Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[SiH2]C1C=CC=CC=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].[N+:20]([CH3:23])([O-:22])=[O:21]>C(O)C>[N+:20]([CH2:23][CH:16]([C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:19][CH:18]=1)[OH:17])([O-:22])=[O:21]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: C[SiH2]c1ccccc1
Solvent: CCO
Product: O=[N+]([O-])CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Poly (methylphenylsilane)-supported copper (204 mg, 5 mmol) was added to an ethanol (2.0 ml) solution of p-nitrobenzaldehyde (0.4 mmol) and nitromethane (1.2 mmol), and was stirred at room temperature for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated, and analyzed by 1H-NMR. Resultantly, 2-nitro-1-(4-nitrophenyl)ethanol was produced at the conversion rate of 95%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][C:23]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[C:28]1([C:23]2([CH2:22][NH:21][C:19]([N:16]3[CH2:15][CH2:14][CH:13]([S:10]([C:7]4[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]5[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=5)=[CH:9][CH:8]=4)(=[O:12])=[O:11])[CH2:18][CH2:17]3)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCCc1ccc(S(=O)(=O)C2CCN(C(=O)NCC3(c4ccccc4)CCCC3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: O=C(NCC1(c2ccccc2)CCCC1)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 33.1 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-[(1-phenylcyclopentyl)methyl]-1-piperidinecarboxamide (0.570 g, 1.20 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.417 g, 1.03 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.298 g, 0.341 mmol).
Reaction SMILES: [CH:1](=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].[FH:19].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[CH2:1]([C:5]1([F:19])[CH2:6][CH2:7][CH:8]([CH:11]2[CH2:12][CH2:13][CH:14]([CH:17]=[CH2:18])[CH2:15][CH2:16]2)[CH2:9][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC=C1CCC(C2CCC(C=C)CC2)CC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCC1(F)CCC(C2CCC(C=C)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20.6 g of 4'-but-3-enylidene-4-vinylbicyclohexyl in 40 ml of dichloromethane were cooled to -25° C. 7.523 ml of a 70% solution of hydrogen fluoride in pyridine were then added dropwise with stirring, and the mixture was stirred at -25° C. for 30 minutes and then at RT for a further 8 hours. The reaction solution was poured into a suspension of 40 g of sodium hydrogencarbonate and 800 g of ice-water. The mixture was extracted with three times 150 ml of hexane. The combined organic extracts were washed once with 50 ml of sodium chloride solution, dried using sodium sulphate, filtered and evaporated to a residue. Crystallization from pentane at -25° C. gave 4-but-3-enyl-4-fluoro-4'-vinylbicyclohexyl (C 13 SmB 37 N 80 I, Δn=0.049, Δε=-1.8, viscosity=13 mm2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:22]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)O1.FC1C2OC(C3(O)CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=C(C2CCN(C(OC(C)(C)C)=O)CC=2)C=1>>[CH2:19]([S:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH:8]2[CH2:7][C:6]3[CH:22]=[C:2]([C:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=4)[CH:3]=[CH:4][C:5]=3[O:9]2)[CH2:11][CH2:12]1)(=[O:18])=[O:17])[CH2:20][CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCCS(=O)(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Agent: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc(F)c4O3)CC2)nc1
Product: CCCS(=O)(=O)N1CCC(C2Cc3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)ccc3O2)CC1

Procedure:
Compound 10B was prepared from Compound 10A and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate in a similar manner to the procedure described for Compound 1I in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:29](COCC[Si](C)(C)C)[C:28]([O:38][C@H:39]3[C@H:43]4[O:44][CH2:45][C@@H:46]([OH:47])[C@H:42]4[O:41][CH2:40]3)=[N:27][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]3([CH2:20][N:19]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:18]3)[CH2:15]2)=[CH:10][CH:9]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl.CO>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[Cl:1][C:2]1[CH:3]=[C:4]2[NH:29][C:28]([O:38][C@H:39]3[C@H:43]4[O:44][CH2:45][C@@H:46]([OH:47])[C@H:42]4[O:41][CH2:40]3)=[N:27][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]3([CH2:18][N:19]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:20]3)[CH2:15]2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(N4CC5(C4)CN(c4ncccn4)C5)cc3)c(Cl)cc21
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(N4CC5(C4)CN(c4ncccn4)C5)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(6-pyrimidin-2-yl-2,6-diazaspiro[3,3]heptan-2-yl)phenyl]-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (54.3 mg, 0.08 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at room temperature. After 2 hours, the reaction mixture was evaporated to give an oil. The oil was dissolved in MeOH (1 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a solid. LC-MS: calculated for C27H26ClN7O4 547.17 observed m/e: 548.35 (M+H)+ (Rt 0.70/2 min); 1H NMR δ (ppm) (CD3OD): 8.44 (d, 2H), 7.96 (s, 1H), 7.56 (d, 2H), 6.81 (m, 1H), 6.65 (d, 2H), 5.58 (qt, 1H), 4.96 (t, 1H), 4.48 (t, 1H), 4.43 (s, 4H), 4.26-4.31 (m, 1H), 4.18 (s, 4H), 4.16 (dd, 1H), 4.12 (dd, 1H), 3.90 (t, 1H), 3.60 (t, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)C.[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].N12CCCC=C1CCCCN2>C1(C)C=CC=CC=1>[CH2:25]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[N:4][CH:3]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCI
Reactant: CCCCCCCCc1ccc(-c2ncc(O)cn2)cc1
Agent: C1=C2CCCCNN2CCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1cnc(-c2ccc(CCCCCCCC)cc2)nc1
Yield: 70 %

Procedure:
To 5-hydroxy-2-(4-octylphenyl)pyrimidine (5 g, 0.018 mol) were added ethanol (50 ml), octyl iodide (12.6 g, 0.053 mol) and diazabicyclo[5.4.0]undec-7-ene (0.053 mol), followed by refluxing the mixture for 4 hours, dissolving the reaction mixture in toluene, sufficeiently washing the solution with 2N--NaOH aqueous solution, further washing it with water, distilling off toluene and recrystallizing the residue from ethanol (75 ml) to obtain 5-octyloxy-2-(4-octylphenyl)pyrimidine (5 g). This product exhibited liquid crystalline properties and its phase transition points were as follows:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1([NH:11][CH:12]2[C:21]3[C:16](=[C:17]([CH2:22][OH:23])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:24][CH3:25])[CH2:14][CH2:13]2)[CH2:10][CH2:9]1.[OH-].[Na+]>C(O)=O>[CH:1]([N:11]([CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][OH:23])[CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:24][CH3:25])[CH2:14][CH2:13]1)[CH:8]1[CH2:9][CH2:10]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1CCC(NC2CC2)c2cccc(CO)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCN1CCC(N(C=O)C2CC2)c2cccc(CO)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (0.5 ml) and formic acid (0.25 ml) were stirred for 1 hour at 60° C, and to this mixture 4-cyclopropylamino-8-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.37 g) was added under ice-cooling and the mixture was stirred overnight at room temperature The reaction mixture was adjusted to alkalinic with 30% aqueous solution of sodium hydroxide under ice-cooling, stirred for 0.5 hour, sequentially extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate The residue, obtained by distilling off the solvent, was purified by silica gel column chromatography [eluent: dichloromethane-methanol (75:1)]to give 4-(N-formyl-N-cyclopropylamino)-8-hydroxymethyl1-ethyl-1,2,3,4-tetrahydroquinoline (0.35 g).
Reaction SMILES: I[C:2]1[O:6][C:5]([P:7]([O:12][CH2:13][CH3:14])(=[O:11])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[O:6][C:5]([P:7]([O:12][CH2:13][CH3:14])(=[O:11])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CCOP(=O)(OCC)c1ccc(I)o1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(F)cc2)o1
Temperature: 75 °C

Procedure:
A mixture of diethyl 5-iodo-2-furanphosphonate (1 mmol), 4-fluorophenylboronic acid (2 mmol), diisopropylethylamine (DIEA) (4 mmol) and bis(acetonitrile)dichloropalladium(II) (0.05 mmol) in 6 mL DMF was heated at 75° C. for 16 h. Extraction and chromatography provided diethyl 5-(4-fluorophenyl)-2-furanphosphonate as an oil.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.Cl.C([O:26][C:27](=[O:30])[CH2:28][NH2:29])C.C(N(CC)CC)C.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:29][CH2:28][C:27]([OH:30])=[O:26])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCC(=O)O
Yield: 85 %

Procedure:
The reaction of 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid with glycine ethyl ester hydrochloride was conducted in the same manner as described in Example 1 except that 6.5 ml of triethylamine was used. Then, a solution of 2.7 g of potassium hydroxide in ethanol was added. The mixture was heated under reflux for 30 minutes. After the completion of the reaction, water was added and the obtained aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. The solvent was distilled off to afford 6.1 g (yield 85%) of the title compound as a pale brown oil.
Reaction SMILES: CS(N)(=O)=O.[CH3:6][O:7][CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11].C([C:16]1([CH2:26][O:27][C:28]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:31]([C:32]([OH:34])=O)=[C:30]([F:40])[CH:29]=2)[CH:23]2[CH2:24][CH:19]3CC(C[CH:17]1[CH2:18]3)[CH2:22]2)#N.C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC1CCCC2>>[C:16]12([CH2:26][O:27][C:28]3[C:36]([CH:37]4[CH2:38][CH2:39]4)=[CH:35][C:31]([C:32]([NH:13][S:10]([CH2:9][CH2:8][O:7][CH3:6])(=[O:12])=[O:11])=[O:34])=[C:30]([F:40])[CH:29]=3)[CH2:22][CH:23]1[CH2:24][CH2:19][CH2:18][CH2:17]2
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with 2-methoxyethanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]-heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.035 g, 39%): 1H NMR (300 MHz, DMSO-d6) δ 11.87 (br s, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.86 (d, J=13.1 Hz, 1H), 3.72 (s, 3H), 3.36-3.31 (m, 4H), 3.22-3.19 (m, 2H), 2.12-1.96 (m, 1H), 1.95-1.67 (m, 3H), 1.66-1.50 (m, 1H), 1.44-1.04 (m, 4H), 1.02-0.82 (m, 3H), 0.76-0.55 (m, 3H), 0.43-0.30 (m, 1H); MS (ES+) m/z 426.1 (M+1)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CN(C=O)C.C(OCC)(=O)C>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:10][CH:9]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Potassium carbonate (1.45 g, 10.47 mmol) and 4-chlorobenzyl chloride (1.82 g, 8.86 mmol) were added to a solution of tert-butyl piperazine-1-carboxylate (1.5 g, 8.05 mmol) in DMF (10 ml), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford tert-butyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (2.50 g, quantitative) as a colorless oil.
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:10][C:11]1[NH:15][N:14]=[C:13]([O:16][CH2:17][CH2:18][OH:19])[C:12]=1[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21].O.[C:30](O)(=[O:32])[CH3:31]>>[C:23]1([S:20]([C:12]2[C:13]([O:16][CH2:17][C:18]([O:32][CH2:30][CH3:31])=[O:19])=[N:14][N:15]3[C:1]([OH:6])=[CH:2][C:3]([CH3:5])=[N:10][C:11]=23)(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1[nH]nc(OCCO)c1S(=O)(=O)c1ccccc1
Reactant: CC(=O)O
Solvent: O
Product: CCOC(=O)COc1nn2c(O)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42 %

Procedure:
0.75 ml of ethyl acetoacetate was added to a solution of 1.14 g (4.9 mol) of 2-(5-amino-4-benzenesulphonyl-1H-pyrazol-3-yloxy)-ethanol in 10 ml of acetic acid and heated at reflux for 3 hrs. After cooling to RT the mixture was treated with 50 ml of H2O and extracted three times with CH2Cl2. The organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 19:1) of the residue yielded 0.8 g (42%) of ethyl 2-(3-benzenesulphonyl-7-hydroxy-5-methyl-pyrazolo[1,5-a]pyrimidin-2-yloxy)-acetate as a colorless oil.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([NH:15][C:16]([NH2:18])=[NH:17])(=[O:14])[CH3:13]>CN(C=O)C>[C:12]([NH:15][C:16]1[NH:17][C:2]([CH3:11])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:18]=1)(=[O:14])[CH3:13]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CC(=O)NC(=N)N
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(-c2ccccc2)c(C)[nH]1

Procedure:
Prepared by reacting 2-bromo-propiophenone with 3 equivalents of 1-acetyl-guanidine in DMF (ambient temperature, 3 days).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([NH2:32])=[C:27]([Cl:33])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([Cl:33])[C:28]([NH2:32])=[C:29]([Cl:31])[CH:30]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCc1cc(Cl)c(N)c(Cl)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane and N-methyl-N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-amine.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17].O(Cl)[Cl:19].[P+5]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17]
Reactant: ClOCl
Reactant: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Agent: [P+5]
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Temperature: 130 °C
Yield: 56 %

Procedure:
A mixture of compound D5 (1 g, 4.148 mmol) and phosphorus (V) oxychloride (2 ml) was subjected to microwave heating at 130° C. for 15 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was then treated with NaHCO3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The crude product was purified by column chromatography (silica gel; Et2O as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D6 (0.6 g, 56%) as a yellow solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@@H:5]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][C@H:5]1[CH2:6][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C@H:4]1[NH2:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N=[N+]=[N-])[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC[C@@H](N)[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 94.9 %

Procedure:
Ethyl (1R*,3S*,4R*)-4-azido-3-(tert-butoxy-carbonylamino)cyclohexane-1-carboxylate (5.4 g) was dissolved in a mixed solvent of ethanol (10 ml) and ethyl acetate (10 ml), and a catalytic amount of 10% palladium on carbon was added to stir the mixture at room temperature for 20 hours in a hydrogen atmosphere. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.7 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19]C(C)(C)C)=O)[CH2:13][CH2:12]2)[C:5]([Br:24])=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[C:41]1([N:47]=C=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:47][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:19])[CH2:15][CH2:16]2)[C:5]([Br:24])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(C(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A solution of tert-butyl 4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazine-1-carboxylate (250 mg, 0.62 mmol) in CH2Cl2 (2.5 mL) at 0° C. was treated with TFA (2.5 mL) and stirred at 0° C. for 1.5 h. After this time, the solvents were evaporated in vacuo and the excess TFA removed by azeotroping with toluene (3×10 ml). The residue was suspended in CHCl3 (2.5 mL) and treated with DIPEA (5 eq, 3.11 mmol, 0.54 mL) and phenyl isocyanate (1.05 eq, 0.65 mmol, 0.07 mL). The reaction was warmed to room temperature and stirred for 12 h. The formed precipitate was filtered off and dried to give the product as a yellow solid (221 mg, 84% for two steps); 1H-NMR (500 MHz, DMSO-d6) 3.07 (br s, 4H, piperazine N(CH2)2), 3.58 (br s, 4H, piperazine N(CH2)2), 6.94 (tt, J=7.4, 1.1 Hz, 1H, phenyl H-4), 7.03 (br s, 2H, NH2), 7.24 (dd, J=8.5, 7.5 Hz, 2H, phenyl H-3 & H-5), 7.45 (dd, J=8.5, 1.1 Hz, 2H, phenyl H-2 & H-6), 8.21 (s, 1H, pyridine H-6), 8.59 (br s, 1H, NH);
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([Li])CCC.[I:21]I.O>O1CCCC1>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([I:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 15.0 grams (0.051 mole) of 3,5-di(trifluoromethyl)phenyl bromide in 45 mL of dry tetrahydrofuran was cooled to below -80° C., and 20.5 mL (0.051 mole) of n-butyllithium (2.5M in hexanes) was added dropwise while maintaining the reaction mixture temperature below -80° C. Upon completion of addition, an additional 50 mL of tetrahydrofuran was added to promote stirring. The reaction mixture was then stirred at -80° C. for an additional one hour. After this time a solution of 13.0 grams (0.051 mole) of iodine in 30 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature below -80° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then poured into 400 mL of water, and the mixture was extracted with one 200 mL portion of diethyl ether. The ether extract was washed with an aqueous solution of 10 % meta-sodium bisulfate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 13.1 grams of 3,5-di(trifluoromethyl)phenyl iodide.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21]>C(O)(C)C>[CH3:22][C:19]([NH:18][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=1)([CH3:23])[CH2:20][OH:21]
Reactant: CC(C)(N)CO
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Solvent: CC(C)O
Product: CC(C)(CO)Nc1nc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C

Procedure:
A mixture containing 12 g (0.05 mole) of 2 phenyl-4-chloroquinazoline, 4.5 g (0.05 mole) of 2-amino-2-methyl-1-propanol and 150 ml of isopropanol was refluxed for 4 hrs and filtered. The reaction mixture cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. The semi-solid residue was recrystallized with water to give 2.2 g of the title compound, m.p. 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:12])[O:16][CH2:15][CH2:14][O:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: OCCO
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc([N+](=O)[O-])c(Cl)c2)OCCO1
Yield: 106.5 %

Procedure:
A solution of 3'-chloro-4'-nitroacetophenone (3 g), ethylene glycol (9.3 g), and p-toluenesulfonic acid monohydrate (0.5 g) in toluene (30 ml) was refluxed for 6 hours. Water formed in the reaction was removed by means of Dean Stark apparatus. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated to give an oil of 2-(3-chloro-4-nitrophenyl)-2-methyl-1,3-dioxolane (3.9 g).