Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]1)(OC(C)(C)C)=O.[ClH:33]>O1CCOCC1>[ClH:33].[CH3:32][C@@H:28]1[CH2:27][NH:26][CH2:31][CH2:30][N:29]1[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNC[C@H]3C)s2)noc1C(F)(F)F
Reaction time: 2 h
Yield: 86 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-methyl-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford intermediate N-Boc protected product as a colorless solid (106 mg, 92%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately ¼ volume and diluted with ethyl ether (4 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 86% overall). 1H NMR (D2O) 1.27 (d, J=7.5, 3 H), 2.02 (s, 3 H), 3.04 (dt, J=12.7, 3.1, 1 H), 3.12-3.18 (m, 2 H), 3.30-3.50m (m, 2 H), 4.21 (d, J=14.5, 1 H), 7.23 (s, 2 H). 19F NMR −64.1. LC/MS 4.50 min, [M+1]+ 360.
Reaction SMILES: [OH:1][C@@H:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[CH3:23][C:24](OC(C)=O)=[O:25]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:1][C@@H:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1)(=[O:25])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC(=O)CC1[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 6α-hydroxyandrostane-3,17-dione (4.90 g) in pyridine (10 mL) at 0° C., DMAP (94 mg) and Ac2O (4.55 mL) were added. After stirring overnight at room temperature, the solution was evaporated. The residue was treated with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 6α-acetoxyandrostane-3,17-dione (5.57 g, 100%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.66 (m, 1H), 2.47-2.33 (m, 2H), 2.30-2.01 (m, 4H), 2.00 (s, 3H), 1.98-1.08 (m, 12H), 1.05 (s, 3H), 1.00 (m, 1H), 0.84 (m, 1H), 0.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](S)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].OO.[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(S)n1-c1ccc(F)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cncn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
To a suspension of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (737 mg, 1.9 mmol) in DCM (4 mL) at 0° C. was added a solution of 0.6 mL H2O2(35% wt.) in HOAc (2 mL). After stirring 40 min, the mixture was allowed to warm to room temperature. After stirring 6 h, the reaction mixture was neutralized to pH 9 using 2N NaOH and was extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by chromatography (silica, 0-95% EtOAc/Hex) to give 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole as a white solid (455 mg, 69% yield).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][O:35][C:36]([C:38]1[O:39][C:40]([CH3:45])=[C:41]([CH2:43]O)[CH:42]=1)=[O:37].[Br:46][C:47]1[CH:52]=[CH:51][C:50]([SH:53])=[CH:49][CH:48]=1>O1CCCC1>[CH3:34][O:35][C:36]([C:38]1[O:39][C:40]([CH3:45])=[C:41]([CH2:43][S:53][C:50]2[CH:51]=[CH:52][C:47]([Br:46])=[CH:48][CH:49]=2)[CH:42]=1)=[O:37]
Reactant: Sc1ccc(Br)cc1
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CSc2ccc(Br)cc2)c(C)o1

Procedure:
Diisopropylazodicarboxylate (1.27 g, 6.3 mmoles) was added to a solution of triphenylphosphine (1.65 g, 6.3 mmoles) in tetrahydrofuran (15 ml) with stirring and cooling in an ice/water bath. A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (536 mg, 3.15 mmoles) and 4-bromo-thiophenol (584 mg, 3.09 mmoles) in tetrahydrofuran (5 ml) was added and the mixture stirred for 30 minutes at 0° C. then 72 hours at room temperature. The solvent was evaporated and the residue extracted with heptane then diethyl ether. The extracts were combined and evaporated to give a yellow oil which was purified by flash chromatography using heptane/ethyl acetate 9:1 v/v as eluent. This gave compound 150 (600 mg) as a white solid. LC/MS System A; Rt=4.12 mins.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C(O[C:14]([CH3:17])([CH3:16])[CH3:15])(=O)C.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:15][C:14]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:1])([CH3:17])[CH3:16]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCC[C@H](N)C(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 76.4 %

Procedure:
To a suspension of L-norleucine (commercial product) (13.1 g; 0.1 mol) in t-butyl acetate (600 mL; 4.45 mol) maintained at 20° C., 70% aq. HClO4 (10.3 mL; 0.12 mol) was added in 10 min. The reaction was maintained at r.t. for 7 h. Saturated aq. Na2CO3 was slowly added until pH 9 was reached and the organic phase was separated and concentrated. The oily residue was dissolved in Et2O (250 mL) and extracted with 1N HCl (120 mL). The aqueous phase was basified to pH 10 with 1 N NaOH and extracted with Et2O (400 mL). The organic layer, dried over Na2SO4, was concentrated to give the desired compound (14.3 g; 76.4 mmol). Yield 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=O)NC2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2

Procedure:
A stirred mixture of 8-chloro-5,6-dihydro-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-6-one (VIIa) (24.87 g., 0.1 mole) and dry pyridine (1420 ml.) was treated with phosphorus pentasulfide (24.45 g., 0.11 mole) and refluxed for 2.5 hours, under nitrogen. The mixture was cooled, concentrated in vacuo, and the residue mixed with water and chloroform. The mixture was neutralized with sodium bicarbonate and the solid collected by filtration. This solid was washed with chloroform and recrystallized from a chloroform/methanol/ethyl acetate mixture to give 20.31 g., melting point 303°-308° of the titled product (VIIIa). Additional product was obtained from the chloroform filtrates which were washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from a chloroform/methanol/ethyl acetate mixture to give 2.93 g., melting point 298°-303°; and 0.78 g., melting point 302°-305° of the title compound (VIIIa) (91% overall yield). The analytical sample was recrystallized from methylene chloride/methanol and had: melting point 306°-308°; uv (EtOH) λ max 223 mμ (ε31,500), 316 (7700). The ir and nmr spectra support the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 84 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[S:16][C:15]([NH:17][CH2:18][C@@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:14][N:13]=1)=[CH:7][CH:6]=2.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].C(Cl)Cl>>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[NH2:31][C@@H:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=1)[CH2:18][NH:17][C:15]1[S:16][C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[N:3][C:2]([F:1])=[CH:11]3)=[N:13][N:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CNc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of tert-butyl (S)-1-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.047 g, 0.086 mmol) in TFA/DCM (1:1, 4.0 mL) was stirred at room temperature for 30 minutes. The solvent was evaporated to provide the product as an off-white solid (50.3 mg, 100%). LCMS (API-ES) m/z: 449 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.05 (d, J=6.85 Hz, 2H), 3.54-3.65 (m, 2 H), 7.57 (d, J=8.02 Hz, 2 H), 7.72 (d, J=7.82 Hz, 3 H), 7.76 (s, 1 H), 8.03 (s, 3 H), 8.11 (dd, J=8.61, 1.57 Hz, 1 H), 8.28 (d, J=8.80 Hz, 1 H), 8.33-8.39 (m, 2 H).
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH2:10][C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH2:20])[S:18][CH:19]=1>>[S:1]1[C:5]2[C:6]([CH2:10][C:11]([NH:20][C:17]3[S:18][CH:19]=[C:15]([Br:14])[C:16]=3[C:21]3[NH:25][N:24]=[CH:23][N:22]=3)=[O:13])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cc1cccc2ncsc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1cccc2ncsc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(benzo[d]thiazol-7-yl)acetic acid (25.5 mg, 0.13 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (22.3 mg, 0.093 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS Retention time (min)=4.075, method [7], MS (ESI) 421.9 (M+H). 1H NMR (CDCl3) δ 12.39 (s, 1H), 9.02 (s, 1H), 8.22, (d, J=6.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.54 (s, 1H), 7.55-7.49 (m, 1H), 6.90 (s, 1H), 4.19 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:4]2[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=2[OH:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:13]=1
Reactant: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)cc(C)c(C)c1O
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 2,3,5-trimethylphenol (0.80 g, 5.9 mmol), methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (0.30 g, 1.2 mmol) and triphenylphosphine (0.46 g, 1.8 mmol) in 1,2-dichloroethane (20 ml) was added at 10° C. a solution of 95% DEAD (0.54 ml) in 1,2-dichloroethane (5 ml) taking 30 minutes. The mixture was stirred for one hour at the same temperature range, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 0.15 g of methyl (R)-7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoate.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19](=O)O[CH:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:11][CH:10]=1.[N+:25]([C:28]1[S:29][C:30]([CH:33]=C[N+]([O-])=O)=[CH:31][CH:32]=1)([O-:27])=[O:26]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:33]([C:30]3[S:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:32][CH:31]=3)[CH:19]=2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])C=Cc1ccc([N+](=O)[O-])s1
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-c2cc(-c3ccc(Cl)cc3)[nH]c2C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.16 g, 11.3 mmol) is added to a solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-3-oxazolin-5-one (2.97 g, 11.3 mmol) and 2-nitro-5-(2-nitrovinyl)thiophene (2.26 g, 11.3 mmol) in acetonitrile near reflux. The reaction mixture is refluxed for one hour, stirred overnight at room temperature and concentrated in vacuo to obtain a red oil. Chromatography of the oil gives the title product as a tan solid, mp 166°-169° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.ClCCl>[Pt].CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of tert-butyl 2-[(3-nitroquinolin-4-yl)amino]ethylcarbamate (20.0 g, 60.2 mmol) in a 2:1 mixture of dichloromethane:methanol (500 mL) was added to a Parr vessel. The system was purged with nitrogen, and 5% platinum on carbon (7.04 g, 36.1 mmol) was added. The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa) and shaken overnight. The reaction mixture was filtered and concentrated under reduced pressure to provide 15.65 g of tert-butyl 2-[(3-aminoquinolin-4-yl)amino]ethylcarbamate.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[C:15]([CH3:22])=[C:14]([C:23](=[O:25])[CH3:24])[C:13]=2[CH3:26])[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].C[O-].[Na+].[H][H]>CO.[Pd]>[C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[C:17]([CH3:18])=[C:16]([NH2:19])[C:15]([CH3:22])=[C:14]([C:23](=[O:25])[CH3:24])[C:13]=2[CH3:26])[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(C(C)=O)c(C)c([N+](=O)[O-])c2C)CC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)C1=C(O)CC(c2c(C)c(N)c(C)c(C(C)=O)c2C)CC1=O
Yield: 84.5 %

Procedure:
A stirred solution of 2-propionyl-3-hydroxy-5-[3-acetyl-5-nitro-2,4,6-trimethylphenyl]cyclohex-2-en-1-one (4.2 g, 11.3 mmol) and sodium methoxide (0.61 g, 11.3 mmol) in methanol (80 ml) was hydrogenated at atmospheric pressure over 10% palladium on charcoal (0.3 g). After uptake of hydrogen ceased the solution was neutralized and the methanol was removed under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (elution with an increasing gradient of methanol in methylene chloride) to yield 2-propionyl-3-hydroxy-5-(3-acetyl-5-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a red brown solid (3.28 g, 85%) the compound was characterized by proton magnetic resonance spectroscopy (CDCl3, δ in ppm): 1.18 (3H,t ; 2.0 3H,s); 2.12 (3H,s); 2.18 (3H,s ; 2.40 3H,s); 2.4-4.1 (5H,m); 3.07 (2H,q); 3.6 (2H, brs); 18.05 (1H,brs).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29]([NH:28][C:19]3[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=3[F:17])=[O:30])=[CH:12][CH:11]=2)=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]cc(Cl)c1-c1ccc(N)cc1
Solvent: C1CCOC1
Product: NC(=O)c1[nH]cc(Cl)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To 0.03 g (0.127 mmol) of 4-chloro-3-(4-aminophenyl)-1H-pyrrole-2-carboxamide dissolved in 2.7 cm3 of tetrahydrofuran is added, at a temperature in the region of 20° C. under an argon atmosphere, 0.019 cm3 (0.134 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is recrystallized from 4 cm3 of acetonitrile. After filtering through a No. 3 sinter funnel, the solid is washed with 2 cm3 of acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 45° C. for 2 hours to give 0.037 g of 4-chloro-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide in the form of a white solid; 1H NMR (400 MHz, DMSO d6, δ in ppm): 5.83 (broad m, 1H); 7.08 (s, 1H); 7.18 (broad m, 1H); 7.28 (d, J=8.5 Hz, 2H); 7.38 (m, 1H); 7.50 (partially masked m, 1H); 7.55 (d, J=8.5 Hz, 2H); 8.62 (dd, J=2.0 and 7.5 Hz, 1H); 9.04 (broad s, 1H); 9.39 (broad s, 1H); 11.8 (broad s, 1H); ES+: m/z=441: [M+H]+; ES−: m/z=439: [M−H]−.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH:32]=[O:33])=[CH:5][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([CH2:28][CH2:29][CH2:30][CH3:31])=[C:11]4[CH2:20][CH2:19][CH2:18][C:17](=CC5C=CC=CC=5)[C:12]4=[N:13][C:14]=3[C:15]=2[N:16]=1.C[OH:35]>ClCCl>[NH2:2][C:3]1[C:4]([CH:32]=[O:33])=[CH:5][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([CH2:28][CH2:29][CH2:30][CH3:31])=[C:11]4[CH2:20][CH2:19][CH2:18][C:17](=[O:35])[C:12]4=[N:13][C:14]=3[C:15]=2[N:16]=1
Reactant: CCCCc1c2c(nc3c1CCc1cc(C=O)c(N)nc1-3)C(=Cc1ccccc1)CCC2
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: CCCCc1c2c(nc3c1CCc1cc(C=O)c(N)nc1-3)C(=O)CCC2
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 0.46 g (1 mmol) of 2-amino-11-benzylidene-7-n-butyl-5,6,8,9,10,11-hexahydrobenzo[b][1,10]phenanthroline-3-carboxaldehyde HCl salt (XX) in 40 mL of dichloromethane and 20 mL of methanol is stirred at approximately -78° C. and ozone is bubbled through the orangish-yellow solution. When the color of the reaction mixture changes to pale greenish-yellow, the solution is immediately purged by bubbling in N2 for 5 minutes. Dimethylsulfide (1.0 mL) is added and the reaction mixture is allowed to warm to room temperature. The solvents are removed by rotary evaporation and the residue is triturated with 100 mL of ether, yielding 0.39 g (100%) of product.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@@:24]2([CH3:25])[C@H:22]([O:23]2)[CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Li+].[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([C@@H:22]1[CH2:21][CH2:20][C@@H:19]([O:18][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:24]1([CH3:25])[OH:23])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@H]2O[C@@]12C)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N=[N+]=[N-])[C@]1(C)O)(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
The title compound is prepared by essentially following the procedure as described in Preparation 41 using rel-tert-butyl-[[(1R,4S,5R)-5-methyl-6-oxabicyclo[3.1.0]hexan-4-yl]oxy]-diphenyl-silane (enantiomeric mixture), except that the reaction is heated to 90° C. for 48 h and the addition of lithium perchlorate and the second addition of sodium azide are omitted.
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: C[C@@H](O)CC(=O)O
Reactant: O=CCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
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: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COCCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-methoxypropylamine according to general procedure 1 providing the intermediate (43 mg, 54%) as a clear oil: Rf=0.55 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.6 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.53 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.95 (quin, J=6.5 Hz, 2H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.O[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1.C[CH2:33][O:34]C(/N=N/C(OCC)=O)=O.N#N>C1COCC1>[CH3:33][O:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2
Reactant: Oc1n[nH]c2ccccc12
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of PPh3 (1.67 g, 6.4 mmol), MeOH (204 mg, 6.4 mmol) and the hydroxyindazole prepared above (2.0 g, 5.3 mmol) in THF (20 mL) was added DEAD (1.11 g, 6.4 mmol) dropwise under N2. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified with flash chromatography on silica gel (gradient elution with 50:1 to 5:1 petroleum ether:EtOAc) to afford the desired 5-methoxyindazole as a yellow oil. MS (ESI) m/z=391.1 [M+1]+.