Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:8][CH2:9][C:10]1[CH2:11][S:12][C@@H:13]2[C@H:20]([NH:21][C:22](=[O:32])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:33])[N:14]2[C:15]=1[C:16]([OH:18])=[O:17])(=[O:7])[CH3:6].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:31][N:30]=[C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:22]([NH:21][C@@H:20]1[C:19](=[O:33])[N:14]2[C:15]([C:16]([OH:18])=[O:17])=[C:10]([CH2:9][O:8][C:5](=[O:7])[CH3:6])[CH2:11][S:12][C@H:13]12)=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(C)=O)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of acetyl chloride (8 ml.) in methylene chloride (8 ml.) was added 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)-ceph-3-em-4-carboxylic acid (syn-isomer) (500 mg.) in portions over ten minutes with vigorous stirring at room temperature. A gem formed, and ethyl acetate (8 ml.) was added to achieve solution. After stirring for two hours at room temperature, the mixture was added slowly to petroleum spirit (300 ml.) with vigorous stirring. The precipitate was filtered off, washed thoroughly with petroleum spirit, dissolved in chloroform (10 ml.) stirred with activated charcoal and filtered. The filtrate was added dropwise to petroleum spirit (250 ml.) with stirring. The precipitate was filtered off and dried giving the title acid, (350 mg; 62%), τ (DMSO-d6) values include -0.11 (doublet, J 8 Hz; NH), 2.2-2.6 (multiplet; aromatic protons), 7.76 (singlet; CH3. CO2N=), 7.94 (singlet; Ch3C0). Signals at τ 0.05 (doublet, J 9 Hz; NH) and 7.78 (singlet; CH3CO2 =) indicated the presence of about 30% of the anti-isomer.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:16]1[N:34]=[C:19]2[C:20]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:20]2[C:19]3[N:18]([N:17]=[C:16]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:9][CH:10]=4)[N:34]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CNc2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: COc1ccc(CNc2cccn3nc(Nc4ccc(N5CCN(C)CC5)cc4)nc23)cc1

Procedure:
N(8)-(4-Methoxy-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (74.2 mg, 0.388 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product was isolated as a red foam (10.64 mg, 7%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.03 (s, 1H), 7.92 (d, J=6.2 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H), 6.88 (d, J=8.3 Hz, 4H), 6.68 (t, J=13.9, 7.0 Hz, 1H), 6.29 (m, 2H), 4.42 (m, 2H), 3.72 (s, 3H), 3.03 (s, 4H), 2.47 (s, 4H), 2.22 (s, 3H). MS=444 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([OH:22])=[O:21].[I-].ClC1C=CC=C[N+]=1C.[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=[O:38].C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([O:22][C:37]1[CH2:36][CH2:35][CH2:34][C:33](=[O:38])[CH:32]=1)=[O:21]
Reactant: O=C(O)c1cnc(-c2cccnc2)n(-c2ccccc2)c1=O
Reactant: O=C1CCCCC1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2cnc(-c3cccnc3)n(-c3ccccc3)c2=O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1,6-dihydro-6-oxo-1-phenyl-2-(3-pyridinyl)-5-pyrimidinecarboxylic acid (i.e. the product from Example 7, Step C) (10.7 g, 36.3 mmol) in dichloromethane (150 mL) at ambient temperature was added 2-chloro-N-methyl pyridinium iodide (also known as the Mukaiyama reagent) (14.8 g, 57.9 mmol) followed by cyclohexanedione (6.5 g, 58 mmol) and triethylamine (9.2 g, 91 mmol). The reaction mixture was left stirring at ambient temperature overnight, then diluted with dichloromethane, washed with water, brine and dried over anhydrous Na2SO4. The residue obtained after removal of the solvent under vacuum was purified by tituration with n-chlorobutane/petroleum ether mixtures to obtain 9.8 g of the title compound as a light brown solid.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([OH:12])[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]>O>[CH2:6]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH:5]1[O:12][CH2:4]1
Reactant: CCN(CC)CC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CC1CO1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of sodium hydroxide (47.9 g, 1.2 mole) in 78 mL water was added 1-chloro-3-diethylamino-propan-2-ol. The resultant was stirred at 20-25° C. for 1 hour, diluted with 178 mL of water and extracted with ether twice. The combined ether solution was dried with solid potassium hydroxide and evaporated to give 135 g of crude product which was purified by fraction distillation to give pure glycidyldiethylamine (98 g, 76%) as an oil.
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:25]=[CH:24][C:11]2[S:12][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[C:14]([CH3:15])[C:10]=2[C:9]=1[C:26]#[N:27])C.C[OH:29]>ClCCl>[OH:7][C:8]1[C:25]([OH:29])=[CH:24][C:11]2[S:12][C:13]([C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[O:17])=[C:14]([CH3:15])[C:10]=2[C:9]=1[C:26]#[N:27]
Reactant: CO
Reactant: CCOc1ccc2sc(C(=O)N3CCOCC3)c(C)c2c1C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCOCC2)sc2cc(O)c(O)c(C#N)c12
Reaction time: 48 h

Procedure:
A solution of 1 N boron tribromide in dichloromethane (3.4 ml) was added to a solution of 5,6-di(ethoxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carbonitrile (0.19 g) in dichloromethane (40 ml) at 0° C. The mixture was allowed to stay at 6° C. for two days. Methanol was added and the mixture was evaporated to dryness. To the residue 0.1 N HCl was added and the product was extracted into ethyl acetate. Ethyl acetate was dried and evaporated to dryness. The compound was recrystallized from isopropanol.
Reaction SMILES: [NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:36])[CH3:35])[NH:32][C:30](=[O:31])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[NH:23][C:21](=[O:22])[C@@H:16]([CH2:17][C:18](=[O:20])[OH:19])[NH:15][C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:47](OC=O)(=[O:52])C(C)(C)C>CN(C=O)C>[NH:1]1[C:45](=[O:46])[C@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:39][C:37](=[O:38])[C@@H:33]([CH:34]([CH3:36])[CH3:35])[NH:32][C:30](=[O:31])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH:47]=[O:52])[NH:23][C:21](=[O:22])[C@@H:16]([CH2:17][C:18](=[O:19])[OH:20])[NH:15][C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC1=O
Reactant: CC(C)(C)C(=O)OC=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)NC(=O)[C@H](CCCCNC=O)NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclo(-DTrp-DAsp-Lys-DVal-Leu-) (10.5 mg) which was prepared in Example 4, and formic pivalic anhydride(10 ml) in DMF(0. 5ml) was added TEA(10 μl). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was triturated with water (2 ml) to give the title compound(7.8 mg) as an off-white powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17](F)=[C:16]3[C:11]([C:12](=[O:25])[C:13]([C:22]([OH:24])=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:21][CH2:20]3)=[CH:10][C:9]=2[F:26])[CH2:3]1.[CH3:27][O-:28].[Na+]>CS(C)=O>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]([O:28][CH3:27])=[C:16]3[C:11]([C:12](=[O:25])[C:13]([C:22]([OH:24])=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:20][CH2:21]3)=[CH:10][C:9]=2[F:26])[CH2:3]1
Reactant: NC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(N2CCCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2 h

Procedure:
A mixture of 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.21 g) obtained as described in Example 1(b), sodium methoxide (1.2 g) and dimethylsulfoxide (40 ml) was stirred for 2 hours at 120°-140° C. The reaction mixture was concentrated in vacuum and water was added to the residue. Neutralization of the mixture with 1N hydrochloric acid followed by evaporation of the solvent and purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=100:30:5) gave 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. The physical properties of this product wereidentical with those of the compound obtained in Example 6.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Br:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 150–152° C.; 1H NMR (300 MHz, CDCl3): δ 7.09 (s, 1 H), 6.81 (d, J=7.3 Hz, 1 H), 4.95–4.90 (m, 1 H), 4.35 (t, J=8.1 Hz, 2 H), 3.89 (s, 3 H), 3.67 (dd, J=10.6, 5.8 Hz, 1 H), 3.56 (dd, J=10.6, 3.5 Hz, 1 H), 3.36 (s, 3 H), 3.09 (t, J=8.4 Hz, 2 H), 1.96–1.77 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H21N3O3BrClF (M+H)+: 460.0439; found m/z 460.0460.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH:13]([CH3:15])[CH3:14])[C:16](=[O:18])[O:17][CH2:19]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
In toluene (250 mL) were suspended benzyloxycarbonyl-L-valine (25.1 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (23.7 g) as colorless transparent syrup in an yield of 90%.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20]N>C(O)(=O)C.C(O)CCC>[F:17][C:18]([F:23])([F:22])[CH2:19][N:20]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:5][CH:4]=[N:2]1
Reactant: NNCC(F)(F)F
Reactant: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CCCCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1-c1ncnn1CC(F)(F)F

Procedure:
N-[(Dimethylamino)methylene]-2-nitrobenzamide (1.0 g, 4.5 mmol) in acetic acid (25 mL) and n-butanol (15 mL) was treated with 70% aqueous 1,1,1-trifluoroethylhydrazine (1 mL, 11.3 mmol), and heated to reflux for 2 hours, at which time the volume was reduced by ˜25 mL by distillation. The remaining solvent was removed in vacuo, and the residue chromatographed on silica eluting with 3:1-1:1 hexane:ethyl acetate to afford 1-(2,2,2-trifluoroethyl)-5-(2-nitrophenyl)-1,2,4-triazole, which was reduced as in Example 64 to give crude 1-(2,2,2-trifluoroethyl)-5-(2-aminophenyl)-1,2,4-triazole (430 mg).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]2[C:19]3[CH:18]=[C:17]4[O:20][CH2:21][CH2:22][O:23][C:16]4=[CH:15][C:14]=3[N:13]([CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:12]2=[O:30])=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[O:26]1[CH2:27][CH2:28][CH2:29][C@@H:25]1[CH2:24][N:13]1[C:14]2[CH:15]=[C:16]3[O:23][CH2:22][CH2:21][O:20][C:17]3=[CH:18][C:19]=2[C:11]2([C:10]3=[CH:9][C:5]4[CH2:6][CH2:7][O:8][C:4]=4[CH:3]=[C:2]3[O:1][CH2:31]2)[C:12]1=[O:30]
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1C[C@H]1CCCO1)OCCO3
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C[C@H]2CCCO2)c2cc3c(cc2C12COc1cc4c(cc12)CCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-(((R)-tetrahydrofuran-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one was obtained (39%) as a colorless solid: mp 220-225° C.; 1H NMR (300 MHz, CDCl3) δ6.65 (s, 1H), 6.64-6.60 (m, 1H), 6.51-6.46 (m, 1H), 6.36 (s, 1H), 4.72 (dd, J=84.4, 8.9 Hz, 2H), 4.51 (dd, J=8.6, 8.6 Hz, 2H), 4.25-4.19 (m, 2H), 4.19-4.13 (m, 2H), 3.94-3.82 (m, 2H), 3.80-3.67 (m, 2H), 3.64-3.52 (m, 1H), 2.98 (t, J=8.6 Hz, 2H), 2.08-1.94 (m, 1H), 1.94-1.80 (m, 2H), 1.74-1.60 (m, 1H); MS (ES+) m/z 421.9 (M+1).
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH3:5][Si:6]([CH3:37])([CH3:36])[O:7][C@H:8]1[CH2:31][C@@:30]2([CH3:32])[C@@H:19]([CH2:20][CH:21]=[C:22]2[C:23](=[O:29])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@H:18]2[C@H:9]1[C@:10]1([CH3:35])[C:15]([C@@H:16]([F:33])[CH2:17]2)=[CH:14][C:13](=[O:34])[CH:12]=[CH:11]1.[Cl-].[NH4+]>ClCCl>[CH3:37][Si:6]([CH3:5])([CH3:36])[O:7][C@H:8]1[CH2:31][C@@:30]2([CH3:32])[C@@H:19]([CH2:20][C@@H:21]([CH3:2])[C@@H:22]2[C:23](=[O:29])[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@H:18]2[C@H:9]1[C@:10]1([CH3:35])[C:15]([C@@H:16]([F:33])[CH2:17]2)=[CH:14][C:13](=[O:34])[CH:12]=[CH:11]1
Reactant: C[Cu]C
Reactant: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@]12C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: -10 °C

Procedure:
750 mg cuprous iodide was suspended in 10 ml dichloromethane in an atmosphere of nitrogen and cooled to -10° C. To this suspension under stirring and cooling was added 9 ml of a 2% solution of lithium-methyl by drop wise addition maintaining the temperature below -5°. To the so obtained lithium-dimethyl-copper solution was added 425 mg 11β-trimethylsiloxy-21-acetoxy-6α-fluoropregna-1,4,16-triene-3,20-dione obtained according to Example 8 dissolved in 3 ml dichloromethane. The temperature of the reaction mixture was kept below -1°, and the stirring was maintained for a period of 15 minutes. The reaction mixture was poured into an aqueous ammonium chloride solution, the organic phase separated and the aqueous phase re-extracted with dichloromethane. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Trituration with acetone afforded a crystalline product 11β-trimethylsiloxy-21-acetoxy-6α-fluoro-16α-methyl-pregna-1,4-diene-3,20-dione (compound 14) yield 320 mg TLC: homogeneous.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:10][CH:9]1[C:11]([O:13]CC)=O.[C-]#[N:17].[Na+].N>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:10][CH:9]1[C:11]([NH2:17])=[O:13]
Reactant: CCOC(=O)C1CC1OC1CCCCO1
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC(=O)C1CC1OC1CCCCO1

Procedure:
In an autoclave, a solution of 0.25 mol of the compound obtained in Step 2, 2 g of sodium cyanide, 300 ml of a 2N solution of ammonia in methanol and 80 ml of liquid ammonia is heated at 65° C. for 5 days and is then concentrated to dryness. The residue is taken up in a mixture of dichloromethane/saturated potassium carbonate solution, filtered over Celite and then treated in conventional manner. After evaporating under reduced pressure, the residue is triturated in petroleum ether, filtered, rinsed and dried, allowing the expected product to be isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13]1(=[O:18])[CH2:17][CH2:16][CH:15]=[CH:14]1>CC#N>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:15]1[CH2:16][CH2:17][C:13](=[O:18])[CH2:14]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1C=CCC1
Solvent: CC#N
Product: O=C1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of 5-nitroindole (2.0 g, 12.80 mmol) in dry MeCN (10.0 mL) was added cyclopent-2-enone (2.0 mL, 23.87 mmol) and Bi(NO3)3 (0.06 g, 0.13 mmol) and the mixture stirred overnight at room temperature. The solvent then was evaporated and the crude was purified by column chromatography (50% Hexane: 50% EtOAc) to obtain the title compound (1.63 g, 52%) as a yellow solid. 1H-NMR (CDCl3) δ 2.05-2.18 (m, 1H), 2.37-2.48 (m, 3H), 2.54-2.66 (m, 1H), 2.80 (dd, 1H, J=7.2, 7.8 Hz), 3.72-3.82 (m, 1H), 7.15 (d, 1H, J=1.5 Hz), 7.42 (d, 1H, J=9.0 Hz), 8.15 (dd, 1H, J=2.4, 9.0 Hz), 8.39 (brs, 1H, NH), 8.62 (d, 1H, J=2.4 Hz); ESI-MS (m/z, %) 267 (MNa+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][NH2:11].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:11][CH2:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Cc1cc(Cl)cc(Cl)c1CN
Product: Cc1cc(Cl)cc(Cl)c1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using (2,4-dichloro-6-methylphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.[C:15](=O)([O-])[O-].[K+].[K+]>CO>[C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[CH:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 16 h

Procedure:
Dimethyl-1-diazo-2-oxypropylphosphonate (11.5 g, 60 mmol) was added to a solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (10 g, 50 mmol) and potassium carbonate (13.8 g, 100 mmol) in dry methanol (150 mL). After 16 hours, the reaction mixture was filtered and washed with methanol. The filtrate was extracted with diethyl ether, and the organic layer was washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford tert-butyl 3-ethynylpyrrolidine-1-carboxylate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([NH2:37])([CH3:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([NH:37][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)([CH3:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.2 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (750 mg, 2.20 mmol), 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (525 mg, 2.50 mmol) and diisopropylethylamine (1.36 mL, 7.80 mmol) in propan-2-ol (30 mL) was heated to reflux for 65 hours. The cooled reaction mixture was filtered and the yellow solid further purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in cyclohexane) to afford 910 mg (79%) of 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester. LCMS (Method H, ESI): RT=4.35 min, m+H=516.2; 1H NMR (400 MHz, DMSO) δ: 9.42 (s, 1H), 8.95 (s, 1H), 8.15 (dd, 2H), 7.84-7.76 (m, 2H), 7.66 (m, 2H), 7.06 (d, 1H), 3.57 (m, 2H), 3.23-3.08 (m, 1H), 2.09 (d, 2H), 1.80 (m, 2H), 1.57 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:24](=[S:34])(Cl)[O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:24](=[S:34])[O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(OC(=S)Cl)cc1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(OC(=S)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Reaction time: 2 h
Yield: 16.8 %

Procedure:
Into a 25 mL round-bottomed flask were added 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (200 mg, 0.624 mmol), O-4-fluorophenyl carbonochloridothioate (238 mg, 1.249 mmol), and triethylamine (0.348 mL, 2.498 mmol) in THF (5 mL). The solution was stirred under ambient conditions for 2 h before the solvent was removed under reduced pressure. The crude product was added to a silica gel column and was eluted with EtOAc/hexanes gradient to afford the title compound (50 mg, 0.105 mmol, 17%) as a yellow solid: mp 164-169° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.19-8.04 (m, 6H), 7.97 (br s, 1H), 7.66-7.57 (d, J=8.24 Hz, 2H), 7.33-7.19 (m, 4H); ESIMS m/z 475 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH:27]=O)[CH:23]=[CH:22][CH:21]=[N:20]1>>[N:19]1([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cccn2)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 378.17 g/mol.