Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][CH:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)[CH2:14]Br.Cl>C(#N)C>[Br:12][C:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)=[CH2:14]
Reactant: Oc1ccc(-c2nc3cc(O)cc(C(Br)CBr)c3o2)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(Br)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 24 h
Yield: 58 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.25 g, 1.65 mmol) was added into a solution of 7-(1,2-dibromoethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (0.4 g, 0.96 mmol) and acetonitrile (4 mL). The reaction mixture was stirred for 24 h, poured into cold (0° C.) HCl (1N, 10 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/isopropyl alcohol 15/5/1) gave a white solid (185 mg, 58% yield, m.p. 228-230° C.); MS m/e 332 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][S:12][C:11](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:10]2=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(OC(Cl)C)=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][S:12][C:11](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:10]2=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCN(c2ccccc2C=C2SCCN(c3ccc(Cl)c(Cl)c3)C2=O)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C1C(=Cc2ccccc2N2CCNCC2)SCCN1c1ccc(Cl)c(Cl)c1

Procedure:
Under a nitrogen atmosphere, a mixture of 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one (338 mg, 0.756 mmol) in 9 mL of anhydrous 1,2-dichloroethane was treated with a-chloroethyl chloroformate (98 μL 0.907 mmol) and refluxed overnight. The solvent was then removed in vacuo and 10 mL of methanol was added and refluxed for 30 minutes. Following removal of the solvent, the residue was extracted into methylene chloride and washed with saturated aqueous sodium carbonate (Na2CO3) and saturated brine, dried with magnesium sulfate and concentrated to a foam. Flash chromatography using triethyl amine/methanol/ethyl acetate (1:2:97) gave the purified free base of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([S:15]([O-:18])(=[O:17])=[O:16])[CH:3]([O:8]C(=O)C(C)(C)C)[C:4]([F:7])([F:6])[F:5].[Na+:20].[OH-].[Na+].Cl>CO>[F:19][C:2]([F:1])([S:15]([O-:18])(=[O:16])=[O:17])[CH:3]([OH:8])[C:4]([F:5])([F:7])[F:6].[Na+:20]
Reactant: CC(C)(C)C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F

Procedure:
Ester hydrolysis reaction was effected using sodium 1,1,3,3,3-pentafluoro-2-(pivaloyloxy)propanesulfonate, which was prepared according to the formulation described in JP-A 2007-145797, and a sodium hydroxide aqueous solution in methanol. After the completion of reaction, hydrochloric acid was added to turn the reaction system from neutral to weakly acidic. The aqueous solution was directly used in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:21](I)([CH3:23])[CH3:22].O>CN(C=O)C.CCOC(C)=O>[CH:21]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:23])[CH3:22]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 100 °C
Reaction time: 19 h

Procedure:
In a sealed tube, to a suspension of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (566.9 mg, 2.922 mmol) and Cs2CO3 (1.5442 g, 4.739 mmol) in DMF (6 mL), isopropyl iodide (753.3 mg, 4.431 mmol) was added and the reaction was allowed to stir at 100° C. for 19 h. Water was added to dilute the reaction and dissolve all salts that had formed, after which EtOAc was added and the two layers were separated. The organic layer was washed twice with water and once with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The combined aqueous layers were back extracted once with EtOAc, which was combined with the other organic batch. One obtained the title material as yellow oil. It was used without further purification in the next step. 1H NMR (400 MHz, CDCl3): δ=1.33 (s, 12H), 1.51 (d, J=6.8 Hz, 6H), 4.53 (spt, J=6.7 Hz, 1H), 7.75 (s, 1H), 7.80 (s, 1H). MS (AP+): m/z 235.98 (76) [MH+]. HPLC: tR=3.22 min (ZQ3, polar—5 min).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+]>C(O)C>[C:12]1([CH3:15])[CH:13]=[CH:14][C:9]([NH:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(C)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
Ethyl bromoacetate (4.0 g, 30.0 mmol) was added to a solution of p-toluidine (2.1 g, 20 mmol) and sodium acetate (2.1 g, 26 mmol) in ethanol (26 mL). The resulting solution was warmed to 80° C. and stirred for 1 h before being cooled to room temperature. The reaction was quenched with water (20 mL) and the aqueous fraction extracted with ethyl acetate (3×20 mL). The organic fractions were combined, dried (MgSO4) and filtered, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-(p-tolylamino)acetate as a pale oil (1.9 g, 50%). Ethyl 2-(p-tolylamino)acetate (260 mg, 1.4 mmol) was dissolved in toluene (5 mL). Methyl benzylisocyanate (200 mg, 1.4 mmol) was added to this solution. The mixture was heated to reflux and stirred for 5 h, until TLC analysis demonstrated that the reaction was complete. The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate as a pale oil (455 mg, 98%). Ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate (455 mg, 1.3 mmol) was dissolved in THF (10 mL) and added dropwise to a solution of NaH (68 mg, 2.8 mmol) in THF (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature slowly and stirred for 18 h before the reaction was quenched with water (5 mL). The aqueous fraction was then extracted with dichloromethane (3×20 mL). The organic fractions were combined, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. Column chromatography (0-20% ethyl acetate/hexane) provided 14 as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[F:37][C:24]([F:23])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 3 h
Yield: 69.8 %

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5 g, 19.19 mmol, supplier Aldrich), in DCM (80 mL), DIPEA (5.03 mL, 28.8 mmol) was added under argon atmosphere at room temperature then 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (2.326 mL, 19.19 mmol) was added at 0° C. then ice bath was removed and the reaction mixture was stirred for 3 hrs. The reaction mixture was partitioned between DCM (30 ml) and sodium bicarbonate (2×20 ml). The organic phase was washed with HCl (2×20 ml) and water (2×20 ml), then it was dried using phase separator and DCM was removed under vacuum to give the title compound (5.5 g) as a yellow viscous liquid.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.C[O-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([CH2:17]Cl)[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1>CO.O>[NH2:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:17][S:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)[N:16]=1
Reactant: SC1=NCCS1
Reactant: COc1cc(CCl)nc(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(CSC2=NCCS2)nc(N)n1
Reaction time: 1 h

Procedure:
11.9 g of 4,5-dihydro-2-mercapto-thiazole are suspended in 100 ml of methanol, and to the suspension are added 18.0 g of 30% methanolic, sodium methylate solution. To the formed clear solution are subsequently added 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and refluxing is carried out for 1 hour. After the solution has cooled, it is diluted with about 1 liter of water, and the product which precipitates is separated and dried. The yield is 22.5 g (88% of theory) of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl-thiomethyl)-pyrimidine, m.p. 122°-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[C:12]=2[N+:23]([O-])=O)=[O:10])=[N:6][CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:23][C:12]1[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: COc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])c(OC)c1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)Nc2ccc(Br)cn2)c(N)c(OC)c1OC
Yield: 77.7 %

Procedure:
To a solution of the compound of N-(5-bromo(2-pyridyl))(3,4,5-trimethoxy-2-nitrophenyl)carboxamide (790 mg, 1.92 mmol) in ethyl acetate (5 ml) was added tin chloride (11) hydrate (1.73 g, 7.67 mmol). The mixture was stirred under reflux condition for 2 hrs. After filtered by Celite, the filtrate was added 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give (2-amino-3,4,5-trimethoxyphenyl)-N-(5-bromo(2-pyridyl))carboxamide (570 mg, 77%). MS found for C15H16BrN3O4 M+=382, (M+2)+=384.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[O:14][CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1

Procedure:
reacting a 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone of the formula, ##STR14## wherein Bn is as hereinbefore defined with one equivalent of BnBr and one equivalent of triethlyamine in THF for 5 hours at 65--C to provide 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone of the formula, ##STR15## wherein Bn is as hereinbefore defined;
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[OH:63])[CH3:56]>C(Cl)(Cl)Cl>[Br:1][C:61]1[CH:60]=[CH:59][C:58]([OH:63])=[C:57]([CH2:55][CH3:56])[CH:62]=1
Reactant: [Br-]
Reactant: CCc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1O
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of tetrabutyl ammonium tribromide (41.4 g, 86 mmol) in CHCl3 (100 mL) was added to a stirred solution of 2-ethyl phenol (10 g, 81.8 mmol) dissolved in CHCl3 (100 mL). The reaction mixture was stirred for 1 hr and then quenched with 5% solution of sodium thiosulfate (100 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (0-10% EtOAc in hexanes) to give the desired product (14.3 g, 87%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.64 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5, 2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH3:13])[CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:13])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of A-3 (methyl 4-cyano-2-methylbenzoate) (38 g, 0.217 mol) in ethanol (450 mL) was added aqueous sodium hydroxide solution (150 mL, 2.9 M), and the mixture was stirred at room temperature for 12 h. Most of ethanol was removed under reduced pressure, and the residue was diluted with water (300 mL). The aqueous layer was washed with ethyl ether (200 mL×2), and the aqueous layer was acidified with hydrochloric acid (450 mL, 1 M) under 0° C. to pH<6. The mixture was extracted with ethyl acetate (400 mL×3), and the organic layer was washed with brine, dried, and evaporated to give A-4 (4-cyano-2-methylbenzoic acid) (40 g, yield 100%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]1=[O:14])(=[O:3])[CH3:2].[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH2:25]>O1CCCC1>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH:25][C:11](=[O:13])[CH2:10][N:7]1[CH2:8][CH2:9][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]1=[O:14]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Solvent: C1CCOC1
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid is placed in 15 ml of absolute tetrahydrofuran, whereupon 0.89 g of N,N'-carbonyldiimidazole is added in one portion. The mixture is stirred at room temperature until the gas evolution is complete. Thereafter, 0.86 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine is added and the mixture is left to stand overnight at room temperature and then evaporated. The residue is chromatographed on 60 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride has a melting point of 121°-122° after trituration with diethyl ether.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(C1C=CC=CC=1C(C1C2C(=CC=CC=2)N(CC2C=CC=CC=2)C=1C)=O)(O)=O>>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: Cc1c(C(=O)c2ccccc2C(=O)O)c2ccccc2n1Cc1ccccc1
Product: O=C1OCc2ccccc21

Procedure:
If the 3-(2'-carboxybenzoyl)-1-ethyl-2-methyl-indole in Example 1 is replaced by an equimolar amount of 3-(2'-carboxybenzoyl)-1-benzyl-2-methyl-indole, with the procedure otherwise being as described in Example 1, there is obtained 4.5 g of a phthalide compound of the formula ##STR12## which melts at 138°-142° C. This colour former develops on silton clay a blue colour of λmax. 600 nm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]([CH3:12])[CH3:11].[O:13]=O.Cl>C1(C)C=CC=CC=1.C(OP(OCC)OCC)C.CN(C)C=O>[OH:13][C:10]([C:3]1[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=1)([CH3:12])[CH3:11]
Reactant: O=O
Reactant: CC(C)c1ncc([N+](=O)[O-])n1C
Agent: CCOP(OCC)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1c([N+](=O)[O-])cnc1C(C)(C)O
Yield: 23.8 %

Procedure:
A total of 45 ml of a 2.25-N solution of sodium tert.amylate in toluene and 11.2 ml of triethylphosphite were added to a solution, cooled to -15°, of 8.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 85 ml of dimethylformamide. A strong oxygen stream was conducted through this mixture for 6 hours at a temperature of -10° to -15° while stirring vigorously. The mixture was then neutralized by the addition of 45 ml of 2-N hydrochloric acid and concentrated on a rotary evaporator at 50°/12 Torr. The residue was taken up in 250 ml of water and the aqueous solution extracted 3 times with 250 ml portions of dichloromethane. The combined dichloromethane extracts were washed with a small amount of water and concentrated to dryness. The residue was then taken up in ethyl acetate and chromatographed on 600 g of silica gel with ethyl acetate. After evaporation of the solvent on a rotary evaporator and crystallization from isopropyl ether, there were obtained 2.2 g of 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole, melting point 106°-108°. The yield was 23.8%.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:7]2[C:8](=[O:32])[CH:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:6]2[S:5][CH:4]=1.[H-].[Na+].[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)[CH2:37][CH2:36]1.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>CS(C)=O>[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2/[CH:42]=[CH:12]/[C:10]2[N:11]=[C:6]3[S:5][CH:4]=[C:3]([CH3:2])[N:7]3[C:8](=[O:32])[CH:9]=2)[CH2:36][CH2:37]1
Reactant: Cc1csc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc(=O)n12
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3c(C)csc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.096 mmol) in dry DMSO (12 ml) was treated with NaH (92 mg, 2.306 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (475 mg, 2.306 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford 260 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H), 1.18-1.22 (m, 1H), 2.66 (s, 3H), 3.73-3.76 (m, 2H), 3.79 (s, 3H), 6.15 (s, 1H), 6.97-7.13 (m, 4H), 7.30-7.33 (m, 1H), 8.07 (d, J=16.2 Hz 1H); ESI-MS (m/z) 369.26 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:10]1CC[CH2:12][CH2:11]1.[H-].[Na+]>CO.C(OCC)(=O)C>[N:1]1([CH2:12][CH2:11][OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCCn1cnc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 2.3 g benzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 1.0 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 4.0 g 2-Todoethanol were added and the mixture was heated to 50 C for 16 hours. The mixture was quenched slowly with 50 ml water, extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 25% methanol in ethyl acetate. A solid was obtained that was dissolved in a hot mixture of 10% methanol in ethyl acetate, cooled, filtered and dried giving 1.4 g white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)nc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Methyl 6-chloronicotinate (5.0 g) was dissolved in DMF (75 ml) at r.t. under an argon atmosphere. 1-Methylpiperazine (3.66 ml) and diisopropylethylamine (30.7 ml) were added and the solution was stirred for 5 hours at 80° C. The reaction was quenched with water. The solution was extracted with EtOAc. The water phase was twice washed with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 6-(4-methyl-piperazin-1-yl)-nicotinic acid methyl ester (5.59 g) as light yellow solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13]O>OS(O)(=O)=O>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCOc1ccccc1
Yield: 92.5 %

Procedure:
3-phenoxypropionic acid (5.0 g, 30 mmol) was dissolved in MeOH (12 mL) and H2SO4 (18 M, 3 drops) was added. The mixture was place in the microwave reactor (T: 140° C., t: 5 min). The solvent was evaporated, the mixture was partitioned in EtOAc (30 mL) and NaOH (2N, 20 mL). The organic phase was dried over MgSO4, filtered, and evaporated to give methyl 3-phenoxypropanoate (5.0 g, 27.7 mmol, 92.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[O:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:29][C:28]3[C:23]([O:22][CH:19]4[CH2:20][CH2:21][O:16][CH2:17][CH2:18]4)=[N:24][CH:25]=[CH:26][CH:27]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1cccnc1OC1CCOCC1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C

Procedure:
Prepared analogously to 1.1 from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 2-(tetrahydro-pyran-4-yloxy)-pyridin-3-ylamine.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1.CO.O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 71.4 %

Procedure:
The ester 35a (405 mg, 1.0 mmol) was dissolved in 15 ml THF and 50 ml methanol was added. Water (approximately 10 ml) was added until the solution remained cloudy with vigorous stirring, at which time lithium hydroxide monohydrate (840 mg, 20.0 mmol) was added. The reaction mixture was refluxed overnight, acidified with concentrated HCl and cooled. The precipitate was filtered, washed with water and air dried to yield 279 mg (71%) of a white powder.