=CC=1.C([Li])CCC.C1OC1>O1CCCC1>[CH2:27]([O:26][C:19]1[CH:20]=[C:21]([CH2:24][CH3:25])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH2:2][CH2:1][O:8][C:9]2=[O:35])=[CH:12][C:13]=1[F:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CO1
Product: CCc1ccc(Oc2ccc(N3CCOC3=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of [4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-carbamic acid-benzyl ester (500 mg, 1.06 mmol) in 5 ml tetrahydrofuran under nitrogen atmosphere was cooled to −78° C. To this added 2.8M n-butyl lithium (0.075 g, 1.16 mmol) dropwise and the stirring at −78° C. for 1 h. Condensed ethylene oxide (0.5 ml, 9.9 mmol) was then added dropwise to the reaction mixture and warmed slowly to rt. The reaction was stirred at rt overnight and then quenched with saturated ammonium chloride solution. The aqueous phase was extracted with dichloromethane and the combined organic phase was dried over anhydrous Na2SO4 and concentrated. The crude obtained was purified by column chromatography on silica gel using 25% ethyl acetate in petroleum ether as eluant to obtain 350 mg, 81% of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[O:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH2:32])[CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH2:31][CH:27]2[CH2:28][CH2:29][CH2:30][O:25][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CCCOC1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CCCOC2)cn1
Yield: 25 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using (tetrahydro-2-H-pyran-3-yl)methanamine hydrochloride instead of methylamine, to the title compound (33 mg, 25%) which was obtained as a white solid after crystallisation from ethyl acetate:hexane. MS: m/e=408.4 [M+H]+.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([C:29]2[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH2:22][C@H:19]3[CH2:18][CH2:17][C@H:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:21][CH2:20]3)[CH2:27][CH:28]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCCCC[C@H]1CC[C@H](CCCCC2CCC(=O)CC2)CC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCCCC2CC=C(c3cc(F)cc(F)c3)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Under a nitrogen gas stream, 3.13 g (129 mmol) of magnesium was added to 50 ml of THF, and while a reaction temperature was maintained at about 50° C., 300 ml of THF containing 22.7 g (118 mmol) of 3,5-difluoro-1-bromobenzene was added dropwise. After stirring for 1 hour at room temperature, 300 ml of THF containing 30.0 g (97.9 mmol) of 4-(4-(trans-4-pentylcyclohexyl)butyl)cyclohexanone was added dropwise. Next, after stirring at 50 to 60° C. for 2 hours, 200 ml of an aqueous saturated ammonium chloride solution was added, thereby terminating the reaction. The reaction mixture was filtered through Celite, and the solvent was then distilled off under reduced pressure, followed by extraction with 500 ml of toluene. The resulting organic layer was washed 3 times with 200 ml of water, and then dried over anhydrous magnesium sulfate. After drying, 1.50 g of p-toluenesulfonic acid monohydrate was added, and heating was done under reflux for 4 hours. The organic layer was washed 3 times with 200 ml of water, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (a developing solvent: heptane) to obtain 26.4 g of crude 1,3-difluoro-5-(4-(4-(trans-4-pentylcyclohexyl)butyl)cyclohexene-1-yl)benzene.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[CH3:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH:3]1[OH:7]
Reactant: COC(=O)C1(C)CCCC1=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCC1O
Reaction time: 1 h

Procedure:
To methyl 1-methyl-2-oxocyclopentanecarboxylate (20.0 g=128 mmol) in THF (800 ml) add portionwise lithium tri-t-butoxyaluminohydride (40.7 g=160 mmol). Stir 1 hr and partition between Et2O and 1.0N HCl. Dry and concentrate to obtain methyl 1-methyl-2-hydroxycyclopentanecarboxylate, largely the 1β-methyl-2β-hydroxy isomer, as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4N=N[NH:25][N:26]=4)[CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>N1C=CC=CC=1>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:36][C:35]([C:34]5[CH:38]=[CH:39][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=5)=[N:25][N:26]=4)[CH:17]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1cccc(-c2nn[nH]n2)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-c2nnc(-c3cccc(-n4c5ccc(Br)cc5c5cc(Br)ccc54)c3)o2)cc1
Yield: 69.1 %

Procedure:
In a 50 ml two-neck flask, 2.5 g (5.33 mmol) of 3,6-dibromo-9-(3-2H-tetraazol-5-yl-phenyl)-9H-carbazole, 4.19 ml (21.45 mmol) of 4-tert-butylbenzoyl chloride, 3.5 ml of pyridine, and a stir bar were added. After the reaction was carried out with reflux under a nitrogen atmosphere for 8 hours, an extraction was conducted. The crude product was purified by column chromatography to obtain a white solid product of 3,6-dibromo-9-(3-(5-(4-tert-butyl-phenyl)-1,3,4-oxadiazol-2-yl)phenyl)-9H-carbazole (yield: 69.1%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)(=[NH:4])=[O:3].[H-].[Na+].CCCCCC.Cl[CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]>CN(C)C=O.O>[CH2:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][N:4]=[S:2]([CH3:1])([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:3])[CH3:19]
Reactant: CS(=N)(=O)c1ccsc1
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCN(CC)CCN=S(C)(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A solution of S-methyl-S-(thien-3-yl)sulfoximine (Maybridge, 2.56 g, 15.9 mmol) in dimethylformamide (15 mL) was added dropwise to a slurry of sodium hydride (0.76 g, 19.0 mmol, 60% oil dispersion, washed (3×8 mL) hexane) in dimethylformamide (10 mL) at 0° C. The solution was allowed to warm to ambient temperature and was stirred at ambient temperature for 0.5 h. The resulting mixture was cooled to 0° C. and a solution of 1-chloro-2-diethylaminoethane (2.14 g, 15.9 mmol) in dimethylformamide (15 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 15 h. Water (1 mL) was added and the reaction mixture was concentrated in vacuo. The residue was partitioned between water (25 mL) and methylene chloride (25 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (2×25 mL). The combined organic extracts were washed (saturated sodium chloride), dried (MgSO4), and concentrated in vacuo to afford 3.9 g of residue. The residue was chromatographed (flash, SiO2, 9:1:0 to 9:1:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give an oil that was partitioned between water (15 mL) and methylene chloride (15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The oil partially solidified on standing.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:15]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.C([N+](C)(C)C)C1C=CC=CC=1>CO.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)[C:13]#[N:14])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCc1ccc(C=O)cc1
Reactant: CCCCOc1ccc(CC#N)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCCCCCCc1ccc(C=C(C#N)c2ccc(OCCCC)cc2)cc1
Temperature: 70 °C

Procedure:
9.4 g of p-butoxyphenylacetonitrile and 10.2 g of p-heptylbenzaldehyde are dissolved in 30 ml of methanol. 5 ml of a 40% solution of benzyltrimethylammoniumhydrate in water are added to the solution. The whole is heated at 70° C for 30 minutes and then cooled. The precipitate is sucked off and recrystallized from successively methanol and petroleum ether (60 : 80). Melting point of the resulting compound is 34.5°-35.5.° C.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:22]3)=[N:13][N:12]2[CH:41]=1)=[O:8])C.[OH-].[Na+]>C(O)C>[C:35]1([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([CH:41]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:42])=[O:3])=[O:8])[N:10]=4)[N:13]=3)[CH2:22][CH2:23]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
0.810 g of N-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazine-2-carbonyl]glycine ethyl ester was dissolved in 4 ml of ethanol; 2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure; ice water and 2.1 ml of 1 N hydrochloric acid were added to the residue, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was powdered by the addition of ethyl acetate, collected by filtration and washed with ethyl acetate to yield 0.183 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]=[CH2:13])[S:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)(=[O:4])=[O:5]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C=CCN(C)S(=O)(=O)CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of methyl 2-({methyl[allyl]amino}sulfonyl)acetate (300 mg, 1.4 mmol) and 4-bromobiphenyl (370 mg, 1.54 mmol) in acetonitrile (4 ml) was added triethylamine (0.3 ml, 2.1 mmol), palladium(II) acetate (17 mg, 0.07 mmol) and tri-ortho-tolyl phosphine (52 mg, 0.14 mmol) and the solution was heated to reflux under an atmosphere of nitrogen for 3 hours. The mixture was cooled to ambient temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (dichloromethane as eluent) to give the title compound as a pale yellow solid (300 mg).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([CH2:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:5][C:6]([O:8]CC)=O)[CH3:3].[O-]CC.[Na+]>CCOCC>[CH3:3][CH:2]([CH:4]1[CH2:5][C:6](=[O:8])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:12](=[O:20])[CH2:11]1)[CH3:1]
Reactant: CCOC(=O)CC(CC(=O)Cc1ccccn1)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C1CC(=O)C(c2ccccn2)C(=O)C1
Reaction time: 2.83 h

Procedure:
The subject compound was prepared from ethyl 3-(1-methylethyl)-6-(2-pyridinyl)-5-oxohexanoate and a sodium ethoxide solution according to the general procedure of Example 2, but employing a 2.83 hour reflux period following completion of the feed. On working up the reaction the ether-extracted aqueous phase was adjusted to pH 6 causing the product to separate as a tan solid which was extracted with ether, recovered by evaporation and recrystallized twice from cyclohexene to give a solid, mp 110°-112° C. The confirmatory elemental analysis is shown in Table II.
Reaction SMILES: O(P([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[H-].[Na+].[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([Br:40])[C:37]=1[CH:38]=O)[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([Br:40])[C:37]=1/[CH:38]=[CH:17]\[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1cc(Br)c(C=O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(/C=C\C(=O)OC(C)(C)C)c(Br)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (diphenoxyphosphoryl)acetate (267 mg) in THF (7.5 mL) at 0° C. under nitrogen was added sodium hydride and the mixture stirred for 15 min until gas evolution ceased. This anion mixture was then cooled to −78° C. and a solution of methyl 3,5-dibromo-4-formylbenzoate (262 mg) in THF (7.5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for an additional 40 min before being quenched with saturated ammonium chloride solution, extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with 90% hexane:10% ethyl acetate to give the title compound which also contained 20% of the E double-bond isomer. No attempt was made to separate these isomers at this stage. 1H NMR (500 MHz, CDCl3): 88.23 (s, 1H, E isomer); 8.21 (s, 1H, Z isomer); 7.57 (d, J=16.3 Hz, 1H, E isomer); 6.76 (d, J=11.9 Hz, 1H, Z isomer); 6.38 (d, J=16.3 Hz, 1H E isomer); 6.12 (d, J=11.9 Hz, 1H Z isomer); 3.954 (s, 3H, E isomer); 3.948 (s, 3H, Z isomer); 1.28 (s, 9H, both isomers). Mass spectrum: m/z 365 (M+H-t-Bu).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11]([N:15]=[N:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])([O:13][CH3:14])=[O:12].CCCCCC>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:17](=[N:16][NH:15][C:11]([O:13][CH3:14])=[O:12])[CH3:24])[CH3:23]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)/C=C(/C)N=NC(=O)OC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(C)=NNC(=O)OC
Temperature: 70 °C
Yield: 71.1 %

Procedure:
3-Nitroaniline (2.92 g, 21.27 mmol) was added to a solution of ethyl 3-carbomethoxyazocrotonate (4.2 g, 21.13 mmol) (which is known in the literature) in THF (40 mL), and the mixture was stirred at 70° C. for a day and a night. After cooling to room temperature, hexane was added thereto, and the deposited precipitate was filtered out to yield the title compound (5.08 g, 71%).
Reaction SMILES: N1C=CC=CC=1.[S:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>C(Cl)Cl.O>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:14][CH2:13][CH:10]2[CH2:11][CH2:12][S:7][CH2:8][CH2:9]2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCSCC1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (7.6 mL, 98.4 mmol) was added at 0° C. to a solution of (tetrahydro-2H-thiopyran-4-yl)methanol (1.3 g, 9.84 mmol) in CH2Cl2 (20 mL) followed by the addition of TsCl (2.0 g, 10.83 mmol). The reaction mixture was stirred at ambient temperature for 18 h, diluted with H2O (200 mL) and extracted with CH2Cl2 (200 mL). Drying over anhydrous Na2SO4 followed by concentration in vacuo gave (tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate as an off white solid. The crude was carried forward to the next step without additional purification. Yield (0.75 g, 30%).