Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 16 h
Yield: 61.9 %

Procedure:
(3) 4-Hydroxybenzaldehyde (20 g, 0.164 mol) was dissolved in DMF (60 ml) and stirred at RT as imidazole (22.3 g, 0.328 mol) and tert-butyldimethylsilyl chloride (32.1 g, 0.213 mol) were added. The reaction mixture was stirred for 16 h. The solution was diluted with EtOAc, washed with water, brine, then dried (MgSO4) and concentrated in-vacuo to afford 24 g of crude 4-(tert-butyldimethylsilanyloxy)benzaldehyde.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.C([N:51](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.N>CN(C=O)C.CO>[NH2:51][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:26]=[CH:27][C:15]([CH2:14][C@H:13]([NH:12][C:10](=[O:11])[O:9][C@@H:3]2[C@H:4]3[C@H:5]([O:6][CH2:7][CH2:8]3)[O:1][CH2:2]2)[C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:16][CH:17]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of 25 mg (0.037 mmol) of 4-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)butanoic acid and 19 μL (0.11 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF was treated with 28 mg (0.074 mmol) of O-(7-azabenzotriazol-* 1-yl) 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). The resulting solution was stirred at RT for 15 minutes and was then treated with 0.5 mL of 2M NH3 in MeOH. After 20 minutes TLC indicated the reaction to be complete. The solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 11 mg (44%) of the desired compound as a white powder. 1H NMR (CDCl3): 7.30 (d, 1H), 7.14 (s, 1H), 7.07 (d, 2H), 6.85 (d 2H), 6.75 (d, 2H), 6.05 (s, 2H), 5.60 (d, 1H), 5.56-5.34 (m, 2H), 4.97 (m, 2H), 3.94 (m, 3H), 3.78 (m, 3H), 3.66 (m, 2H), 3.09 (m, 1H), 3.00-2.64 (m, 7H), 2.40 (t, 2H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.48 (m, 1H), 0.90 (d, 3H), 0.82 (d, 3H). MS(ESI): 678(M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CO>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:4][C:3]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=2[CH3:1])[CH:18]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1
Temperature: 110 °C
Yield: 78.6 %

Procedure:
2.64 g of 2-methyl-5-nitroaniline and 10.33 g of 4,6-dichloropyrimidine were stirred with heating at 110° C. for 16 hours. After air cooling, the reaction solution was dissolved in methanol. An aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added to separate the aqueous layer. The aqueous layer was further subjected to extraction with ethyl acetate twice. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was washed with diisopropyl ether to obtain 3.61 g of the objective compound as yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[N:4]1)[CH3:2].[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>>[CH2:36]([NH:38][C:39]([NH:33][C:32]1[CH:31]=[CH:30][C:29]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][C:15]([C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]6[CH2:28][CH2:27][CH2:26][CH2:25]6)=[CH:21][CH:22]=5)=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:35][CH:34]=1)=[O:40])[CH3:37]
Reactant: CCN=C=O
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)cc1

Procedure:
Following the procedure described in Example 48 4-(1-ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 534.4
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18]([NH:21][NH2:22])(=O)[CH3:19]>C(O)CCC>[CH3:19][C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:22][N:21]=1
Reactant: CC(=O)NN
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(C(F)(F)F)cc3)nn12

Procedure:
A mixture of 4.50 g. of 3-chloro-6-(α,α,α-trifluoro-p-tolyl)pyridazine, 2.58 g. of acethydrazide and 100 ml. of n-butanol is heated at reflux temperature for 3 days. The solvent is removed and the resin dissolved in methylene chloride, passed through magnesol and the solid from the filtrate recrystallized from methylene chloride/hexane to afford the product as tan crystals, m.p. 199°-201° C.
Reaction SMILES: C1([C@H](N[C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])C)C=CC=CC=1.CC[O-:30].[Na+]>CCO>[O:30]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of 252D (460 mg, 1.22 mmol) and NaOEt (1.25 mL, 21% wt in EtOH) in EtOH (10 ml) was stirred at 50° C. for 3 hrs, then at RT for about 48 hours. The reaction mixture was concentrated in vacuo, followed by the addition of water. The mixture was acidified with 1N HCl to pH 4–5 and the solid was collected by filtration, washed with water and dried to give 300 mg (yield: 71%) of 252A. It had an analytical HPLC retention time=2.065 min. (Chromolith SpeedROD column 4.5×50 mm, 10–90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm). Mass (M+1)+=349.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[C:7]([NH:9]N)[CH:8]=1.O.[NH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl>CCO>[Br:2][C:3]1[C:8]2[C:19]3[CH2:18][NH:17][CH2:22][CH2:21][C:20]=3[NH:9][C:7]=2[C:6]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:5][CH:4]=1
Reactant: O=C1CCNCC1
Reactant: NNc1cc(Br)ccc1SCCCCl
Agent: Cl
Solvent: O
Solvent: CCO
Product: ClCCCSc1ccc(Br)c2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 58 %

Procedure:
1-{5-Bromo-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloride (784 mg, 2.4 mmol) and 4-piperidone monohydrate.HCl (398 mg, 2.6) were dissolved in EtOH (5mL). Conc. Hcl (0.2 mL, 2.4 mmol) were added. The reaction was refluxed for 18 hrs and then cooled to rt. The ppt was collected by filtration and the residue was washed with EtOH (3mL). 9-bromo-6-[(3-chloropropyl)sulfanyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloroide (500.4 mg, 58%) was isolated as a white powder. 1H NMR (CD3OD, 300 Mhz) δ7.18 (d, 1H, 8.0 Hz), 7.12 (d, 1H, 8.0 Hz), 4.73 (s, 2H), 3.64 (t, 2H, 6.6 Hz), 3.58 (t, 2H, 6.3 Hz), 3.16 (t, 2H, 6.3 Hz), 3.02 (t, 2H, 6.6 Hz), 1.87-1.96 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH2:14][CH2:13][CH2:12][CH:11]=3)=[C:7]([C:15]([NH:17][CH3:18])=[O:16])[C:6]=2[CH:19]=1.[Zn](CC)[CH2:27]C.C(I)I.[NH4+].[Cl-]>C(Cl)Cl>[C:10]12([C:8]3[O:9][C:5]4[CH:4]=[C:3]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:22])=[O:23])[C:2]([Br:1])=[CH:19][C:6]=4[C:7]=3[C:15]([NH:17][CH3:18])=[O:16])[CH2:27][CH:14]1[CH2:13][CH2:12][CH2:11]2
Reactant: CC[Zn]CC
Reactant: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: ClCCl
Product: CNC(=O)c1c(C23CCCC2C3)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 5-bromo-2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, 1.40 mmol) and ZnEt2 (15 mL, 14.04 mmol) in DCM (10 mL) was added dropwise CH2I2 (1.2 mL, 14.04 mmol) at 0° C., and then the mixture was stirred at 25° C. After 3 hours, 10 mL NH4Cl (a.q.) was added, and the mixture was extracted with DCM (30 mL*3), and dried over Na2SO4. After concentration, the residue was purified by column chromatography (DCM:EtOAc=3:1) to give the product of 2-(bicyclo[3.1.0]hexan-1-yl)-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.60 (s, 1H), 6.16 (d, J=2.0 Hz, 1H), 3.34 (s, 3H), 3.12 (d, J=4.8 Hz, 3H), 3.07 (s, 3H), 2.10˜2.21 (m, 2H), 2.01˜2.09 (m, 2H), 1.86˜1.99 (m, 2H), 1.38˜1.46 (m, 1H), 1.37 (d, J=4.0 Hz, 2H). MS (M+H)+: 441/443.
Reaction SMILES: Cl[CH2:2][P:3](=[O:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:7]([NH:14][CH2:2][P:3](=[O:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CP(C)(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCO
Product: CP(C)(=O)CNCc1ccccc1
Yield: 63 %

Procedure:
A solution of 316.3 g of chloromethyl-dimethylphosphine oxide, 547 ml of benzylamine and 500 ml of ethanol is refluxed for 18 hours. After cooling to 20° to 25° C., the turbid suspension is filtered; the clear filtrate is then concentrated by evaporation, and to the residue are added 500 ml of 10% sodium chloride solution. The aqueous solution is extracted 4 times with 500 ml of methylene chloride each time; and the combined organic phases are subsequently dried over sodium sulfate and concentrated by evaporation. Vacuum distillation of the oily crude product yields 311.0 g (63% of theory) of N-benzyl-P,P-dimethyl-aminomethylphosphine oxide in the form of yellowish oil, b.p. 150° C./0.2 mb.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].CCN(CC)CC.[CH3:24][O:25][CH2:26][C:27]#[CH:28]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:28]#[C:27][CH2:26][O:25][CH3:24])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: C#CCOC
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCC#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 55 °C
Yield: 77.7 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (3.0 g, 8.69 mmol) and Et3N (22 mL) in dry dioxane (22 mL) was purged with argon during 15 min. (Ph3P)2PdCl2 (305 mg, 0.435 mmol), CuI (166 mg) and 3-methoxy-propyne (2.20 mL, 26.08 mmol) were added and the mixture was heated to 55° C. for 100 min. After cooling, the reaction mixture was filtered and the filtrate diluted with EtOAc, washed with water and brine and dried (Na2SO4). Evaporation of the volatiles gave a residue which was purified by MPLC (silica gel, cyclohexane/EtOAc 4:1) to yield the title compound (1.94 g, 78%) as a beige solid, m.p. 107-111° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH3:16].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH2:24])[CH3:16]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccccc1-c1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccccc1-c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethanone (3.67 g, 15.8 mmol) in anhydrous methanol (200 mL) was added solid ammonium acetate (12.2 g, 158 mmol). The reaction mixture was heated at 60° C. for one hour, followed by the addition of a methanolic solution of sodium cyanoborohydride (5 mL, 1.99 g, 31.6 mmol). After 16 hours, the methanol was removed in vacuo and aqueous ammonium hydroxide was added. The aqueous phase was extracted with diethyl ether (3×200 mL) until the amine was no longer present in the aqueous phase. The combined organic phase was washed with 2 N aqueous hydrochloric acid (3×100 mL) and the aqueous phases combined. The solid formed during the acid wash was determined to be the dialkyated amine and was segregated from the aqueous phase. Aqueous sodium hydroxide was added to the acidic aqueous phase until the solution was neutralized to pH 8 to 9. The basic aqueous phase was extracted with diethyl ether until the primary amine was no longer detected in the aqueous phase. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford a clear oil that was used without further purification;
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[C:8]1([CH2:14][CH2:15][CH:16]=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[C:8]1([CH2:14][CH2:15][C@H:16]2[O:5][C:4](=[O:6])[CH2:3][C@@H:2]([CH3:7])[O:1]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CCCc1ccccc1
Reactant: C[C@@H](O)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CC(=O)O[C@H](CCc2ccccc2)O1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of (R)-3-hydroxybutanoic acid (7.8 g), 3-phenylpropionaldehyde (6.71 g) and pyridinium toluene-4-sulphonic acid (ca. 10 mmol %) in dichloromethane (300 ml) was stirred, under reflux, for 48 hours with removal of water. The reaction mixture was cooled to room temperature, washed three times with saturated sodium bicarbonate, dried (MgSO4) and evaporated under reduced pressure. The residue was crystallised from ether/pentane to give (2R,6R)-2-(2'-phenylethyl)-6-methyl-1,3-dioxan-4-one (7.0 g), m.p. 49.7°-50.9° C.; [α]DR.T. =15.2(c=1.05; CHCl3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([O:16][CH2:17][C:18]1[S:22][C:21]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])=[CH:20][CH:19]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)s1
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)s1

Procedure:
In a manner similar to Example 1(d), by reaction of 1.6 g (7 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 1.4 g (7 mmol) of allyl 5-hydroxymethyl-2-thiophenecarboxylate, 1.5 g (55%) of allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20].[Br-]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:20]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Br)CBr
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A solution of methyl anthranilate (10.0 g, 66 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to -5° C. using an ice-bath. Bromoacetyl bromide (13.32 g, 5.8 mL, 66 mmol) was added dropwise, keeping the internal temperature between -5° to 0° C. over a 1/2 h period. After the addition of the bromide was completed, the solution was warmed to rt, stirred overnight and then the resulting solution was slowly poured into 500 mL of ice-water, causing a white solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 16.4 g (91%) of the title compound as a white solid, mp 86°-87° C.: 1H NMR (DMSO-d6) δ11.07 (s, 1H), 8.24 (dd, J=8.4, J=1.2, 1H), 7.94 (dd, J=8.0, J=1.6, 1H), 7.64 (dt, J=8.8, J=1.6, 1H), 7.24 (dt, J=8.4, J=1.2, 1H), 4.23 (s, 2H), 3.87 (s, 3H); 13C NMR (DMSO-d6) δ167.26, 165.02, 138-82, 133.97, 130.62, 123.91, 121.13, 118-09, 52.46, 30.34; MS (EI, m/z) 271 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][OH:25])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(CCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of 0.174 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)octanoate in 2 ml methylene chloride is cooled to 0° and 0.1 ml of triethylamine is added followed by 0.042 ml of methylsulfonyl chloride. After 1 h, the reaction mixture is washed with saturated sodium bicarbonate and the organic layer is dried, filtered and evaporated to yield methyl 8-(p-chlorophenylsulfonamido)-4-(2-methylsulfonyloxyethyl)-octanoate as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([S:30]([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:21]([F:22])=[CH:20][N:19]=[C:18]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][S:30]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)(=[O:32])=[O:31])[CH:35]=2)[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(CS(=O)(=O)C2CCCCC2)c1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Product: O=S(=O)(Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1)C1CCCCC1

Procedure:
Example 6 was prepared under similar conditions as described in the preparation of Example 3 using 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and 3-[(cyclohexylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The batch was purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.O=S(Cl)[Cl:12].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: OCc1cc(Br)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-2-pyridylmethanol (3.38 g, 0.016 mol) in CH2Cl2 (210 mL) was slowly added SOCl2 (21 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 20 h, then satd. NaHCO3 was added. The organic layer was washed with brine, dried (MgSO4), and concentrated to give crude 4-bromo-2-(chloromethyl)pyridine (2.93 g, 79%) as a yellow oil. APCI MS m/z 205.7, 207.7 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.47 (d, J=5.3 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.42 (dd, J=5.3, 1.75 Hz, 1H), 4.64 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:13]1[CH2:14][O:15][C:5]2([CH2:4][CH2:3][C:2]([CH3:1])([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6]2)[O:8]1
Reactant: COC(=O)C1(C)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C1(C)CCC2(CC1)OCCO2
Yield: 100 %

Procedure:
Methyl 1-methyl-4-oxocyclohexanecarboxylate (30 g) was dissolved in benzene (300 ml). Ethylene glycol (30 ml) and p-toluenesulfonic acid monohydrate (1 g) were added, and the mixture was refluxed for 4 hours. The water which formed during the heating was removed by using a water trap. After cooling, the mixture was washed with water and dryed (MgSO4). The solvent was distilled off to give methyl 4,4-ethylenedioxy-1-methylcyclohexanecarboxylate as an oil (37.8 g, 100%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[OH:44])/[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:46]1([C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[O:44][C:46]2([C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:27]([O:29][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1(Br)CCCCC1
Product: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\OC1(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCCCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 61 %

Procedure:
Benzhydryl 2-(2-tritylaminothiazol-4-yl)-(Z)-2(hydroxyimino)acetate (3.44 g) was treated with 4-nitrobenzyl 1-bromocyclohexanecarboxylate as described in Example 5a to give the title compound (3.0 g, 61%) as a foam. δH (CDCl3) 1.26-2.30 (10H, m), 5.22 (2H, s), 6.39 (1H, s), 6.77 (1H, br s), 7.14 (1H, s), 7.28 (25H, s), 7.46 (2H, d), and 8.01 (2H, d).