Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].CN(C)CCNC(=O)N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1.[CH3:90][N:91]([CH3:103])[C@H:92]1[C@H:96]([N:97]2[CH2:102][CH2:101][NH:100][CH2:99][CH2:98]2)[CH2:95][O:94][CH2:93]1>>[CH3:90][N:91]([CH3:103])[C@@H:92]1[CH2:93][O:94][CH2:95][C@H:96]1[N:97]1[CH2:102][CH2:101][N:100]([C:2]([NH:1][C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)=[O:3])[CH2:99][CH2:98]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)[C@@H]1COC[C@H]1N1CCNCC1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)N3CCN([C@@H]4COC[C@H]4N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 20 %

Procedure:
The title compound was prepared in 20% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (3S,4S)—N,N-dimethyl-4-(piperazin-1-yl)tetrahydrofuran-3-amine was used instead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 755.6 (M+H)+, 1.85 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.93 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 5.31 (d, J=6.1 Hz, 1H), 4.78 (s, 1H), 4.64 (br. s., 1H), 4.09 (d, J=3.4 Hz, 1H), 4.05 (d, J=4.9 Hz, 2H), 4.02 (td, J=3.5, 6.8 Hz, 1H), 3.96 (td, J=5.1, 10.1 Hz, 1H), 3.73 (d, J=5.2 Hz, 1H), 3.56-3.41 (m, 4H), 2.96 (s, 6H), 2.87-2.66 (m, 5H), 2.59 (d, J=13.1 Hz, 1H), 2.45 (dd, J=8.7, 11.7 Hz, 1H), 2.16 (dd, J=6.4, 17.1 Hz, 1H), 1.97-1.90 (m, 1H), 1.90-1.82 (m, 1H), 1.82-1.74 (m, 2H), 1.73 (s, 3H), 1.66-1.54 (m, 3H), 1.51 (d, J=12.5 Hz, 4H), 1.45-1.26 (m, 6H), 1.23-1.15 (m, 2H), 1.13 (s, 3H), 1.10 (d, J=13.4 Hz, 2H), 1.06 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: N.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[N:15]=[C:16]=[O:17].ClC1C=C(Cl)C(OC(OC)=O)=CC=1[N+:31]([O-])=O>C1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[NH:15][C:16]([NH2:31])=[O:17]
Reactant: COC(=O)Oc1cc(N=C=O)c(Cl)cc1Cl
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: N
Solvent: c1ccccc1
Product: COC(=O)Oc1cc(NC(N)=O)c(Cl)cc1Cl
Yield: 88 %

Procedure:
An ammonia gas was introduced while strongly stirring on cooling in an ice bath into a benzene solution (120 ml) of 2,4-dichloro-5-methoxycarbonyloxyphenyl isocyanate (5.04 g, 19.2 mmol) which has been synthesized by the identical method as the Comparative Examples 1 to 4 from 2,4-dichloro-5-methoxycarbonyloxynitrobenzene. Thirty minutes later, a white solid deposited was filtered and sufficiently washed with benzene. This product was confirmed to be the desired 2,4-dichloro-5-methoxycarbonyloxyphenyl urea (4.68 g, yield 88%) by means of spectral analyses.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[C:18]([CH3:31])[CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C.CO>[CH3:31][C:18]1[CH:17]=[C:16]([CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)[CH:30]=[CH:29][C:19]=1[O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1
Reactant: c1ccc(C2CCCCNC2)cc1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(CN2CCCCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Yield: 66.1 %

Procedure:
Using a method similar to Example 365 step 2, using 3-phenyl-azapane (0.0610 g, 0.348 mmol), 6-(4-formyl-2-methyl-phenoxy)-nicotinonitrile (compound of example 365 step 1) (0.0816 g, 0.342 mmol), sodium triacetoxyborohydride (0.110 g, 0.519 mmol), and acetic acid (0.032 mL, 0.56 mmol) in 1,2-dichloroethane (4.0 mL), (no aqueous work-up) provides, after ion exchange chromatography (methanol→2 M ammonia/methanol) and silica gel chromatography (4:1→1:1 hexanes:ethyl acetate), 0.0899 g (65%) of the title compound as a yellow oil: Mass spectrum (electrospray): m/z=398.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.ClCCl.[Br:36][C:37]1[N:42]=[C:41]([NH2:43])[CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCCl.CN(C=O)C>[Br:36][C:37]1[N:42]=[C:41]([NH:43][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:20])[CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: Nc1cccc(Br)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(C#N)cc21
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (1.00 g, 2.83 mmol) and a drop of DMF in DCE (10 ml) was added oxalyl chloride in dichloromethane (2M) (1.55 mL, 3.11 mmol). After stirring for 1 hour, 6-bromopyridin-2-amine (0.489 g, 2.83 mmol) and triethylamine (0.788 mL, 5.66 mmol) were added. After stirring overnight, the reaction was loaded onto silica gel and the product eluted to provide the desired product (0.939 g, 65%).
Reaction SMILES: B.CSC.[C:5]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].OS([O-])(=O)=O.[K+].[OH-].[Na+]>C1COCC1.CO>[C:5]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH2:25])=[CH:26][CH:27]=1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1)C1CCCCC1
Agent: B
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(CN)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Under a nitrogen atmosphere, add borane-dimethylsulfide complex (29.3 mL, 58.7 mmol, 2M solution in THF) to 4-[N-(tert-butoxycarbonyl)-N-(cyclohexyl)-aminomethyl]-benzonitrile (3.7 g, 11.7 mmol) in THF (100 mL) at 0° C. Warm to room temperature and stir overnight. Heat the mixture under reflux for 30 min. Cool the mixture in an ice-bath, and add methanol (20 mL). Warm to room temperature, and add KHSO4 (20 g in 100 mL of water). Stir the mixture for 2 h and adjust the pH to 10 with 3N aqueous NaOH. Extract the mixture with DCM. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (150 g) eluting with a gradient of DCM to 1:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as an oil (2.43 g, 65%). MS (ES+) m/z: 319 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:10]([Mg]Br)[CH3:11]>O1CCCC1>[CH2:10]([C:6]1([OH:9])[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)[CH3:11]
Reactant: CC[Mg]Br
Reactant: O=C1CCC(CO)CC1
Solvent: C1CCOC1
Product: CCC1(O)CCC(CO)CC1
Temperature: 25 °C

Procedure:
4-(Hydroxymethyl)cyclohexanone (1.22 g) in tetrahydrofuran (20 mL) was treated with 1M ethylmagnesium bromide in tetrahydrofuran (28.6 mL) at 0° C. The reaction was warmed to room temperature over 4 hours and quenched with methanol (2 mL) and water (2 mL). The resulting mixture was concentrated and the residue was suspended in ethyl acetate. The precipitates were filtered off and the filtrate was concentrated and purified by flash chromatography, eluted with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]4([CH3:29])OCC[O:25]4)=[CH:19][C:18]=3[Cl:30])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([O:14]C)[N:11]=[CH:10][CH:9]=3.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[C:24]([C:20]1[CH:19]=[C:18]([Cl:30])[C:17]([NH:16][C:7]2[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]3[CH:3]=[C:2]([Br:1])[CH:32]=[CH:31][C:5]=3[N:6]=2)=[C:22]([Cl:23])[CH:21]=1)(=[O:25])[CH3:29]
Reactant: COc1nccc2c(Nc3c(Cl)cc(C4(C)OCCO4)cc3Cl)nc3ccc(Br)cc3c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 85 °C

Procedure:
To a solution of 9-bromo-N-[2,6-dichloro-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]-1-methoxybenzo[c]-2,6-naphthyridin-5-amine (1.40 g, 2.62 mmol) in THF (24 mL) was added 6 N HCl (8mL) and the reaction mixture was heated to 85° C. for 45 min. The solution was cooled to room temperature and neutralized with sat. NaHCO3. The mixture was extracted with a mixture of 1:3 iPrOH/CHCl3. The organic layers were combined, dried over MgSO4, filtered, and concentrated to afford the title compound.
Reaction SMILES: [Si]([O:8][CH:9]([C:23]([CH3:27])([CH3:26])[CH2:24]O)[CH:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11])(C(C)(C)C)(C)C.C(N(CC)CC)C.S(Cl)(C)(=O)=O.O>C1COCC1>[OH:8][CH:9]1[C:23]([CH3:24])([CH3:26])[CH2:27][N:12]([C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:22])[CH:10]1[CH3:11]
Reactant: CC(NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1C(O)C(C)(C)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
A solution (20 mL) of benzyl [2-(tert-butyldimethylsilyloxy)-4-hydroxy-1,3,3-trimethylbutyl]carbamate (1.38 g) and triethylamine (0.73 mL) in THF was added mesyl chloride (0.352 mL) at 0° C., and the mixture was stirred at 0° C. for 45 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a solution (20 mL) of the residue in THF was added 1M potassium tert-butoxide—THF solution (3.8 mL). After stirring at room temperature for 1 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a solution (10 mL) of the residue in THF was added 1M tetrabutylammonium fluoride—THF solution (4 mL), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/2) to give the title compound as a colorless solid (yield: 842 mg, yield: 92%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:13])([F:12])[CH2:8][CH2:9][CH:10]=O>>[CH2:1]([NH:5][CH2:10][CH2:9][CH2:8][C:7]([F:13])([F:12])[F:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=CCCC(F)(F)F
Product: CCCCNCCCC(F)(F)F

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, butan-1-amine (293 mg, 4.00 mmol) and 4,4,4-trifluorobutanal (504 mg, 4.00 mmol) were converted to a crude oil which was used without purification. MS(ESI+) m/z 184.1 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:42])([F:41])[C:7]([C:37]([F:40])([F:39])[F:38])([C:33]([F:36])([F:35])[F:34])[O:8][CH2:9][C:10]1([CH2:18][O:19][C:20]([C:29]([F:32])([F:31])[F:30])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH2:15]OS(=O)(=O)[O:12][CH2:11]1>CC(C)=O>[N:1]([CH2:15][C:10]([CH2:9][O:8][C:7]([C:6]([F:5])([F:41])[F:42])([C:37]([F:38])([F:39])[F:40])[C:33]([F:34])([F:35])[F:36])([CH2:18][O:19][C:20]([C:21]([F:22])([F:24])[F:23])([C:25]([F:28])([F:27])[F:26])[C:29]([F:32])([F:31])[F:30])[CH2:11][OH:12])=[N+:2]=[N-:3]
Reactant: O=S1(=O)OCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(CO)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
Sodium azide (4.4 g, 66.9 mmol) was added to a stirred solution of compound 10 (21.2 g, 33.4 mmol) in dimethylformaldehyde (120 mL). The reaction mixture was stirred at 60° C. for 4 hours. The solvent was removed under vacuo and the residue was dissolved in tetrahydrofuran (120 mL). Sulfuric acid (0.87 mL) and water (0.32 mL) were added to the stirred tetrahydrofuran solution and the resulting mixture was stirred at room temperature for an additional hour. After removal the solvent, the residue was redissolved in dichloromethane (200 mL) and extracted with perfluorohexane (100 mL 4 times). The combined extraction was washed with dichloromethane (10 mL) and concentrated under vacuo to give the pure azide 11 as a clear oil (19.3 g, 97%). 1H NMR (400 MHz, CDCl3) δ 3.47 (s, 2H), 3.63 (s, 2H), 4.02 (s, 4H); 19F NMR (376 MHz, CDCl3) δ −73.21 (s); 13C NMR (100.7 MHz, CDCl3) δ 45.8, 49.8, 60.2, 66.8, 79.6 (m), 120.2 (q, J=293.3 Hz); MS (CI) m/z 598 (M++1, 72), 570 (100); HRMS (CI) Calcd for C13H10F18N3O3: 598.0435, Found: 598.0418.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:27])C=CC=1)=O.II.OS([O-])=O.[Na+]>C(Cl)Cl>[I:27][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5]
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To the N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVI) (20 g, 97.4 mmol) in DCM (1 L) was added bis(trifluoroacetoxy)iodobenzene (46 g, 107 mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at room temperature. After 1 hour, 600 mL of saturated NaHSO3 was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with brine, dried over MgSO4, concentrated and the remaining solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVII) as a white solid (23.2 g, 70 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 3.45 (s, 4H), 3.77 (s, 4H), 7.45-7.54 (m, 1H), 7.66 (dd, J=8.81, 1.51 Hz, 1H), 8.40 (d, J=1.01 Hz, 1H); ESIMS found for C10H10IN3O2 m/z 331 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=1[N+:21]([O-:23])=[O:22])=[O:9]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1cc(C(=O)O)c(C)o1
Product: CCOc1ccc(NC(=O)c2cc(C)oc2C)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2,5-dimethyl-3-furoic acid and 4-ethoxy-2-nitroaniline as an orange solid as described in Example 15. 1H NMR (CDCl3): 10.59 (s, 1H), 8.83 (d, J=9.0, 1H), 7.70 (d, J=3.0, 1H), 7.27-7.25 (m, 1H), 6.24 (s, 1H), 4.08 (q, J=6.9, 2H), 2.62 (s, 3H), 2.30 (s, 3H), 1.45 (t, J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:19][OH:20])=[CH:4][CH:3]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:19]=[O:20])=[CH:4][CH:3]=1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Yield: 65.9 %

Procedure:
A mixture of 5-(5-chlorothiophen-2-yl)-2-(4-fluoro-phenyl)-4-hydroxymethyloxazole (1.44 g) and manganese dioxide (4.76 g) in tetrahydrofuran (20 ml) was refluxed for 3 hours. The reaction mixture was filtered through Cellite and the filtrate was concentrated under reduced pressure. The resulting reside was triturated with diethyl ether to obtain 5-(5-chlorothiophen-2-yl)-2-(4-fluorophenyl)-4-formyl-oxazole (943 mg) as colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][N:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:36][O:35][C:33]([C:30]1[CH:31]=[CH:32][C:27]([O:25][CH2:24][C@@H:9]2[CH2:10][C@H:11]([O:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:28][CH:29]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Reactant: COC(=O)c1ccc(O)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)OC(C)(C)C)nc1
Yield: 25.2 %

Procedure:
To a stirred mixture of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (484 mg, 1.41 mmol), methyl 2-hydroxy-5-pyridinecarboxylate (216 mg, 1.41 mmol) and PPh3 (370 mg, 1.41 mmol) in THF (15 ml) was added DIAD (0.28 ml, 1.41 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [50 g, n-hexane/EtOAc(2/1)], to give methyl-2-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxypyridine-5-carboxylate (170 mg, 25%) as a colorless oil. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 2.37 (m, 1H), 2.46 (d, J=14.2 Hz, 1H), 3.71–4.00 (m, 2H), 3.89 (s, 3H), 4.30–4.56 (m, 2H), 4.74 (dd, J=9.8, 4.6 Hz, 1H), 5.06 (br, 1H), 6.70 (d, J=8.8 Hz, 2H), 7.05–7.09 (m, 21H), 7.33 (t, J=6.9 Hz, 1H), 7.42 (t, J=6.9 Hz, 1H), 7.67–7.75 (m, 3H), 8.09 (d, J=8.8 Hz, 1H), 8.77 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:15]O>O>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH3:15])=[O:4]
Reactant: CO
Reactant: CCCCC(C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(C)C(=O)OC
Temperature: 50 °C
Yield: 93 %

Procedure:
A solution of 2-methylhexanoic acid (20 g, 153 mmol) in methanol (500 mL) was treated with concentrated sulfuric acid (8.0 mL) and heated to 50° C. for 16 h. The reaction was diluted with water and extracted with ether. The combined organic layers were dried and concentrated to afford 20.57 g (93%) of methyl 2-methylhexanoate as a colorless liquid.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[O:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:29][N:30]=4)=[CH:22][CH:21]=3)(O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([C:38]3[CH:43]=[CH:42][C:41]([C:44]4[O:45][C:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[N:47][N:48]=4)=[CH:40][CH:39]=3)(O)[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I-].[K+].O.[PH2](=O)[O-].[Na+].[PH2](=O)O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:38]3[CH:39]=[CH:40][C:41]([C:44]4[O:45][C:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[N:47][N:48]=4)=[CH:42][CH:43]=3)[C:9]3[C:14]([C:15]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]4[O:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:29][N:30]=4)=[CH:24][CH:25]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(O)(c1ccc(-c3nnc(-c4ccccc4)o3)cc1)c1ccccc1C2(O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Agent: O=C([O-])O
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(-c3ccc(-c4nnc(-c5ccccc5)o4)cc3)c3ccccc3c(-c3ccc(-c4nnc(-c5ccccc5)o4)cc3)c2c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
In a recovery flask were placed 2-tert-butyl-9,10-bis[4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl]anthracene-9,10-diol, 6.0 g (36 mmol) of potassium iodide, and 29 g (83 mmol) of sodium phosphinate monohydrate. They are dissolved by the addition of 50 mL of glacial acetic acid. This solution was stirred at 120° C. for 4 hours. Then, 50 mL of a 50% solution of phosphinic acid was added to this solution, and the mixture was stirred at 120° C. for 1 hour. Then, an aqueous solution of sodium hydrogen carbonate was added to this mixture, followed by stirring. After that, the resulting mixture was suction filtered to give a solid. This solid was washed with ethyl acetate. After that, the resulting solid was dissolved in chloroform, and this solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and with saturated brine. Then, magnesium sulfate was added to the organic layer to thy it.
Reaction SMILES: CO[CH:3]([C:5]1[C:6]([O:25]CC2C=CC=CC=2)=[CH:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@H:20]([C:21]=2[CH:22]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]1[O:23][CH3:24])[CH3:4].ClCCl>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH2:3]([C:5]1[C:6]([OH:25])=[CH:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@H:20]([C:21]=2[CH:22]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]1[O:23][CH3:24])[CH3:4]
Reactant: COC(C)c1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]12
Reaction time: 8 h
Yield: 104.8 %

Procedure:
290 mg of 2-(1-methoxyethyl)-3-benzyloxy-17β-methoxy-estra-1,3,5(10)-triene was dissolved in 20 ml each of ethyl acetate and dichloromethane and then mixed with 3 drops of acetic acid and 110 mg of palladium on activated carbon (10%). The hydrogenation was carried out under normal pressure over 8 hours. The catalyst was filtered out, and the solution was concentrated by evaporation in a rotary evaporator and co-evaporated several times with toluene. Flash chromatography (toluene/acetone=80:1) yielded 220 mg (98%) of 2-ethyl-3-hydroxy-17β-methoxy-estra-1,3,5(10)-triene as a colorless foam.