Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:44]([CH2:54][C:55](=[CH:57][CH2:58][CH2:59]/[C:60](=[CH:62]/[CH2:63]O)/[CH3:61])[CH3:56])/[CH:45]=[C:46](/[CH2:48][CH2:49][CH:50]=[C:51]([CH3:53])[CH3:52])\[CH3:47]>C1COCC1>[CH3:61]/[C:60](/[CH2:59][CH2:58]/[CH:57]=[C:55](\[CH3:56])/[CH2:54][CH2:44]/[CH:45]=[C:46](\[CH3:47])/[CH2:48][CH2:49][CH:50]=[C:51]([CH3:53])[CH3:52])=[CH:62]\[CH2:63][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A solution of N-hydroxyphthalimide (1.12 g, 6.88 mmol), triphenylphosphine (1.81 g, 6.88 mmol) and diethylazodicarboxylate (1.19 mL, 7.57 mmol) in anhydrous THF (60 mL) was treated with geranylgeraniol (2.0 g, 6.88 mmol) and the resulting mixture was stirred for 18 h at rt. After addition of triphenylphosphine (0.905 g, 3.44 mmol) and diethylazodicarboxylate (0.595 mL, 3.78 mmol), the mixture was stirred at rt for another 24 h. The solvent was evaporated and the residue was purified on 230-400 mesh silica gel (Macherey-Nagel Silica Gel 60 Art. Nr. 81538) eluting with CH2Cl2-hexane (6:4) and collecting 10 mL fractions. The appropriate fractions were combined and evaporated to give the intermediate 20 (2.63 g, 88%) as a white solid: mp 40-41° C.; 1H-NMR (CDCl3, 80 Mhz) δ 1.58 (s, 9H, 3×CH3), 1.67 (s, 3H, CH3), 1.71 (s, 3H, CH3), 2.03 (m, 12H, 6×CH2), 4.71 (d, 2H, J=7.2 Hz, CH2), 5.07 (br, 3H, 3×CH), 5.52 (t, 1H, J=7.2 Hz, CH), 7.73 (m, 4H, Ar); Anal. Calcd for C28H37NO3 (MW 435.3); C, 77.26; H, 8.50; N, 3.22. Found: C, 77.38; H, 8.38; N, 3.04.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][CH2:15][CH3:16]>>[CH2:18]([N:17]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC1CO1
Reactant: CCCCNCCCCCCNCCCC
Product: CCCCCCCCCC(O)CN(CCCC)CCCCCCN(CCCC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-dibutylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-butyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = CH3 (CH2)3, X = (CH2)6, Z = H).
Reaction SMILES: C[N:2](C)C=O.[Cl:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[NH:20][C:19]2=[O:29])=[C:9]([F:30])[CH:8]=1.[N+](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[N:20]([NH2:2])[C:19]2=[O:29])=[C:9]([F:30])[CH:8]=1
Reactant: CN(C)C=O
Reactant: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Agent: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)c2o1
Temperature: 65 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
80 ml of N,N-dimethylformamide was added to 3.4 g (9.0 mmol) of 3-(4-chloro-2-ethyl-6-fluorobenzofuran-7-yl)-6-trifluoromethyluracil, 2.7 g (14 mmol) of 2,4-dinitrophenoxyamine and 5.0 g (36 mmol) of potassium carbonate, followed by stirring at 60 to 70° C. for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.0 g (yield: 58%) of the desired product as white crystals. Melting point: 145-147° C.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([OH:19])=O)[CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([C:17]([NH:30][C@@H:28]([C:25]2[CH:24]=[N:23][C:22]([C:21]([F:32])([F:31])[F:20])=[N:27][CH:26]=2)[CH3:29])=[O:19])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(C)C)n2)nc1
Reactant: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C(F)(F)F)nc3)cc(C(C)C)n2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
To a solution of 6-isopropyl-5′-methyl-2,2′-bipyridine-4-carboxylic acid (25.0 mg, 0.07 mmol) in DMF (0.3 mL) were added hydrochloride salt of (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (22.1 mg, 0.08 mmol), HATU (38.2 mg, 0.10 mmol) and diisopropylethylamine (58.5 μL, 0.34 mmol). The mixture was stirred at ambient temperature. After 20 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (24 mg), HRMS 430.1850 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 2H), 8.48 (s, 1H), 8.43 (d, 8.1 Hz, 1H), 8.37 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.63 (s, 1H), 6.96 (d, J=6.7 Hz, 1H), 5.44-5.35 (m, 1H), 3.24-3.14 (m, 1H), 2.42 (s, 3H), 1.74 (d, J=7.2 Hz, 3H), 1.37 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH:13]=1)[C:10](Cl)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH3:50])[C:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[NH:27]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:25]2)=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([C:10]2[NH:25][C:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)([CH3:50])[C:28]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([CH3:29])[N:27]=2)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(C(C)(C)C)cc1C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1ccc(C(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S,5R*)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 5-tert-butyl-2-ethoxy-benzoyl chloride (prepared from 5-tert-butyl-2-hydroxy-benzoic acid) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:35])[CH3:34])[NH:27][C:26](=[O:38])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][C:30]([NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:34])[CH3:35])=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:38])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(NC(=O)C(C)(C)O)c(F)cc43)c(C)c2C1=O
Yield: 65.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (48 mg, 65.7%) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH:8]1([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.O1CCNC1=O.[Li]CCCC.[C:38]1([CH2:44][C@H:45]2[CH2:49][O:48][C:47](=[O:50])[NH:46]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[CH:8]1([CH2:14][CH2:15][CH2:16][C:17]([N:46]2[C@@H:45]([CH2:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:49][O:48][C:47]2=[O:50])=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCCC1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCC1CCCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A solution of pivaloyl chloride (3.57 g, 2.96 mmol) in THF (25 ml) was added to a cold (-78° C.) solution of 4-cyclohexylbutyric acid (5.042 g, 29.62 mmol) and triethyl amine (3.60 g, 35.6 mmol) in THF (100 mL). The resultant white suspension was stirred for 10 min. at -78° C. and then warmed to 0° C. and kept there for 30 min. The reaction mixture was recooled to -78° C. and a cold (-78° C.) metallated oxazolidinone solution in THF (125 ml) [prepared by the addition of n-BuLi (17.65 ml. of 1.65M solution in hexane, 28.2 mmol) to a -78° C. solution of (S)-4-(phenylmethyl)-2-oxazolidinone in THF (125 ml)] was added via a cannula under the positive pressure of argon. The reaction mixture was then warmed to 0° C. and kept there for another 30 min. The reaction was quenched by the addition of saturated NH4Cl (75 ml). The volatiles were removed on rotavapor at reduced pressure and the residue was extracted with CH2Cl2 (3×200 ml). The combined organic phases were washed with 1N NaOH (150 ml) and dried (Na2SO4). The organic layer was concentrated and the residue was purified by flash silica gel chromatography, eluting with hexane:ethyl acetate (3:1) to yield 8.066 g (85%) of (S)-3-(4-cyclohexyl-1-oxobutyl)-4-(phenylmethyl)-2-oxazolidinone: Rf 0.34 (3:1 hexane:ethyl acetate), m.p. 69°-70° C. [α]D25 +47.3° (c 0.97 CHCl3).
Reaction SMILES: C(C([NH:7][C@H:8]([C:15]([NH:17][C@@H:18]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:19]([OH:33])[CH2:20][C@@H:21]([C:29]([OH:32])([CH3:31])[CH3:30])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[O:16])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=O)(C)(C)C.Cl.[CH2:42]([C@H:49]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[C:50]([OH:52])=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:42]([C@H:49]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[C:50]([NH:7][C@H:8]([C:15]([NH:17][C@@H:18]([CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C@@H:19]([OH:33])[CH2:20][C@@H:21]([C:29]([OH:32])([CH3:30])[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[O:16])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=[O:52])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)C(C)(C)C)C(C)(C)O
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of 200.7 mg (0.336 mmole) of (2S, 4S, 5S)-5-[N-(t-butylcarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-butylhexanamide in 6 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then benzene was added to the residue. The solvent was removed by distillation under reduced pressure from the resulting solution. The same operation was repeated, in total, three times, and the residue was then dried by evaporation under reduced pressure for 8 hours. The dried material was then suspended in 10 ml of anhydrous tetrahydrofuran, and 98.2 mg (0.354 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension. 0.06 ml (0.396 mmole) of 95% diethyl cyanophosphate and 0.2 ml (0.143 mmole) of triethylamine were then added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from a mixture of ethyl acetate and diisopropyl ether, to give 229.8 mg of the title compound as white crystals, melting at 92°-95° C.
Reaction SMILES: [C:1]([NH:9][C:10](=[NH:18])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCl)(C)(C)C.[OH-].[Na+].O>C(O)C>[O:11]([C:10]1[N:9]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:8][N:18]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N=C(NC(=O)c1ccccc1)Oc1ccccc1
Agent: CC(C)(C)OCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(Oc2noc(-c3ccccc3)n2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
N-benzoyl-O-phenylisourea (0.8 g) was dissolved in ethanol (40 ml), and t-butylhypochlorite (0.36 g) was added at 0° to 5° C. After one hour, 2 molar aqueous sodium hydroxide (2 ml) was added and the mixture was stirred for 2 hours at ambient temperature (20° C.). The reaction mixture was poured into an equal volume of water and extracted with dichloromethane (100 ml). The separated organic layer was evaporated under reduced pressure and the residue was purified by chromatography over silica gel using dichloromethane as eluant to give 3-phenoxy-5-phenyl-1,2,4-oxadiazole (0.4 g, 57%), m.p. 62° C.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=1[OH:37])([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:19]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=1[O:37][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:37][C:24]2[C:25]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:26][C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:28][C:23]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP2N(c3ccccc3)P(Oc3c(C(C)(C)C)cc(C(C)(C)C)cc3C(C)(C)C)N2c2ccccc2)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, 2,4,6-tri-tert-butylphenol and triethylamine to give the title compound.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[N:10][N:11]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCOC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 4-(4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (167 mg) in acetonitrile (15 mL) were added sodium iodide (134 mg) and chloro(trimethyl)silane (0.452 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate to give the title compound (142 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]OS(C)(=O)=O)[CH:5]=[N:6][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.O>[N:14]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:15]=[N-:16]
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cncc(Br)c1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of crude methanesulfonic acid 5-bromo-pyridin-3-ylmethyl ester (4.20 g) in DMF (60 mL) was added NaN3 (10.0 g, 153.8 mmol). The mixture was stirred under N2 overnight then diluted with water. The mixture was extracted with EtOAc (2×300 mL) and the combined organic layers washed with water before drying over Na2SO4. The solution was concentrated in vacuo to afford crude 3-azidomethyl-5-bromo-pyridine (2.04 g) as a dark brown oil. This crude material was used directly in the next step.
Reaction SMILES: [CH2:1]1[CH2:26][O:25][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:17]3([OH:22])[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([CH3:24])[C:12]3=O)[CH2:4]2)[O:2]1.[Cl:27][C:28](Cl)(Cl)[C:29]([O:31][CH2:32][CH3:33])=[O:30].[Cl-].C([Al+]CC)C>[Zn].C1(C)C=CC=CC=1.CC(C)=O>[Cl:27]/[C:28](=[C:12]1\[C@@H:11]([CH3:24])[CH2:10][C@@H:9]2[C@:13]\1([CH3:14])[CH2:15][CH2:16][C@@:17]1([OH:22])[C@H:8]2[CH2:7][CH:6]=[C:5]2[C@:18]1([CH3:21])[CH2:19][CH2:20][C:3]1([O:25][CH2:26][CH2:1][O:2]1)[CH2:4]2)/[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Reactant: C[C@H]1C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]2(C)C1=O)OCCO5
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)/C(Cl)=C1/[C@@H](C)C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5

Procedure:
Using the procedure of Example 18, 3,3-ethylenedioxy-9α-hydroxy-16β-methylandrost-5-en-17-one (3.60 g) was reacted with ethyl trichloroacetate (2.78 ml) in the presence of zinc dust (2.83 g) and diethylaluminium chloride (20 ml, 1M in hexane). Chromatography (silica gel, toluene/acetone 3/1) of the crude product (3.0 g) afforded the title compound as a single isomer.
Reaction SMILES: CC[Mg+].[Br-].Br[C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1.CON(C)[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=1>C(Cl)Cl>[CH3:11][N:10]1[C:6]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[O:26])=[CH:7][N:8]=[CH:9]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(C)c1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of EtMgBr (3.0 M in diethylether, 15.1 mL, 45.2 mmol) was added dropwise, to a solution of 5-bromo-1-methyl-1H-imidazole (7.28 g, 45.2 mmol) in dry DCM (40 mL) at 0° C. and stirred for 10 minutes. The mixture was then stirred at room temperature for 30 minutes, cooled in an ice-brine bath and N-methoxy-N,3-dimethyl-4-nitrobenzamide (8.45 g, 37.7 mmol, Intermediate 14: step a) dissolved in 22 mL of DCM was added dropwise. A dark brown solid mass formed. The ice bath was removed and mixture stirred at room temperature for 18 hours. Water was added to the suspension followed by 6 M aqueous HCl slowly to neutralize the mixture (pH=6-7). More DCM was added and layers separated. The organic layer was dried over MgSO4, filtered and concentrated. Et2O was added, the slurry sonicated, and precipitates were filtered and dried to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.C[N:34]1[C:38](=O)[CH2:37][CH2:36][CH2:35]1>N1CCCC1>[F:27][C:26]([F:29])([F:28])[C@:25]([C:23]1[N:22]=[N:21][N:20]([CH2:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[CH:11][C:2]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=1)([OH:32])[CH2:30][CH3:31]
Reactant: CCC(O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Reactant: CN1CCCC1=O
Solvent: C1CCNC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(N4CCCC4)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (75 mg, 0.16 mmol) in NMP (0.5 mL) and pyrrolidine (0.5 mL) was stirred at 130° C. in a microwave for 20 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with NH4OH/ethanol/dichloromethane, 1:9:90) gave the title compound. MS (+ESI): 501 (M+H)+.
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[N:14]1[CH:13]=[CH:12][CH:17]=[N:16][C:15]=1[C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][CH:21]=[C:20]2[CH2:18][OH:19]
Reactant: O=Cc1cccc2ccccc12
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cccc2c(-c3ncccn3)cccc12
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck flask round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 100 ml of anhydrous diethyl ether and 62.5 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 15.90 gm of 5-bromopyrimidine in 50 ml of tetrahydrofuran is added over 2 hours. After addition of the 5-bromopyrimidine, the system is stirred for an additional 45 minutes. At this time, 15.60 gm of 1-formylnaphthalene in 50 ml of tetrahydrofuran is added to the system while still maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 3 hours after addition of the 1-formylnaphthalene and afterwards is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH2 with HCl solution. The product is extracted with methylene chloride. The methylene chloride is washed with a 10% NaOH solution and then is dried over sodium sulfate. The methylene chloride is removed by stripping and the residue is triturated with hexane to give the 5-pyrimidyl-1-naphthylcarbinol.