Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>ClCCl>[CH3:13][S:14]([O:9][CH2:8][CH:7]([O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)Oc1ccc(F)cc1

Procedure:
As described in Example 56, 7.7 g of 2-(p-fluorophenoxy)-1-propanol is reacted with 8.8 ml of methanesulfonyl chloride in 400 ml of dichloromethane in the presence of 12.5 ml of triethylamine. The product is obtained as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.O>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a reaction container equipped with a dropping funnel, 8 g of 2,5-dibromopyridine and 90 ml of diethyl ether were added. The obtained solution was cooled at −70° C. and then, 21.37 mL of butyl lithium (1.58 M/hexane solution) was added dropwise thereto. The obtained mixture was stirred for 1 hour and 30 minutes and then, a solution obtained by dissolving 4.32 mL of trimethylchlorosilane in 6.2 mL of diethyl ether was added dropwise thereto. The obtained mixture was stirred for 2 hours and 40 minutes and then, 60 mL of water was added dropwise thereto at 0° C. The obtained mixture was stirred at room temperature overnight and then, 30 mL of diethyl ether was added thereto. The obtained solution was extracted three times with 30 mL of diethyl ether. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography to obtain 5.96 g of 2-bromo-5-trimethylsilylpyridine. Purity: 90% (area percentage value obtained by gas chromatography analysis).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26].ClC1C=C(C=CC=1)C(OO)=[O:32].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])(=[O:32])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-methyl-3-{3-[(methylsulfinyl)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.480 g, 1.24 mmol) and 3-chloroperoxybenzoic acid (0.600 g, 60%, 2.10 mmol) in methylene chloride is stirred at room temperature for four hours, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% diethyl ether in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH:18]=O)=[CH:7]2.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1.[NH2:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[N:42]2>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH:38][C:39]1[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[N:42]3)=[CH:7]2
Reactant: Nc1ccc2nccnc2c1
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3)nc12
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc2cc(CNc3ccc4nccnc4c3)c(-c3ccccc3)nc12
Temperature: 100 °C
Yield: 37.4 %

Procedure:
To a solution of 8-methyl-2-phenylquinoline-3-carboxaldehyde (80 mg, 0.32 mmol) in THF (5 mL) was added di-n-butyltin dichloride (10 mg, 0.032 mmol), phenylsilane (70 mg, 0.64 mmol) and 6-aminoquinoxaline (46 mg, 0.32 mmol). The mixture was heated in a microwave at 100° C. for 3 h. Purification by preparative HPLC (Method 2) gave the title compound as an off-white solid (45 mg, 37%). δH (CDCl3) 8.61 (d, J 2.1 Hz, 1H), 8.51 (d, J 1.9 Hz, 1H), 8.24 (s, 1H), 7.84 (d, J 9.0 Hz, 1H), 7.71-7.76 (m, 1H), 7.61-7.66 (m, 1H), 7.40-7.58 (m, 6H), 7.10 (dd, J 9.2, 2.6 Hz, 1H), 6.88 (d, J 2.6 Hz, 1H), 4.64-4.69 (m, 2H), 4.52-4.60 (m, 1H), 2.82 (s, 3H). LCMS (ES+) 377.2 (M+H)+, RT 4.23 minutes (Method 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[CH3:29][N:30]([CH3:32])[NH2:31]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:31][N:30]([CH3:32])[CH3:29])=[O:22]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CN(C)N
Product: CN(C)NC(=O)c1c(Nc2ccc(I)cc2F)n(C)c(=O)n(C)c1=O

Procedure:
Example 45 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 1,1-dimethylhydrazine. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.0 Hz, 1H) 7.58 (d, J=8.0 Hz, 1H) 6.99 (t, J=8.0 Hz, 1H) 3.33 (s, 3H) 3.08 (s, 3H) 2.60 (s, 6H). [M+H] calc'd for C15H17FIN5O3, 462. found, 462.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.C(O)(=O)C>C(O)C>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:20]([C:16]4[S:15][CH:19]=[CH:18][CH:17]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=Cc1cccs1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4cccs4)nc3cc21
Reaction time: 1 h

Procedure:
A solution of 3.8 g. (20 mmol) 5,6-diamino-3,3-dimethylindolin-2-one, 2.25 g. (20 mmol) thiophene-2-aldehyde and 4 ml. glacial acetic acid in 40 ml. ethanol is heated under reflux for 1 hour and then further boiled for 1 hour, while passing through air. The reaction mixture is then distilled to dryness and the residue stirred up with ethyl acetate and filtered off with suction. The crystallisate obtained is recrystallised from acetone. Yield: 1.7 g. (30% of theory); m.p. 332°-336° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Br[CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCOC(=O)C(Br)CC
Reactant: Nc1ccc2ccccc2c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(CC)Nc1ccc2ccccc2c1

Procedure:
Following General Procedure AJ above and using 2-aminonaphthalene (Aldrich) and ethyl 2-bromobutyrate (Aldrich), the title compound was prepared as a solid, m.p. 81-83° C. The reaction was monitored by silica gel tlc (Rf=0.5 in CHCl3). Purification was by chromatography (silica gel using chloroform as the eluant).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.[CH2:14](I)[CH3:15].C(OC(=O)C)C>CN(C=O)C.CCCCCC>[CH2:14]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1)[CH3:15]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1cc(C=O)c2ccccc21
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
NaH (1.51 g, 37.891 mmol) was added to a solution of 1H-indole-3-carbaldehyde (I-38a: 5 g, 34.447 mmol) in dry DMF (40 mL) at 0° C. and the reaction mixture was stirred for 5 minutes. This was followed by dropwise addition of ethyl iodide (6.45 g, 41.336 mmol) over a period of 5 mins and stirring was continued for a further 1 hr. The reaction was monitored by TLC (40% ethylacetate in hexane). The reaction mixture was quenched with chilled water and filtered. The residue was washed with water and dried to afford 5.2 g of the product (86% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.[O-]S([O-])(=O)=O.[Ca+2]>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ccc(CCCC(=O)OCc2ccccc2)cc1

Procedure:
A mixture of 8.14 g (0.455 mol) of 4-(p-aminophenyl)butyric acid, 34.1 ml of benzyl alcohol and 8.65 g (0.455 mol) of p-toluene sulfonic acid hydrate in 115 ml of carbon tetrachloride is heated overnight at reflux with the solvent return through a tower of Drierite (ca. 30 ml of partially powdered indicating Drierite). The partially cooled mixture is diluted to 600 ml with ethyl ether to give a precipitate which is collected to give 4-(4-aminophenyl)butyric acid benzyl ester, p-toluenesulfonate; m.p. 114°-115° C. This is used in the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:18][CH2:19][C:20]([OH:22])=[O:21])[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:27][O:21][C:20](=[O:22])[CH2:19][NH:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]acetic acid (0.66 g, 2.0 mmol) in DMF (20 mL), were added methyl iodide (0.34 g, 2.4 mmol) and potassium carbonate (0.33 g, 2.4 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, giving a yellow oil. The oil was dissolved in CH2Cl2 (100 mL), washed with sat. aq. sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL), and dried (MgSO4). The solvent was evaporated in vacuo to give a yellow solid. This material was triturated with diethyl ether and then filtered, and the resulting solid was chromatographed, eluting with 9:1 methylene chloride-ethyl acetate. The resulting solid was triturated in 1:1 ethyl ether-water, filtered, and dried under high vacuum, providing 0.42 g (61%) of the product as a yellow solid: mp 210-212° C.; 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.47-2.63 (m, 2H), 2.96-2.83 (m, 1H), 3.69 (s, 3H), 4.23 (d, J=6.0 Hz, 2H), 5.08 (dd, J=12.4 Hz, J=5.2 Hz, 1H), 6.91-7.11 (m, 3H), 7.61 (t, J=7.7 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.10, 30.96, 43.62, 48.51, 51.90, 109.76, 111.22, 117.65, 132.01, 136.09, 145.76, 167.21, 168.70, 170.12, 170.65, 172.77; Anal. calcd. for C16H15N3O6: C, 55.65; H, 4.38; N, 12.17. Found: C, 55.64; H, 4.28; N, 11.98.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH3:16][I:17]>CC(C)=O>[I-:17].[CH3:16][N+:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:2]=1[CH3:1]
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Reactant: CI
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C(C)=[N+](C)CC2
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a stirred solution of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline in acetone was added methyl iodide and the reaction mixture was stirred at room temperature for 16 hours. A bright yellow precipitate formed. The by-products and methyl iodide were removed in vacuo to afford the desired compound in 95% yield.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16](O)=O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]=1[NH2:35].P(Cl)(Cl)(Cl)=O>>[Cl:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[C:21]=1[N:35]=[C:16]([CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][CH2:11]1)[N:26]2[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1
Reactant: Nc1c(Cl)ncnc1NCc1ccc(F)cc1
Reactant: O=C(O)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3c(Cl)ncnc32)cc1
Yield: 75 %

Procedure:
A mixture of 20.65 parts of 1-(phenylmethyl)-4-piperidineacetic acid hydrochloride, 19.5 parts of 6-chloro-N4 -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine and 510 parts of phosphoryl chloride was stirred and refluxed for 13 hours. The reaction mixture was evaporated. The residue was poured into ice water. The whole was treated with sodium hydroxide. The product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 23.6 parts (75%) of 6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-9H-purine as an oily residue (compound 1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:26]([O-:28])=[O:27])=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1.[H-].[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[CH:12]=[CH:13][C:14]([N+:26]([O-:28])=[O:27])=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C#N)cc2)ccc1[N+](=O)[O-]
Yield: 57 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-cyanophenol (5.1 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (11.5 g), sodium hydride (55 wt. %, 1.19 g) and anhydrous N,N-dimethylformamide/anhydrous tetrahydrofuran=5/3 (80 ml) and the reaction mixture was purified to give the title compound (8.45 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH2:26]([CH2:28][NH2:29])[OH:27].COC(O)C.[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:29][CH2:28][CH2:26][OH:27])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NCCO
Agent: COC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: Nc1nc(NCCO)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A flask charged with (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.53 g, 2.00 mmol) from Example 4, triethylamine (0.92 g, 9.10 mmol), ethanolamine (0.172 g, 2.82 mmol) and methoxyethanol (6 mL) was stirred at reflux for 2 hours. The solution was allowed to cool to room temperature before the addition of 2 mL of 1.0 N NaOH. Concentration of the solution left the crude product which was purified by elution from a silica gel column with 10% methanol chloroform (0.430 g, 74%). Crystallization of such a sample from ethanol-water gave a white powder, m.p. 150-152° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10](=O)[CH2:11][CH3:12])=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[NH:47]1[CH2:51][CH2:50][NH:49][C:48]1=[S:52]>>[BrH:14].[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]3[N:49]4[CH2:50][CH2:51][N:47]=[C:48]4[S:52][C:11]=3[CH3:12])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CCC(=O)c1cccc2sccc12
Reactant: [Br-]
Reactant: S=C1NCCN1
Agent: C[N+](C)(C)c1ccccc1
Product: Br
Product: CC1=C(c2cccc3sccc23)N2CCN=C2S1

Procedure:
1-(Benzo[b]thiophen-4-yl)propan-1-one (32.3 g; prepared in a manner similar to that described above) was reacted with phenyltrimethylammonium tribromide (63.9 g) followed by 2-imidazolidinethione (17.4 g) using methodology similar to that described in Example 9 Method A to give 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (46.8 g) as a colourless solid, m.p. 262-264° C. This was combined with a sample of 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (25.4 g) prepared according to the methodology described in Example 9 Method A. The combined sample was then basified and converted into the hydrochloride salt in a manner similar to that described in Example 9 Method A to give 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (46.8 g) as a colourless solid, m.p. 242-245° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]2[N:16]([CH3:27])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:18]=[N:17][N:16]([CH3:27])[C:15]=2/[CH:14]=[CH:13]/[C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nnc(-c2ccc(F)cc2)c1/C=C/c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of lithium hydroxide monohydrate (34 mg, 0.8 mmol) in water (1.0 mL) was added dropwise to a suspension of 6-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-nicotinic acid methyl ester (136 mg, 0.4 mmol) in THF (1.0 mL) and methanol (0.2 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (114 mg, 87%) as a white solid. MS: m/e=323.2 [M−H]−.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:12])[N+:18]([O-:20])=[O:19]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(Oc1ccccc1)C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 54.3 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-phenoxypropionic acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.49 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]([N:20]2[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Yield: 67.2 %

Procedure:
A solution of 5 g of 5-chloro-2-nitrobenzaldehyde dimethylacetal and 8.8 g of 4-hydroxypiperidine in 20 ml of N,N-dimethylformamide was heated at 80 ° C. for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under a reduced pressure. The residue was purified by a silica gel column chromatography to give 4.3 g of 5-(4-hydroxypiperidino)-2-nitrobenzaldehyde dimethylacetal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].P(Cl)(Cl)([Cl:19])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[N:14][C:13]([Cl:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2ccc(=O)[nH]n2)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2ccc(Cl)nn2)cc1Br

Procedure:
A suspension of 100 g. of 6-(3-bromo-4-methoxyphenyl)-3(2H)-pyridazinone [J. Heterocyclic Chem. 11, 775 (1974) ]in 150 ml. of phosphorus oxychloride is refluxed until a clear solution is obtained (approximately 5 hours). The solution is cooled and excess phosphorus oxychloride is removed under vacuum to give a brown solid which is triturated with ice water. The solid is collected by filtration and is recrystallized to afford 3-(3-bromo-4-methoxyphenyl)-6-chloropyridazine.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#N)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:24].[Na+].[OH2:26]>>[CH2:1]([C:5]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]([OH:26])=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cc2ccc(C#N)cc2)c2ccccc2n1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Product: CCCCc1cc(Cc2ccc(C(=O)O)cc2)c2ccccc2n1

Procedure:
Using the procedure of Example 2, 0.750 g of the product of Example 3 and 2.5 ml of water and 2.5 ml of sodium hydroxide were reacted to obtain 205 mg of the desired product which after crystallization melted at 158° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO[C:14](OC)([CH3:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]#[N:11])=[CH:3][C:2]=2[O:1]1
Reactant: COC(C)(C)OC
Reactant: N#CCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(CC#N)cc2O1
Yield: 16.3 %

Procedure:
To a solution of (3,4-dihydroxy-phenyl)-acetonitrile (0.2 g, 1.3 mmol) in toluene (4 mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g, 0.065 mmol). The mixture was heated at reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 solution, H2O, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (Petroleum Ether/EtOAc 10:1) to give 2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile (40 mg, 20%). 1H NMR (CDCl3, 400 MHz) δ 6.68-6.71 (m, 3H), 3.64 (s, 2H), 1.67 (s, 6H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[P:17]([OH:20])([OH:19])[OH:18]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([NH:16][CH:9]([P:17](=[O:18])([OH:20])[OH:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccccc1
Reactant: OP(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=P(O)(O)C(NCc1ccccc1)c1ccccc1

Procedure:
The imine from benzaldehyde and benzylamine (65 g; 0.33 mole) was added to phosphorous acid (27.3 g; 0.33 mole) and the mixture stirred with heating. As the temperature reached 95°-100° the whole mixture became a homogeneous liquid which reacted vigorously as the temperature reached 115°-120°. The reaction mass became very viscous and was allowed to cool to a glass. This glass was dissolved in aqueous sodium carbonate and upon acidification gave N-benzyl α-aminobenzylphosphonic acid, mp 233°-4°, 90 g (98%).