Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[NH:21][C:20](=[O:23])[N:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[CH2:24]([N:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:22]=2[NH:21][C:20]1=[O:23])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2[nH]c(=O)n3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c(N3CCNCC3)cccc2n1Cc1ccccc1

Procedure:
To a solution of 0.112 g of 4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 15 mL ethyl acetate with 5 mL ethanol is added 3 mL of 2M ethanolic hydrogen chloride. The resulting solution is refluxed for one hour, and on cooling, a solid precipates. The solid is filtered and dried over night under vacuum to give 82 mg of 1-benzyl-4-piperazin-1-yl-1,3-dihydro-benzoimidazol-2-one hydrochloride. MS: 309 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:11]1[CH:10]=[C:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1)=[C:16]=[S:17]
Reactant: COc1ncccc1-c1ccnc(N)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1ncccc1-c1ccnc(N=C=S)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.62 g, 2.7 mmol) and the reaction mixture was stirred at 40° C. for 4 hours. The reaction was cooled to room temperature and chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield 2′-isothiocyanato-2-methoxy-3,4′-bipyridine (0.46 g, 1.9 mmol, 71.8% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.67 (d, J=2.44 Hz, 1H), 8.26 (dd, J=4.88, 1.53 Hz, 1H), 8.15 (dd, J=8.24, 2.44 Hz, 1H), 7.89 (dd, J=7.32, 1.53 Hz, 1H), 7.48 (d, J=8.24 Hz, 1H), 7.15 (dd, J=7.32, 4.88 Hz, 1H), 3.91 (s, 3H). MS (LC/MS) R.T.=2.87; [M+H]+=244.9.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([Cl:21])[C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:22])[CH:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:22][C:4]1[CH:3]=[C:2]([NH:1][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:20]=[C:19]([Cl:21])[C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C:8]1=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Product: O=C1C(Cc2c(Cl)cc(NS(=O)(=O)c3ccccc3)cc2Cl)CCN1C1CCCCC1
Yield: 65.2 %

Procedure:
Using the procedure to synthesize Example 250 and using reagents 3-(4-amino-2,6-dichlorobenzyl)-1-cyclohexylpyrrolidin-2-one (250 mg, 0.73 mmol) and benzene sulfonyl chloride (0.19 mL, 1.5 mmol) affords 229 mg (65%) of the title compound. Mass spectrum (apci) m/z=481.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH:14]([C:16]1[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]2[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]2)=[O:15].[Cl-].[NH4+]>C1(C)C=CC=CC=1.ClCCl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:15])[C:16]2[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(O)c2ccc(Br)cn2)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (2.00 g, 8.44 mmol) in 50 mL of toluene at −78° C. was added n-butyllithium (2.5 M in toluene, 4.05 mL, 10.1 mmol) dropwise. After 2 h, a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (1.86 g, 7.60 mmoL) in 50 mL of dichloromethane was added dropwise. The mixture was warmed to rt, and after 1 h, treated with saturated aqueous ammonium chloride and concentrated in vacuo. The residue was redissolved in dichloromethane, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 30-100% ethyl acetate in hexanes to provide ethyl 1-[(5-bromopyridin-2-yl)(hydroxyl)methyl]-4-oxo-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 404.7 (81Br) for [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C@@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]([C@H:16]([NH:15][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:26])=[O:25]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Product: O=C(O)c1cc2ccccc2nc1N[C@H](Cc1ccccc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2-chloroquinoline-3-carboxylic acid is reacted with D-phenylalanine to provide the title compound in moderate yield.
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:14]Br.Cl>CO.O>[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:14]=[O:5]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1c(Cl)ccc(Cl)c1CBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(Cl)ccc(Cl)c1C=O
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
122.4 g (0.68 mol) of a 30% strength solution of sodium methoxide are dissolved in 1030 ml of methanol, and 56.4 g ( 0.57 mol) of 90% pure 2-nitropropane and 188.5 g (0.52 mol) of 61.6% pure 3,6-dichloro-2-methylbenzyl bromide are then added. The reaction is exothermic to 53° C., and the mixture is then stirred for 90 min. The reaction mixture is poured into 2.5 l of water, the pH is adjusted to pH 7.0 using 10% strength HCl, the mixture is extracted three times with 1 l of ethyl acetate, and the organic phases are combined, washed twice with 500 ml of saturated NaCl solution, dried over Na2SO4 and concentrated under reduced pressure: the 161.0 g of crude product are distilled using a 10 cm column packed with 10 mm Raschig rings. The crystals from the last fractions are filtered. This gives 9.8 g comprising 85.9% of the desired product and 4.5% and 6.9% of isomers. Yield: 9.7%. The residue is distilled over a Spaltrohr column, giving another 3.2 g of 94.3% pure product.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.CC(O)C>ClCCl>[CH2:1]([S:8]([C:9]1[N:10]=[CH:11][C:12]([Cl:15])=[CH:13][N:14]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cnc(SCc2ccccc2)nc1
Solvent: ClCCl
Solvent: CC(C)O
Product: O=S(Cc1ccccc1)c1ncc(Cl)cn1
Yield: 88 %

Procedure:
The oxidation of 2-benzylthio-5-chloropyrimidine was carried out using one molar equivalent of 85% m-chloroperbenzoic acid in dichloromethane, initially at -10° C. and then at 0° C., as described in Example 40 above; yield 88%, m.p. 92° C. (iPrOH). 1H NMR (CDCl3) δ4.30 and 4.33 (CH2), 7.23 (Ph), 8.73 (H-4, H-6).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][NH:50][CH3:51])[CH3:46]>C(N(CC)CC)C.C1COCC1>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][N:50]([C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=1)[CH3:51])[CH3:46]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CNC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)C(=O)c1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-fluorobenzoyl)benzoic acid (3.00 g), 1-hydroxybenzotriazole (2.07 g), 1,3-dicyclohexylcarbodiimide (3.00 g) and anhydrous THF (50 ml) was stirred at room temperature for 1 hour. To this mixture were added N-methylglycine ethyl ester hydrochloride (2.84 g) and triethylamine (2.58 ml), followed by stirring at room temperature for 16 hours and with heating and refluxing for 4 hours. After the solvent was distilled off, ethyl acetate was added to the residue, and the insoluble crystals were separated by filtration. The filtrate was washed successively with water, aqueous sodium hydrogen carbonate, water, dilute hydrochloric acid and water and then dried, after which the solvent was distilled off, to yield N-[2-(4-fluorobenzoyl)benzoyl]-N-methylglycine ethyl ester as a colorless oily substance (4.2 g).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:6]([CH:12]=[O:13])=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1>C1COCC1>[Cl:4][C:5]1[C:6]([CH:12]([OH:13])[CH3:1])=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=Cc1nc(Cl)ccc1Cl
Solvent: C1CCOC1
Product: CC(O)c1nc(Cl)ccc1Cl
Temperature: 0 °C

Procedure:
Methyl magnesium bromide (3.0M Et2O, 0.25 mL, 0.75 mmol) was added dropwise to a THF (2 mL) solution of 3,6-dichloropyridine-2-carbaldehyde (100 mg, 0.57 mmol) cooled to 0° C. After 1 hour the solution was partitioned between ethyl acetate and 1N aqueous HCl. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J=8.4 Hz, 1H); 7.30 (d, J=8.2 Hz, 1H); 5.22-5.14 (m, 1H); 3.83 (d, J=8.7 Hz, 1H) 1.50 (d, J=6.5 Hz, 3H). LCMS1 2.40 min. (M−H2O)=174
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1([F:42])[O:34][C:33]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:32]=2[O:31]1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:42][C:30]1([F:29])[O:31][C:32]2[CH:38]=[CH:37][C:36]([O:27][C:25]3[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:35][C:33]=2[O:34]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OC(F)(F)O3)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 1.4 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.20 g, 0.493 mmol), (2,2-difluoro-1,3-benzodioxol-5-yl)boronic acid (303 mg, 1.5 mmol), copper (II) acetate (0.202 g, 1.11 mmol), triethylamine (0.52 mL, 3.71 mmol) and freshly activated 4 Å molecular sieves (1 g) in DCM (40 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through celite, washed with DCM (2×10 mL), the DCM removed in vacuo. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of the residual oil dissolved in methanol (5 mL) and the mixture stirred at room temperature for 20 minutes. The solution was neutralised with saturated sodium bicarbonate solution, the methanol removed in vacuo and the residual solution partitioned between ethyl acetate (50 mL) and water (10 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 3% methanol in DCM, to give the desired compound (3.1 mg).
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([OH:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[O:13][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1F
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(C=O)c(F)c1[N+](=O)[O-]

Procedure:
Using 2-fluoro-4-hydroxy-3-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a white solid: ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:1](=[O:18])[O:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNCc1cccc([N+](=O)[O-])c1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.65 g, 6.6 mmol) was added to a solution of N-methyl-1-(3-nitrophenyl)methanamine (1 g, 6 mmol) in CH2Cl2 (24 mL) and DIEA (2.7 mL, 15 mmol) and the reaction mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 (100 mL), washed with NH4Cl, NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo to yield 60A (1.75 g, 99%) as a white solid. MS (ESI) m/z 301.03 (M+H)+.
Reaction SMILES: C([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:30]=1)[C:22]1[CH:21]=[C:20]([Cl:23])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:24]4[CH:25]=[N:26][CH:27]=[N:28][CH:29]=4)=[CH:13][CH:14]=3)[C:9]3([CH2:8][S:7][C:6]([NH2:5])=[N:30]3)[C:22]=2[CH:21]=1
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(CS1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 25 °C

Procedure:
A vial was charged with rac-N-tert-butyl-2′-chloro-7′-(5-pyrimidinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine (63.0 mg, 144 μmol) and TFA (1111 μl, 14418 μmol) resulting in a dark orange mixture. The vial was capped and placed in a 150° C. oil bath for 2 d. The reaction mixture cooled to RT, poured into 6N NaOH (aq.), and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-50% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give racemic-2′-chloro-7′-(5-pyrimidinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine as an off-white solid. MS m/z=381.0 [M+H]+. Calc'd for C19H14ClN4OS: 381.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:17][CH2:18][CH:19]=[O:20])[CH2:12][CH2:13][CH:14]=[CH:15][CH3:16]>C1C=CC=CC=1>[CH2:11]([N:17]([CH2:18][CH:19]=[O:20])[C:9]([NH:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH2:13][CH:14]=[CH:15][CH3:16]
Reactant: CC=CCCCNCC=O
Reactant: CSc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CC=CCCCN(CC=O)C(=O)Nc1nnc(SC)s1

Procedure:
A mixture of 5-methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-hex-4-enylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the diethyl acetal of 2-[1-hex-4-enyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: C(CC[O:5][P:6]([O-])([O-:8])=[O:7])#N.[N:10]([C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14]1)=[N+:11]=[N-:12].C1(N=C=NC2CCCCC2)CCCCC1.O>N1C=CC=CC=1.[OH-].[K+]>[P:6]([O:19][CH2:18][C@H:17]1[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14][C@@H:13]1[N:10]=[N+:11]=[N-:12])([OH:8])([OH:7])=[O:5]
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
A freshly prepared pyridinium salt of 2-cyanoethylphosphate (8.05 g, 23.64 mmol) was added to a solution of 3'-azido-2',3'-dideoxyuridine (2.50 g, 9.7 mmol) in dry pyridine (50 ml) and evaporated to dryness at 30° C. The concentrated residue was dissolved in pyridine (50 ml) and the solution again evaporated to dryness. The process was repeated twice and then the residue obtained was dissolved in dry pyridine (50 ml). Dicyclohexylcarbodiimide (8.08 g, 39.1 mmol) was added to the solution. The reaction mixture was stirred for 48 hours at room temperature. Water (10 ml) was added and the solution was then filtered to remove dicyclohexylurea. The clear solution was evaporated to dryness. The residue obtained was then dissolved in 1N KOH (250 ml) and heated for 15 minutes at 100° C. The cold solution was passed through a column of acidic Dowex 50 (H+), the effluent brought to pH 9 and passed through a column of Dowex (1×4 Cl-). A linear gradient elution of 0.015N HCl to 0.15N HCl resulted in 3'-azido-2',3'-dideoxyuridine-5'-monophosphate with a 73% yield.
Reaction SMILES: [Li].Br[CH:3]1[CH:7]2[CH2:8][CH2:9][CH:4]1[CH2:5][CH2:6]2.[C:10](=[O:12])=[O:11]>O1CCCC1>[CH:7]12[CH:3]([C:10]([OH:12])=[O:11])[CH:4]([CH2:9][CH2:8]1)[CH2:5][CH2:6]2
Reactant: BrC1C2CCC1CC2
Reactant: O=C=O
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(O)C1C2CCC1CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-4′-di-t-butylbiphenyl (8.25 g, 31 mmol) in anhydrous tetrahydrofuran (70 mL) under a nitrogen atmosphere was added freshly cleaned lithium wire (0.21 g, 30 mmol). The resulting mixture was stirred at room temperature for 15 minutes to initiate reaction, then cooled in an ice bath and stirred for an additional 4 hours. The resulting blue solution was cooled with a dry ice/acetone bath and a solution of 7-bromo-bicyclo[2.2.1]heptane (2.0 g, 11.4 mmol) in anhydrous tetrahydrofuran (5 mL) was added in one portion. The reaction mixture was stirred for 20 minutes, during which time the blue color changed to orange. Solid dry ice was then added to the reaction, which became colorless. The dry ice bath/acetone bath was removed and the reaction was stirred for 2 hours, during which time it came up to room temperature. 2.5 N aqueous sodium hydroxide (200 mL) was added and the mixture was stirred for 5 minutes. The layers were separated and the aqueous layer was extracted twice with diethyl ether (50 mL). The aqueous layer was then made acidic by addition of concentrated HCl and extracted with three portions of diethyl ether (75 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to yield the desired compound of formula (VIII) as a white solid (1.54 g, 96%), mp=74–75 ° C. (lit. mp=77.5–785° C., J. Am. Chem. Soc. 1954, 76, 4072).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(OCC)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([Br:32])[CH3:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(O)c1ccc(C#N)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(Br)c1ccc(C#N)cc1

Procedure:
To a solution of 1-(4-Cyanophenyl)ethanol 1.01 g, 6.84 mmol), in diethyl ether (15 ml) and triphenylphosphine (2.14 g, 8.17 mmol), was added carbon tetrabromide (2.82 g, 8.50 mmol) in dieathylether (20 ml) at room temperature. After 30 min the reaction was filtered through celite and evaporated to dryness. The residue was purified by chromatography (SiO2, 5% EtOAc in hexanes) to afford the title compound as an oil
Reaction SMILES: [CH:1]1([C:4]([OH:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.N1C=CN=C1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH:1]1([C:4]([O:12][Si:19]([CH3:22])([CH3:21])[CH3:20])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCCC)C1CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 27.8 g. of 4-cyclopropyl-4-hydroxy-1-octyne (Example 9) and 33.3 g. of imidazole in 130 ml of dimethylformamide at 5° C. is added 24 ml. of chlorotrimethylsilane during 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned with 600 ml of hexane and 250 ml of ice-water. The hexane phase is separated and washed successively with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid, p.m.r. spectrum (C D Cl3):δ0.12 (singlet, trimethylsiloxy group), 2.02 (triplet, HC≡C), and 2.45 (doublet, C≡CH2).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:7][CH2:6][N:5]1[CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH3:3]>CCO.[Pd]>[CH3:3][CH:2]([C@@H:4]1[N:5]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:9]1)[CH3:1]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1N
Yield: 99.1 %

Procedure:
(2S)-2-(1-Methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]-1-[2-(methylsulfonyl)-ethyl]piperazine (0.382 g, 0.991 mmol) was dissolved in 15 mL of EtOH with stirring. 10% Palladium on carbon (0.105 g, 0.0987 mmol) was added, and the reaction was placed under 1 atm of H2 using a balloon. The reaction was stirred for 8 h and filtered through celite washing with EtOAc. The filtrate was concentrated in vacuo to provide the title compound of step G (0.349 g, 0.982 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ 6.47 (d, J=8.4 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 6.25 (dd, J=8.4, 2.4 Hz, 1H), 4.17 (br. s., 2H), 3.69 (s, 3H), 3.28-3.39 (m, 1H), 3.04-3.23 (m, 4H), 2.98 (s, 3H), 2.90 (d, J=11.0 Hz, 1H), 2.70-2.81 (m, 1H), 2.48-2.58 (m, 1H), 2.30-2.44 (m, 2H), 2.16-2.25 (m, 1H), 2.02-2.15 (m, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.83 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:15]>>[CH3:1][O:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[O:15][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: COc1ccc(C(=O)CBr)c(OC)n1
Product: COc1cc(OC)c2cc(-c3ccc(OC)nc3OC)oc2c1
Yield: 53 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(2,6-dimethoxypyridin-3-yl)ethanone: Yield 53% following procedure A.2; m.p. 155-156° C.; IR 2937, 2961, 1605, 1504, 1475, 1460, 1272, 1107, 1011 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 8.12 (d, J=8.2 Hz, 1H), 7.18 (s, 1H), 6.66 (s, 1H), 6.41 (d, J=8.2 Hz, 1H), 6.32 (s, 1H), 4.10 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.85 (s, 3H); 13C-NMR (126 MHz, δ ppm, CDCl3) 161.9, 159.1, 158.7, 155.9, 153.7, 149.7, 137.4, 113.9, 106.7, 101.7, 101.5, 94.3, 88.4, 55.9, 55.8, 53.8, 53.7.