Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:36]([CH2:35][CH:34]([OH:38])[C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)[CH3:37])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccc(OC)cc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.20 mmol), 1-(4-methoxyphenyl)-2-(methylamino)ethanol (Tetrahedron 1999, 55, 4831-4842) (58 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 16 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:10]1([CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCOCCc1ccccc1
Product: c1ccc(CCOCCCCCNCc2ccccc2)cc1

Procedure:
N-[5-(2-Phenylethoxy)pentyl]benzenemethanamine (8.6 g) was prepared in a similar manner from [2-[(5-bromopentyl)oxy]ethyl]benzene (10 g) and benzylamine (30 ml). The undistilled product was used without further purification in Example 1(c).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1cccc(N)c1
Solvent: Cc1ccccc1C
Product: Cc1cccc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 65 %

Procedure:
4-Hydroxy-2-methyl-N-(3-tolyl)- 2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and m-toluidine. Yield: 65% of theroy; m.p. 240-242° C (decomp.; from xylene).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]=[O:12].[CH2:13](O)[CH2:14][OH:15]>C1C=CC=CC=1.C([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: OCCO
Reactant: O=Cc1oc2ccccc2c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Brc1c(C2OCCO2)oc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.5 %

Procedure:
3-bromo-1-benzofuran-2-carbaldehyde (5.49 g, 24.4 mmol) is combined with para-toluene sulfonic acid hydrate (232 mg, 1.2 mmol) and ethylene glycol (2.44 ml, 43.9 mmol) in benzene (75 ml). The reaction is refluxed with a Dean-Stark trap for 5 h. The mixture is cooled to rt and diluted with saturated NaHCO3 solution (20 ml) and left to stir for an additional 12 h. The layers are allowed to separate, and the organic layer is dried over Na2SO4, filtered, and concentrated to afford 6.6 g (100%) of 3-bromo-2-(1,3-dioxolan-2-yl)-1-benzofuran as a dark brown oil. HRMS (FAB) calcd for C11H9BrO3+H: 268.9814, found 268.9821.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([CH2:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc(C(=O)O)cn1
Product: CC(=O)CNc1ccc(C(=O)O)cn1

Procedure:
A 1.5 g portion of 6-methylaminonicotinic acid in 20 ml of acetic anhydride was heated under reflux for 1.5 hours. After evaporation of the solvent under reduced pressure, the residue was dissolved with saturated aqueous sodium bicarbonate, and the aqueous layer was washed with ethyl acetate and then adjusted to pH 3 using concentrated hydrochloric acid. Then the aqueous layer was extracted with chloroform, the organic layer was washed and dried, and then the solvent was evaporated under reduced pressure to obtain 280 mg of the title compound as white crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)(=[O:3])[CH3:2].NC(C(O)=O)CCSC.CS(O)(=O)=O.C(OCC)C>O>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(CC2CCCCC2COC(C)=O)c1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)OCC1CCCCC1Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
The reaction mixture of [2-(3-methoxybenzyl)cyclohexyl]methyl acetate (66 mg), DL-methionine (357 mg), and methanesulfonic acid (1.55 mL) was stirred at ambient temperature for 18 hours. To the reaction mixture was added diethylether and water. The reaction mixture was stirred. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The mixture was purified by silica gel column chromatography (n-hexane:EtOAc=5:1) to afford [2-(3-hydroxybenzyl)cyclohexyl]methyl acetate (42 mg) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]1([CH2:24][OH:25])[CH2:23][O:22][CH2:21]1.BrCC(CBr)(CO)CO>C1COCC1>[OH:25][CH2:24][C:20]1([CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)[CH2:23][O:22][CH2:21]1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: OCC1(CBr)COC1
Agent: OCC(CO)(CBr)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(OCC2(CO)COC2)cc1
Temperature: 50 °C

Procedure:
Dissolve 4-hydroxybenzophenone in anhydrous THF and treat it with equimolar quantity of sodium hydride at 0° C. for 2 h. Stir and warm the suspension to 50° C. and treat it with an equimolar quantity of 3-Bromomethyl-3-hydroxymethyloxetane (readily prepared in one step by method described in U.S. Pat. No. 5,489,700 or Tet. Lett. 2011, 52, p. 565-567 from commercially available 2,2-bis-(bromomethyl)propane-1,3-diol). Stir overnight at 50° C., filter the reaction mixture, evaporate the filtrate to dryness and purify the residue by column chromatography to provide (4-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}phenyl)(phenyl)methanone.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:21])([CH3:20])[CH2:11][C:10]2=O.CN1CCCN(C)C1=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:19])[C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:21])([CH3:20])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: COc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reaction time: 12 h

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 3.15 mL, 6.29 mmol), 6-bromo-8-chloro-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 9, 400 mg, 1.26 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 2 mL) in THF was reacted then quenched with 10% HCl, and stored at room temperature for 12 h. Purification by flash chromatography (silica gel, 95:5 hexane/ethyl acetate) afforded the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C@@:5]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:7][C@H:6]1[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:4].[OH-].[Li+].Cl>CO.O>[ClH:31].[C:22]([NH:21][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14][N:9]([CH2:8][C@@H:6]2[CH2:7][C@:5]2([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[C:3]([OH:4])=[O:2])[CH2:10][CH2:11]1)(=[O:24])[CH3:23]
Reactant: COC(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1CN1CCC(NC(C)=O)(c2ccccc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NC1(c2ccccc2)CCN(C[C@@H]2C[C@@]2(C(=O)O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
The oxalate salt of (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid methyl ester (10 mmol) was dissolved in methanol (80 mL) and water (20 ml). Lithium hydroxide (50 mmol) was added and the mixture was heated to reflux for 2 h. The mixture was cooled to rt and acidified to pH 3 with concentrated hydrochloric acid and the precipitated product (1S,2R)-2-(4-Acetylamino-4-phenyl-piperidin-1-ylmethyl)-1-(3,4-dichlorophenyl)cyclopropanecarboxylic acid hydrochloride was isolated by filtration and dried in vacuo.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.CO.[CH2:59]([N:66]1[CH2:70][CH:69]=[C:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O>[CH2:59]([N:66]1[CH2:70][C@H:69]([C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][CH:50]=2)[C@@H:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 55 °C
Yield: 33 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (45 mg, 0.05 eq.), (R)-BINAP (110 mg, 0.05 eq.) and 4-chloro-phenylboronic acid (1.20 g, 2.2 eq.). 100 mL of MeOH and 10 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (0.70 g). The reaction mixture was heated at 55° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 0.36 g (33%) of the title product as a light yellow oil. ES-MS m/e: 314.0 (M+H+).
Reaction SMILES: [N+:1](=[C:3]([C:14]([CH3:16])=[O:15])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[N-:2].C(N(CC)CC)C.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[I-].[Na+]>C(#N)C.C(Cl)Cl>[N+:1](=[C:3]([C:14]([O:15][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH2:16])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To 1.5 ml of dry acetonitrile were added 83 mg (0.380 millimole) of benzyl 2-diazoacetoacetate, 130 μl (0.933 millimole) of triethylamine and 140 mg (0.929 millimole) of tert-butyldimethylsilyl chloride. A solution obtained by dissolving 70 mg (0.467 millimole) of sodium iodide in 0.5 ml of dry acetonitrile was added dropwise thereto at a room temperature. After the conclusion of the dropwise addition, the reaction mixture was further agitated at 40° C. for 4 hours. To the reaction mixture was added 30 ml of methylene chloride, and the resultant was washed twice with 10 ml portions of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 118 mg (yield 93.7 %) of the desired compound in a yellow solid. 1H NMR (90 MHz, CDCl3) 4 (ppm): 0.28 (6H, s), 0.97 (9H, s), 4.24 (1H, d), 5.03 (1H, d), 5.21 (2H, s), 7.31 (5H, s).
Reaction SMILES: C(O)C(C)C.[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:20]([NH2:19])=[N:21][C:22]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([CH:7]4[O:6][CH2:10][CH2:9][CH2:8]4)=[O:12])[CH2:18][CH2:17]3)=[N:23][C:24]2=[CH:25][C:26]=1[O:32][CH3:33]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: O
Solvent: CC(C)CO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 109.2 %

Procedure:
To a solution of iso-butanol (306 ml), water (34 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 13 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 12 hours. The crystals were collected by filtration, washed with iso-butanol and dried in vacuo at 40° C. to yield 39.2 g (91.9%) of Terazosin.HCl dihydrate. See Trial A in Table I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
The 4-fluorophenylacetic acid (20 g, 0.13 mol), benzoyl peroxide (130 mg, 0.540 mmol), and N-bromosuccinimide (23.1 g, 0.130 mol) were combined in 500 ml carbon tetrachloride under N2 and refluxed under UV irradiation (GE sunlamp) for 5 hours. The reaction was cooled to RT and the succinimide filtered away. The carbon tetrachloride was removed in vacuo and the remaining oil recrystallized from hexanes yielding 26.2 g (87%) of product as a light yellow solid. EA, MS(FD).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:17]1(N2C=CC(=O)NC2=O)[O:24][C@H:22]([CH3:23])[C@@H:20]([OH:21])[C@H:18]1[OH:19].[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>>[NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([C@@H:17]3[O:24][C@H:22]([CH3:23])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Product: C[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)ccnc32)[C@H](O)[C@@H]1O
Yield: 77 %

Procedure:
7-Anilino-3H-imidazo[4,5-b]pyridine (0.8 g, 3.77 mmol) and 5'-deoxyuridine (2 g, 0.87 mmol) were added to a 10 mL solution of 10 mM KxHxPO4, pH 7.4 and 0.04% potassium azide. After mixing, 180 units of uridine phosphorylase and 1800 units of purine nucleoside phosphorylase were added. The reaction was continuously mixed at 35° C. for 6 days. Solids were collected by filtration and recrystallized from boiling ethanol yielding 0.943 g of the 7-anilino-3-(5-deoxy-β-D-ribofuranosyl)-3H-imidazo[4,5-b]pyridine. This corresponded to a yield of 77%; m.p. 219° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:25]=1[NH2:26]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:25]=1[N:26]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1](=[N:26][C:25]2[C:24]([F:23])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: Nc1c(F)cccc1F
Reactant: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)n1
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1N=C(c1ccccc1)c1cccc(C(=Nc2c(F)cccc2F)c2ccccc2)n1
Reaction time: 72 h

Procedure:
2,6-Dibenzoylpyridine (464 mg, 1.61 mmol) and 2,6-difluoroaniline (7.33 mg, 5.67 mmol) were dissolved in 30 ml of toluene. To this solution molecular sieves (4 Å) were added. After standing for 3 days at room temperature (with addition of more molecular sieves after 2 days) the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 250 mg (30%) of 2,6-bis[(2,6-difluorophenylimino) (phenyl) methyl]pyridine 8 as a mixture of 3 isomers.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3B(O)O)=[N:11][N:10]=[N:9]2)C=CC=CC=1.[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51](Br)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[NH:8][N:9]=[N:10][N:11]=3)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 14 h
Yield: 43 %

Procedure:
A solution of 21.7 g (50.2 mmol) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid from step 6 in 80 mL, of ethanol and 130 mL, of toluene was added to a mixture of 5 g (4 mmol) of tetrakis(triphenylphosphine) Pd(0), 16.75 g (45.8 mmol) of 1,4-dibutyl-1,3-dihydro-3-[(6-bromo-3-pyridinyl)methyl]-2H-imidazol-2-one from step 5, 225 mL of toluene, 100 mL of 2 M sodium carbonate, and 150 mL of ethanol. The reaction mixture was heated to reflux and vigorously stirred under nitrogen for 14 h. The pH was adjusted to 6 with acetic acid and the reaction concentrated in vacuo. The product was purified by silica gel chromatography (Waters Prep-500A) using 2-propanol/methylene chloride (0-50%) followed by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (30-35:70-65) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the acetonitrile removed in vacuo, and the water extracted 4 times with chloroform. The extracts were combined, dried (MgSO4), and concentrated in vacuo. Recrystallization from ethyl acetate gave 8.5 g (43%) of colorless 1,4-dibutyl-1,3-dihydro-3-[[6-[2-(1H-tetrazol-5-yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one as a colorless solid: mp 170-171° C.; NMR (CDCl3) δ0.88 (t, J=7 Hz, 3H), 0.96 (t, J=7 Hz, 3H), 1.28-1.54 (m, 6H), 1.61-1.72 (m, 2H), 2.28 (t, J=8 Hz, 2H), 3.63 (t, J=7 Hz, 2H), 4.96 (s, 2H), 5.96 (s, 1H), 7.36 (d, J=9 Hz, 1H), 7.47-7.58 (m, 3H), 7.67 (dd, J=9 and 2 Hz, 1H), 8.06-8.13 (m, 1H), 8.52 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 432 (100), 404 (18), 237 (14), 209 (92), 180 (82); HRMS. Calc'd for M+H: 432.2512. Found: 432.2554. Anal. Calc'd for C24H29N7O: C, 66.80; H, 6.77; N, 22.72. Found: C, 66.59; H, 6.85; N, 22.57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17]Br)=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+].O1CCOCC1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH2:17][C:19]#[N:20])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Clc1ccc(-c2onc3c(CBr)cccc23)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3)onc12
Yield: 60 %

Procedure:
A solution of 11.5 g (0.036 mole) of crude 3-(4-chlorophenyl)-7-(bromomethyl)-2,1-benzisoxazole, 9.8 g (0.15 mole) of potassium cyanide, 150 ml of dioxane and 75 ml of water was heated at reflux under a nitrogen atmosphere for 2.5 hr. The solution was cooled and poured into 400 ml of methylene chloride. The layers were separated and the organic layer was washed with four 200 ml portions of water, dried over sodium sulfate, and concentrated to give a solid as residue. The solid was recrystallized (charcoal) twice from ethyl acetate to yield 5.8 g (61%) of crystals, m.p. 165°-169° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:5][CH2:4][CH2:3][CH2:2][N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1
Reactant: ClCCCBr
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(N2CCN(CCCCl)CC2)cc1

Procedure:
1-(3-Chloropropyl)-4-(4-fluorophenyl)piperazine can be obtained as follows: a solution of 1-bromo-3-chloropropane (68 cc) and 4-(4-fluorophenyl)piperazine (50 g) in acetonitrile (400 cc) is stirred at 25° C. for 20 hours with potassium carbonate (97 g). The mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 9-cm diameter, 60-cm height) and eluted with ethyl acetate, 500-cc fractions being collected. Fractions 5 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (44.4 g) in the form of a yellow oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:1]([O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCCCCC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 6-heptenoic acid (4.71 g, 36.75 mmol) in AcOEt (80 mL) at 0° C. were successively added triethylamine (15.3 mL, 110.24 mmol), benzyl bromide (13.1 mL, 110.24 mmol) and Bu4NI (6.79 g, 18.37 mmol). The reaction mixture was stirred at 0° C. for 2H and concentrated in vacuo. The residue is taken up in AcOEt, the organic phase was washed with a saturated aqueous NaHCO3 and H2O. The organic phase was dried over MgSO4 and the solvent removed in vacuo. Flash chromatography of the residue on silica gel (n-heptane/EtOAc, 9:1) provided compound C-9 (6.00 g 75%) as a colorless oil. 13C-NMR (62.89 MHz, CDCl3): 24.42, 28.34, 33.37, 34.13, 66.08, 114.73, 128.19, 128.55, 136.16, 138.37, 173.43.