Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([N:25]=[CH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])=[CH:21][CH:20]=3)[C:11]=12>CS(C)=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)[N:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][CH:26]4[CH2:2][O:33][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]4=5)=[CH:23][CH:24]=3)[C:11]=12
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(N=Cc4ccccc4O)cc3)c3c(N)ncnc32)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(NC4COc5ccccc54)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Salicylaldehyde (0.063 g, 0.000513 mol) and tert-butyl 4-[4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (0.200 g, 0.000489 mol) were combined in absolute ethanol (5 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate which was used without further purification. Trimethylsulfoxonium iodide (0.269 g, 0.00122 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.049 g, 0.00122 mol) was added at once. After 10 min., the solution of tert-butyl 4-[4-amino-3-(4-{[-1-(2-hydroxyphenyl)methylidene]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (70 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to yield crude tert-butyl 4-{4-amino-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-1-piperidinecarboxylate which was used without further purification. The crude compound was dissolved in ethyl acetate (5 mL )and treated with a 4N aqueous solution of hydrochloric acid (1.5 mL). The resulting emulsion was vigorously stirred for 1 hour; the water layer was neutralized with saturated solution of sodium bicarbonate in water and the layers were separated. The organic phase was concentrated under reduced pressure and residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield 3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.038 g, 0.000078 mol) as a white solid
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:37]=[CH:36][C:35]([N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)=[CH:43][CH:42]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCN(c5nccc6c5CCO6)CC4)CC3)cc2)CC1

Procedure:
The title compound, white solid (95 mg, 71%), MS (ISP) m/z=533.3 [(M+H)+], mp 236° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.
Reaction SMILES: CC(C)(C)[Si]([O:6][CH:7]([CH:18]1[CH2:27][CH2:26][C:21]2([O:25][CH2:24][CH2:23][O:22]2)[CH2:20][CH2:19]1)[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:17][C:8]([F:16])([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])[CH:7]([CH:18]1[CH2:19][CH2:20][C:21]2([O:22][CH2:23][CH2:24][O:25]2)[CH2:26][CH2:27]1)[OH:6]
Reactant: CC(C)(C)[Si](C)(C)OC(C1CCC2(CC1)OCCO2)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CCC2(CC1)OCCO2)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of trimethyl (2,2,3,3,4,4,4-heptafluoro-1-(1,4-dioxaspiro[4.5]decan-8-yl)butoxy)trimethylsilane (265 mg, 0.643 mmol, prepared in the previous step) in THF (10 mL) was added a TBAF (0.64 mL, 0.64 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was at room temperature 2 hours and then concentrated in vacuo. The residue purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to afford the product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:23][CH:24]([NH2:27])[CH2:25][OH:26]>>[OH:26][CH2:25][CH:24]([NH:27][C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH3:23]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)n(C)n1
Reactant: CC(N)CO
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(C)CO)n(C)n1
Yield: 70 %

Procedure:
As described for example 85b, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (60 mg, 0.2 mmol), was converted, using DL-2-amino-1-propanol instead of ethanolamine, to the title compound (48 mg, 70%) which was obtained as a colorless oil. MS: m/e=351.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](Br)(Br)([Br:13])[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:12][C:11]([Br:13])=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(C=C(Br)Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Into a solution of 2,4-dichlorobenzaldehyde (8.7 g, 50 mmol) and carbon tetrabromide (18.3 g, 55 mmol) in dichloromethane (200 ml) was added portionwise triphenylphosphine (28.8 g, 10 mmol) at 0° C. The slightly yellow mixture was stirred at room temperature for 1 hour and diluted with hexanes (800 ml). This mixture was then filtrated through a short silica gel column with 1:10 ethyl acetate-hexanes and the filtrate was concentrated in vacuo to give a white solid (16.5 g, 100%). recrystallization from ether-hexanes gave a white crystalline product (14.2 g, 86% yield); 1H NMR (TMS/CDCl3):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]#[C:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][C:17]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(C(F)(F)F)ccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F

Procedure:
A suspension of 10% Pd/C (0.050 g) and tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)-4-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A106) (0.196 g, 0.295 mmol) in DMF (20 mL) was stirred under a hydrogen atmosphere at 50 Psi pressure for 24 hours. The resulting mixture was filtered through Celite, washing with MeOH (2×50 mL). The filtrate was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound A107 as a light yellow liquid (0.157 g, 80%); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.52-7.43 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 4.25 (brs, 2H), 3.79 (s, 2H), 3.70 (s, 3H), 3.17 (m, 2H), 3.09 (m, 2H), 2.81 (t, J=11.4 Hz, 2H), 2.70-2.56 (m, 1H), 1.83 (d, J=12.7 Hz, 2H), 1.72-1.55 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.199 min; m/z 667.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:24]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:18]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:20][C:19]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Temperature: 0 °C
Yield: 90.4 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with CH3I (0.68g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at 27° C. for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-methyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6a, 1.10 g, 91%). Nitro compound (6a, 1.21 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7b, 960 mg, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylamino propyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7b, 0.27 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8b, 351 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([O-:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10]>FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[O:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=[O:10]
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3ccccc3O)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3O)[C@H]2SC1

Procedure:
A solution of diphenylmethyl (6R,7R,2'R and S)-7-(2'-hydroxyphenylacetamido)-3-methylceph-3-em-4-carboxylate (529mg, 1.03mmole) in trifluoroacetic acid (1.3ml) was stirred at +20 to +25° for 10mins, and then evaporated. The residual oil was dissolved in ethyl acetate (50ml) and washed with 3%-sodium bicarbonate solution (3×15ml). The combined aqueous layers were washed with ethyl acetate (3×15ml), then covered with ethyl acetate (50ml) and adjusted to pH2.5. The ethyl acetate layer was combined with the ethyl acetate wash (15ml) of the aqueous layer, dried, and evaporated, leaving the title compound (as a 5:3=S:R-mixture of diastereomers, [nmr]) as a foam containing 1/2 mole-equivalent of ethyl acetate (nmr and microanalysis) and 2mole-equivalents of water (i.r. and microanalysis) (258 mg, 0.60mmole, 58%); λmax 257.5nm, inflexions at 254 and 262.5nm (ε5,870; 5,780 and 5,830 respectively); νmax 3640 (OH, H2O), 3450 (NH), 1784 (azetidin-2-one), 1730 (CO2H) and 1690; and 1510 cm-1 (CONH); τ assignments of minor component (2'R) follow those of the major component (2'S) 1.52 and 1.36 (total 1H, 2d, J 9Hz, NH), 2.40 to 2.73 (5H,m,C6H5), 4.36 and 4.33 (total 1H,2d, J9 and 4.5Hz, C7 -H), 4.90 and 4.83 (total 1H,2S,C6H5CH), 4.93 and 4.98 (total 1H, 2d, J4.5Hz, C6 -H), 6.51(S) and 6.38 and 6.64 (ABq J18Hz) total 2H,C2 -H2), 7.95 (3H,C3 -CH3), and signals at 5.91, 7.98 and 9.78 revealed the presence of 1/2mole-equivalent of ethyl acetate. (Found: C,50.7; H,4.9; N,6.0 and 6.1; S,7.3. C16H16N2O5S. 1/2 CH3CO2C2H5. 2H2O (428.4) requires C,50.4; H,5.6; N,6.5;S,7.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[CH:6]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[N:5]2[CH:6]=[C:2]([CH3:1])[CH:3]=[N:4]2)=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1cnn(-c2sccc2N)c1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cc(C)cn2)cc1

Procedure:
The title compound was prepared from 2-(4-methyl-1H-pyrazol-1-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B and purified by HPLC. Method [7] Retention time 6.16 min by HPLC (MH+ 328). 1H NMR (300 MHz, CDCl3) δ 9.93 (broad s, 1H), 7.97 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 7.27 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 6.90 (d, J=6.0 Hz, 1H), 3.87 (s, 3H), 3.70 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [Na].[CH3:2][C:3]([C@@H:5]1[C@@:9]2([CH3:24])[CH2:10][CH2:11][C@@H:12]3[C@@:17]4([CH3:23])[CH2:18][CH2:19][C@@H:20]([NH2:22])[CH2:21][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:8]2[CH2:7][CH2:6]1)=[O:4].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O>[NH2:22][C@@H:20]1[CH2:19][CH2:18][C@@:17]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:12]2[CH2:11][CH2:10][C@@:9]2([CH3:24])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[CH:3]([OH:4])[CH3:2])[CH2:21]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCCO
Solvent: CC(=O)O
Solvent: O
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a refluxing 100 ml of propanol were simultaneously added, over a period of 20 minutes, in small portions 5 g of sodium and a solution of 5 g of holamine in 5 ml of propanol while continuing reflux. After 1 hour and 25 minutes, the temperature was returned to ambient, the mixture chilled and acidified with acetic acid to pH 6. The pH raised to pH 8 with potassium carbonate and the mixture was diluted with 500 ml of water, partially evaporated, 300 ml of water were added and the mixture was allowed to crystallize for 24 hours in the refrigerator. The filtered crystals were washed in water and dissolved in 10 ml of methylene chloride to which was added 50 ml of ethyl acetate and 30 ml of isopropyl ether. The methylene chloride was evaporated and the product allowed to crystallize during 16 hours in the refrigerator. 3 g of 3α-amino pregn-5-ene- 20-ol was obtained melting at 160°.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[CH:13][C:14]=2[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 9-benzyl-6-(4-methoxy-phenyl)-2,3,4,9-tetrahydro-1H-carbazole (1.930 g, 5.252 mmol) was reacted with BBr3 (6.3 ml of a 1M solution in CH2Cl2) to give the product (0.840 g, 2.377 mmol, 45%) as a pale-green foam. 1H NMR (DMSO-d6) δ 1.78-1.85 (m, 4H), 2.63-2.70 (m, 4H), 5.32 (s, 2H), 6.81 (d, J=8.4 Hz, 2H), 7.03 (d, J=7.5 Hz, 2H), 7.19-7.23 (m, 2H), 7.28 (t, J=7.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.53 (s, 1H), 9.32 (s, 1H); [ESI(+)], m/z 354 (M+H)+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:35](=[NH:50])[NH:36][C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=4)=[O:38])[CH2:31][CH2:30]3)=[O:28])[CH2:10]2)=CC=1.[F:53][C:54]([F:60])([F:59])[S:55]([OH:58])(=[O:57])=[O:56]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[F:53][C:54]([F:60])([F:59])[S:55]([OH:58])(=[O:57])=[O:56].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35](=[NH:50])[NH:36][C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=3)=[O:38])[CH2:31][CH2:30]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=N)NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
880 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzyloxycarbonylamidino)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (d) above] were dissolved in a mixture of 4.4 ml of trifluoroacetic acid and 0.88 ml of anisole, and then 160 μl of trifluoromethanesulfonic acid were added dropwise to this solution, whilst stirring and ice-cooling. The resulting mixture was then stirred at room temperature for 3 hours, after which it was concentrated by evaporation under reduced pressure. The resulting residue was washed three times with diethyl ether, and the powder thus formed was dried to obtain 918 mg of the title compound, as a powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[OH-].[Na+].O>C(O)C>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cc1cc(C)cc(CCl)c1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(COc2ccc(S(C)(=O)=O)cc2)c1
Yield: 74.7 %

Procedure:
To a solution of 2.9 g (18.9 mmol) of 1-chloromethyl-3,5-dimethylbenzene and 3.9 g (22.7 mmol) of 4-methylsulfonylphenol in ethanol (10 mL) was added 10 mL (20.0 mmol) of 2 N aqueous sodium hydroxide solution, followed by heating under reflux for 2 hours. After standing to cool, water was added and the precipitates were collected by filtration and dried under a reduced pressure to obtain 4.1 g (yield 75.3%) of 1-(4-methanesulfonylphenoxymethyl)-3,5-dimethylbenzene (VI-5). Its physical properties are shown below.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH3:27])[CH:7]=1)[CH3:2].CN(C)N.C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:31][CH2:32]2)=[O:29])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(=O)C2CC2)c1
Agent: C
Agent: CN(C)N
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: (3-{2-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4-nitro-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester, 1,1-dimethylhydrazine, ferric chloride, and DARCO.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[N:10]=[CH:9][NH:8][C:7]2=O)[CH3:2].O=P(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH2:15][CH3:16])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2nc[nH]c(=O)c2cc1OCC
Solvent: Cc1ccccc1
Product: CCOc1cc2ncnc(Cl)c2cc1OCC
Temperature: 120 °C
Yield: 98 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6,7-diethoxyquinazolin-4(3H)-one (1.70 g, 7.3 mmol) and POCl3 (3 mL) in toluene (10 mL) was heated at 120° C. for 5 hours to afford 4-chloro-6,7-diethoxyquinazoline as a solid (1.794 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 4.31 (m, 4H), 1.58 (m, 6H); LC-MS (ESI) m/z 253 (M+H)+.
Reaction SMILES: ClC1C(C2CCCC(C3C(Cl)=CC=CN=3)N2)=NC=CC=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28](C#N)[CH:27]=[CH:26][C:25]=1CBr.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: Clc1cccnc1C1CCCC(c2ncccc2Cl)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1
Yield: 208.1 %

Procedure:
Using General Procedure A: 3,3″-dichloro-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (304 mg, 0.987 mmol), 2-Bromomethyl-5-cyano-benzoic acid methyl ester (351 mg, 1.38 mmol), KI (32.7 mg, 0.197 mmol), DIPEA (0.34 mL, 1.97 mmol), and DMF (5 mL) were stirred at 60° C. for 3 h. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH, 98:2) afforded 5-Cyano-2-3,3″-dichloro-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (391 mg,82%) as a yellow oil. 1H NMR (CDCl3) δ 1.63-1.78 (m, 3H), 2.01-2.14 (m, 1H), 2.18-2.38 (m, 2H), 3.87 (s, 3H), 3.95 (s, 2H), 4.52 (dd, 2H, J=11.4, 1.6 Hz), 6.89 (dd, 2H, J=8.4, 4.9 Hz), 7.38-7.48 (m, 3H), 7.57 (d, 1H, J=1.7 Hz), 8.22-8.32 (m, 3H).
Reaction SMILES: FC1C=C(C2C=C([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])C(=O)N(CC(C)C)N=2)C=CC=1C.O[C:27]1[C:28](=[O:48])[N:29]([CH2:44][CH:45]([CH3:47])[CH3:46])[N:30]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[C:32]=1C>>[CH2:44]([N:29]1[C:28](=[O:48])[C:27]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:32][C:31]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=2)=[N:30]1)[CH:45]([CH3:46])[CH3:47]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(CC(C)C)c(=O)c1O
Product: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Yield: 89.9 %

Procedure:
Following the procedure of Example 1 (9), 4-hydroxy-methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 89.9%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([CH2:11][O:12]C(=O)C)[O:9][CH2:8][CH:7]=[CH:6]1)(=O)C.C[O-].[Na+]>CO>[CH2:8]1[O:9][C@H:10]([CH2:11][OH:12])[C@@H:5]([OH:4])[CH:6]=[CH:7]1
Reactant: CC(=O)OC[C@H]1OCC=C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1OCC=C[C@@H]1O

Procedure:
4,6-di-O-acetyl-1,5-anhydro-2,3-dideoxy-D-erythro-hex-2-enitol (16 g; 74.7 mmol) was deacetylated with 1N sodiummethoxide (5 ml) in dry methanol (50 ml) for 3,5 h at r.t. The mixture was neutralised with ion exchange resin [Lewatit CNP-LF(H+)] and evaporated.