Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[O:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]1[CH2:30][C:31](=[S:33])[NH2:32].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:32]=[C:31]([CH2:30][N:21]2[C:20](=[O:19])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:29])[S:33][C:2]=1[S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1F)C(Br)Sc1ccccc1
Reactant: NC(=S)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2F)c(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of 2-bromo-1-(2-fluorophenyl)-2-(phenylthio)ethanone (496 mg) in N,N-dimethylformamide (5 mL) was added 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanethioamide (357 mg), and the mixture was stirred at room temperature for 12 hr. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and 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=4:1→2:1) to give the title compound as a pale-yellow oil (yield 351 mg, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.O[NH:16][C:17](=[NH:26])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:26]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)[N:16]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1Cl
Temperature: 122.5 °C

Procedure:
N,N-Dicyclohexylcarbodiimide (1.07 g, 0.0052 mol) is added to a solution of 3-chloro-4-isobutylbenzoic acid (0.74 g, 0.0035 mol), N-hydroxy-4-hydroxymethylbenzamidine (0.867 g, 0.0052 mol) and N-hydroxybenzotriazole monohydrate (0.798 g, 0.0052 mol) in N,N-dimethylformamide (15 mL). The reaction mixture is heated at 120-125° C. for 2 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×20 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (2×30 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 15:85) to give {4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]-phenyl}methanol.
Reaction SMILES: FC(F)(F)S(OC1C=C(F)C=CC=1[N+]([O-])=O)(=O)=O.COC1C=C2C(=CC=1)C=C([Sn](C)(C)C)CC2.[F:35][C:36]1[CH:37]=[CH:38][C:39]([N+:54]([O-])=O)=[C:40]([C:42]2[CH2:43][CH2:44][C:45]3[C:50]([CH:51]=2)=[CH:49][CH:48]=[C:47]([O:52][CH3:53])[CH:46]=3)[CH:41]=1>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([NH2:54])=[C:40]([CH:42]2[CH2:43][CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[C:47]([O:52][CH3:53])[CH:46]=3)[CH2:51]2)[CH:41]=1
Reactant: COc1ccc2c(c1)CCC(c1cc(F)ccc1[N+](=O)[O-])=C2
Agent: COc1ccc2c(c1)CCC([Sn](C)(C)C)=C2
Agent: O=[N+]([O-])c1ccc(F)cc1OS(=O)(=O)C(F)(F)F
Product: COc1ccc2c(c1)CCC(c1cc(F)ccc1N)C2
Yield: 79.7 %

Procedure:
Synthesized from 5-fluoro-2-nitrophenyl trifluoromethanesulfonate and (6-methoxy-3,4-dihydronaphthalen-2-yl)trimethyltin according to an analogous synthetic method to Preparation Example 77, 3-(5-fluoro-2-nitrophenyl)-7-methoxy-1,2-dihydronaphthalene (396 mg) was used according to an analogous synthetic method to Example 30 to provide the title compound (286 mg).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)[C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:28][O:27][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH2:10][N:6]1[C:5]2[CH:29]=[CH:30][C:2]([C:35]3[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[NH2:9]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(Br)ccc43)cc2OC)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5cnn(C)c5)ccc43)cc2OC)cc1
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 119.1 %

Procedure:
To a stirred suspension of 5-bromo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine (0.28 g, 0.59 mmol) in 1,4-dioxane (8 mL) and water (6 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.73 mmol), potassium phosphate (0.44 g, 2.06 mmol), tricyclohexylphosphine (0.016 g, 0.059 mmol), and palladium(II)acetate (0.007 g, 0.029 mmol). The reaction mixture was heated to 125° C. in a microwave reactor. After 15 min, the reaction mixture was diluted with water. The mixture was extracted with ethyl acetate (×3), and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 0.33 g of a light green solid. Chromatographic purification (Combi-Flash, 12 g SiO2 gold column, 1-5% 2 M ammonia in methanol/dichloromethane elute) afforded 0.13 g (48%) of the product as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.71 (s, 1H), 7.34-7.24 (m, 3H), 7.05-6.87 (m, 6H), 6.65-6.60 (m, 1H), 6.50 (s, 2H), 5.11 (s, 2H), 4.90 (s, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.69 (s, 3H) ppm; (M+1) 470.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:5].CCN(C(C)C)C(C)C.C1C=CN=CC=1.O=S(=O)=O>C(Cl)Cl.CS(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@@H](CO)CC1)c1cc(C(F)(F)F)ccc1Cl
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C[C@H]1CC[C@@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of Cis-2-chloro-N-(−4-(hydroxymethyl)cyclohexyl)-5-(trifluoromethyl)-benzamide (1 g, 2.98 mmol) in DCM (18 mL) is added DIPEA (2.081 mL, 11.91 mmol). The reaction mixture is cooled to 0° C. and pyridine-sulfur trioxide (1.896 g, 11.91 mmol) in DMSO (6 mL) is added. The reaction mixture is stirred at this temperature for 30 mins. The reaction mixture is partitioned between water and DCM and passed through a phase separator. The DCM layer was collected and concentrated under reduced pressure to give a colourless oil. Purification by chromatography on a pre-packed silica gel column using 0-100% EtOAc in isohexane gradient elution gave the desired product as a colourless solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11]C)[CH:3]=1>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1cc(I)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(O)cc(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 1-iodo-3-methoxy-5-nitro-benzene (8.2 g, 29.39 mmol) in methylene chloride (600 mL) was added 1.0 M solution of borontribromide (58.78 mL, 58.78 mmol) in methylene chloride at −78° C. The resulting solution was stirred for 30 minutes and then the cooling bath was removed to warm to room temperature. After stirring for 15 h at this temperature, the reaction mixture was heated to reflux for 4 h in order to complete the reaction. Then, it was cooled to room temperature and diluted with water (100 mL) and the methylene chloride was removed under vacuum. Then, the organic compound was extracted into diethyl ether (2×100 mL) and the combined ether extracts were washed with brine solution (200 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 120 g column, eluting with 0-15% ethyl acetate in hexanes to obtain 3-iodo-5-nitro-phenol (4.8 g, 62%) as a light yellow solid: ES(+)-HRMS m/e calculated for C6H4INO3 (M−H)+ 263.9163, found 263.9162.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([F:15])[CH:4]=1.Cl.C1([O:23][C:24](=O)[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)C=CC=CC=1>>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:24](=[O:23])[NH:1][CH2:2][C:3]2[CH:4]=[C:5]([F:15])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([F:9])[CH:8]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Reactant: CC(C)(C)c1ccc(CNC(=O)Oc2ccccc2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(CNC(=O)NCc2cc(F)c(NS(C)(=O)=O)c(F)c2)cc1
Yield: 12 %

Procedure:
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide and HCl salt (100 mg, 0.36 mmol) were reacted with (4-t-butyl-benzyl)-carbamic acid phenyl ester following the general procedure to give a white solid (18 mg, 12%).
Reaction SMILES: [Cl:1]C1C(OC)=C(COC)N=CN=1.O[C:14]1[C:19]([S:20][CH3:21])=[C:18]([CH2:22][S:23][CH3:24])[N:17]=[CH:16][N:15]=1>>[Cl:1][C:14]1[C:19]([S:20][CH3:21])=[C:18]([CH2:22][S:23][CH3:24])[N:17]=[CH:16][N:15]=1
Reactant: CSCc1ncnc(O)c1SC
Reactant: COCc1ncnc(Cl)c1OC
Product: CSCc1ncnc(Cl)c1SC

Procedure:
The preparation was analogous to the synthesis of the starting compound 4-chloro-5-methoxy-6-methoxymethylpyrimidine, using 42 g of 4-hydroxy-5-methylthio-6-methylthiomethylpyrimidine
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>N.CO>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([S:39]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:40])=[O:41])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.05 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 3,4-Dimethoxybenzenesulfonyl chloride (24 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (6.2 mg). MS m/z 389 [M+H]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1(=[O:19])[O:16]CC[O:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][C:7]1=[CH:8][CH:9]=2.C(=O)=O>O>[C:6]([OH:19])(=[O:16])[C:7]1[CH:18]=[CH:17][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C1OCCOC(=O)c2ccc1cc2
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 200 °C

Procedure:
In a heated autoclave, provided with a mixer and filled partially with water, cut poly/ethyleneterephtalate/ wastes in a form of scraps of foil and pieces of industrial shapes were placed in the amount of 1000 g together with a solution of 875 g of sodium bicarbonate (NaHCO3) in 10 liters of water, and then a content of the reactor was heated up to 200° C. and the temperature was kept till the digestion of poly/ethylene terephtalate/ was completed and the formation of carbon dioxide was stopped. Then the autoclave was relieved and carbon dioxide and water excess were separated, then a resulted solution was filtered hot through a filter with active carbon. The filtrate was neutralised with hydrochloric acid and a precipitate of terephtalic acid was separated from a reaction solution using a centrifuge. The resulted product was washed with a distilled water and crystallised from water, giving 864 g of terephtalic acid. At the same time ethylene glycol was separated from the neutralised filtrate using extraction with diethylcarbonate, obtaining 322,6 g of ethylene glycol.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].C(OC)(OC)OC.[CH2:19]([O:21][C:22](=[O:28])[CH:23]=[C:24]1[CH2:27][CH2:26][CH2:25]1)C>CO.S(=O)(=O)(O)O>[CH3:19][O:21][C:22](=[O:28])[CH2:23][C:24]1([S:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=2[CH3:11])[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C=C1CCC1
Reactant: Cc1cc(S)c(C)c(C)c1O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC(OC)OC
Product: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2C)CCC1
Yield: 71.8 %

Procedure:
4-Mercapto-2,3,6-trimethyl-phenol (1.8 g) was dissolved in anhydrous methanol (30 mL) containing trimethyl orthoformate (2 mL). To this solution was added cyclobutylidene-acetic acid ethyl ester (4.0 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with NaHCO3 and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 2.26 g of [1-(4-Hydroxy-2,3,5-trimethyl-phenylsulfanyl)-cyclobutyl]-acetic acid methyl ester as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[C:14]1([C:20]2[C:21]([O:23][C:24](=O)[CH:25]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:22]=[C:21]1[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][C:24](=[O:23])[N:1]1[CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)C=C(c2ccccc2)C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (1.0 g, 56%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (1.00 g, 5.29 mmol) and phenylmaleic anhydride (1.10 g, 6.34 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O>>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: O=C1OCCc2cc(O)ccc21
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Product: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21

Procedure:
6-Hydroxy-isochroman-1-one was reacted with Methanesulfonic acid (S)-1-(tetrahydro-furan-2-yl)methyl ester by method K1. The product with the molecular weight of 248.28 (C14H28FN3O3) was obtained in this way; MS (ESI): 249 (M+H+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[S:20][CH:21]=2)=[C:13]([F:28])[CH:12]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([N:22]3[C:23]([CH3:26])([CH3:27])[CH2:24][O:25][C:30]3=[O:32])[S:20][CH:21]=2)=[C:13]([F:28])[CH:12]=1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2F)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2F)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 111.5 %

Procedure:
N,N-diisopropylethylamine (1.2 mL, 6.9 mmol) was added to a solution of 2-{[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (1.0 g, 2.9 mmol), prepared in the previous step, in 50 mL of dry methylene chloride at 0° C. Triphosgene (1.0 g, 3.4 mmol) in 10 mL of dry methylene chloride was added drop-wise over 10 min. The orange solution was stirred at 0° C. for 3 h and then allowed to warm to room temperature. The reaction was washed with 2N HCl and the aqueous layer was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.2 g of a green residue. The crude product was purified on silica gel using a step-wise gradient of 5-30% ethyl acetate:hexane to give the title compound (0.9 g, 89%). MS (ES) m/z 372 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]([OH:25])([CH3:24])[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH2:22][OH:23])[CH:14]=2)=[O:11])=[CH:5][C:4]=1[F:28])#[N:2]>ClCCl.[O-2].[Mn+4].[O-2]>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]([OH:25])([CH3:24])[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:22]=[O:23])[CH:14]=2)=[O:11])=[CH:5][C:4]=1[F:28])#[N:2]
Reactant: CC(O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc([N+](=O)[O-])c(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(4-Cyano-3-fluorophenoxy)-2-hydroxy-N-(3-hydroxymethyl-4-nitrophenyl)-2-methylpropionamide (0.2 g, 0.51 mmol) was dissolved in dichloromethane (10 ml) and manganese(IV) oxide (0.4 g, 4.6 mmol) was added. The mixture was stirred at room temperature for 48 hours. The solid oxidant was removed by filtration and the solvent was evaporated. The crude product was purified by flash chromatography (dichloromethane-3% methanol). 1H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 4.13 (1H, d, J=10.0 Hz), 4.38 (1H, d, J=10.0 Hz), 6.32 (1H, s), 6.94-6.97 (1H, m), 7.16-7.20 (1H, m), 7.77-7.82 (1H, m), 8.18-8.24 (2H, m), 8.36 (1H, d, J=2.1 Hz), 10.28 (1H, s), 10.55 (1H, s).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:37]1[CH:46]2[CH:41]([CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:37]3[CH:46]4[CH:41]([CH2:42][CH2:43][CH2:44][CH2:45]4)[CH2:40][CH2:39][CH2:38]3)=[O:17])=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3]
Reactant: C1CCC2NCCCC2C1
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)N3CCCC4CCCCC43)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.3 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (1 g, 0.00433 mol) in dry DMF (7.0 mL) was added with stirring HOBt (0.876 g, 0.00649 mol), DIPEA (2.25 mL, 0.0129 mol), decahydroquinoline (0.902 g, 0.00649 mol) at 0° C. To the resulting mixture was added EDCl (1.24 g, 0.00649 mol) and stirred for 15 h at an ambient temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with water, dried (Na2SO4) and the solvent evaporated to give [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone (1.5 g, 98%).
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C3CC3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cn2c(C3CC3)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a 250 mL round bottomed flask containing DMF (50 mL) was added 4-bromo-2-cyclopropyl-6-nitro-1H-benzo[d]imidazole (4.3 g, 15.24 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (3.6 mL, 21.34 mmol) and potassium carbonate (6.32 g, 45.7 mmol). The resultant suspension was heated to 50° C. and after stirring for 30 minutes the mixture was allowed to cool to rt and diluted with 100 mL H2O. The mixture was stirred overnight and the next day a brown filterable solid was isolated by filtration providing crude 4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (5.97 g, 13.14 mmol, 86% yield). MS (ES+) m/e: 453.0, 454.0 [M+H]+
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH3:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][N:43]1[CH2:48][C:49]([OH:51])=O>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:51])[CH2:48][N:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH:42]1[CH3:41])[CH2:19][CH2:18]2
Reactant: CC1CCCCN1CC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)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
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCCCC3C)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

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-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 general procedure described for the parallel synthesis of C-17 amides above, using (2-methylpiperidin-1-yl)acetic acid as the reacting carboxylic acid. LCMS: m/e 669.7 (M+H)+, 4.73 min (method 3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Reactant: COCCN
Product: COCCNc1ccc([N+](=O)[O-])c(C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
A mixture of 2-fluoro-5-nitro-6-picoline (656 mg, 4.2 mmol) and 2-methoxyethylamine (365 μl, 4.2 mmol) was stirred at 0° C. After 10 min, crude (2-methoxy-ethyl)-(6-methyl-5-nitro-pyridin-2-yl)-amine (957 mg) was obtained as a solid. 1HNMR (CDCl3, 400 MHz) δ 2.77 (s, 3H), 2.85 (s, 2H), 3.40 (s, 3H), 3.57-3.60 (m, 2H), 5.51 (s br, 1H), 6.26-6.29 (m, 1H), 8.18-8.20 (m, 1H). Exact mass calculated for C9H13N3O3 211.10. found 212.2 (MH+).