Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>FC(F)(F)C(O)=O>[CH3:9][C:4]1[N:5]=[C:6]([OH:8])[C:7]([N+:10]([O-:12])=[O:11])=[C:2]([OH:1])[N:3]=1
Reactant: Cc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Powdered 4,6-dihydroxy-2-methylpyrimidine (9 g, 71 mmol) was dissolved in trifluoroacetic acid (54 mL). The reaction mixture was cooled in ice-water as nitric acid (4.3 mL) was added dropwise over a period of 30 minutes. During addition the internal temperature was maintained below 15° C. After the addition, the cooling was removed and the reaction stirred overnight. Water (50 mL) was added to the reaction mixture and the resulting solid was filtered and dried under vacuum to obtain 2-methyl-5-nitropyrimidine-4,6-diol (5.8 g). 1H NMR (400 MHz, DMSO-d6): δ 12.97 (br, 2H), 2.32 (s, 3H). MS (m/z) 172 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>ClCCl>[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH2:44][N:45]([C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:32])[CH2:46][CH2:47]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCC(NC(=O)OC(C)(C)C)(c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 120 h
Yield: 15.9 %

Procedure:
A mixture of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (384 mg), (4-phenylpiperidin-4-yl)-carbamic acid tert-butyl ester (230 mg), DIPEA (427 μL) and BEP (456 mg) in dichloromethane (10 mL) was stirred at r.t. for 5 d. The solvent was distilled off in vacuo, the residue was re-dissolved in MTBE/ethyl acetate (v/v=1/1, 40 mL) and washed once with water, twice with saturated sodium bicarbonate solution, once with 1N sodium hydroxide solution and with brine. After evaporation of the solvents, the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 95 mg (16%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].CCO>[Fe].O>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:20])[F:21])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(N)cnc3c2CCO3)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a mixture of tert-butyl [(3S,5R)-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (227.1 mg, 0.5252 mmol), iron powder (289.6 mg, 5.186 mmol) and ammonium chloride (462.4 mg, 8.644 mmol) was added EtOH (5.0 mL) followed by water (2.5 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was eluted with a 10% aqueous solution of K3PO4 (50 mL), and EtOAc (50 mL). The separated organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude sub-title compound (211.5 mg). The crude product was used directly in the next step without further purification. LCMS calc. for C18H26F3N4O3 (M+H)+: m/z=403.2. found 403.2.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([NH:28][NH2:29])=[N:16][C:17]([CH3:27])=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1>C1COCC1>[Br:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:29][N:28]=2)[C:17]([CH3:27])=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(NN)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a solution of triphosgene (225 mg, 0.75 mmol) in anhydrous THF (2.5 mL) at 60° C. was added 3-bromo-4-(4-chlorophenyl)-2-hydrazinyl-6-methylpyridine (80 mg, 0.256 mmol) in small portions over 5 min. The resulting suspension was refluxed for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the THF. Water (5 mL) was added carefully to the remaining solution to destroy the excess triphosgene. The resulting aqueous suspension was stirred at room temperature for 30 min, then filtered. The collected solid was washed with water (5 mL×2), the hexanes, and dried in a 45° C. vacuum oven for 3 h to afford 70 mg (84%) of the title compound as a yellow solid. HPLC/MS: retention time=3.38 min, [M+H]+=338.0.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)Cl
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: C=CCOC(=O)Oc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with allyl chloroformate (274 μl) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=O)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[O:22][C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)=[N:12][N:11]=1
Reactant: N#Cc1ccc(C(=O)NNC(=O)Cc2cccc(I)c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(-c2nnc(Cc3cccc(I)c3)o2)cc1
Temperature: 110 °C
Yield: 77.7 %

Procedure:
Suspend 4-cyano-benzoic acid N′-[2-(3-iodo-phenyl)-acetyl]-hydrazide (0.50 g, 1.23 mmol) in phosphorous oxychloride (2.00 mL, 21.0 mmol) and heat at 110° C. for 1 h, resulting in complete dissolution. Cool the mixture to room temperature, pour into ice water and stir until all of the ice melts resulting in a solid precipitate. Collect the formed solid by filtration, wash with H2O and dry on the filter pad to provide 0.37 g 77% yield of 4-[5-(3-iodo-benzyl)-[1,3,4]oxadiazol-2-yl]-benzonitrile as a powder.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]([O:34][C:35]([CH:37]1[CH2:39][CH:38]1[CH:40]=O)=[O:36])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:40][CH:38]3[CH2:39][CH:37]3[C:35]([O:34][CH2:32][CH3:33])=[O:36])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CCOC(=O)C1CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3C(=O)OCC)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
To solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (500 mg; 1.20 mmol) in anhydrous DCE (30 mL) were added ethyl-2-formyl-1-cyclopropanecarboxylate (Aldrich, 0.40 mL; 3.01 mmol), triacetoxyborohydride (382 mg; 1.81 mmol).The resulting mixture was stirred at 50° C. under N2 atmosphere for 4 hours. The mixture was poured into a saturated solution of NaHCO3 (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtrated and the solvents were removed under reduced pressure to give 872 mg. Purification of this crude by flash chromatography on silicagel (c-Hex/EtOAc, gradient 95:5 to 90:10) gave 340 mg (65%) of the title compound as a yellow oil. HPLC, Rt: 6.06 min (purity=96.2%). LC/MS, M+(ESI): 542.3. 1H NMR (CDCl3) δ: 7.43 (t, J=8.5 Hz, 4H), 7.32 (m, 1H), 7.22 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 6.93 (m, 2H), 4.54 (s, 2H), 4.08 (m, 2H), 3.89 (s, 3H), 3.35 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.32-1.58 (m, 7H), 1.24 (t, J=7.0 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.88 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[C:33]#[N:34])=[N:19]S(C(C)(C)C)=O)[CH:15]=[CH:16][CH:17]=1.Cl>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:18]2([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:26]3[C:27](=[C:28]([F:32])[CH:29]=[CH:30][CH:31]=3)[C:33]([NH2:34])=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1
Yield: 94.8 %

Procedure:
4-Methoxyphenylmagnesium bromide (6.00 mL, 3.00 mmol) was added to a solution of N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.407 g, 1 mmol) in THF (10 mL) at 0° C. under an argon atmosphere. The resulting mixture was stirred and allowed to reach r.t. over night, then quenched with saturated aqueous NH4Cl, diluted with saturated aqueous NaHCO3 and extracted with DCM. The combined organics were passed through a phase separator (Sorbent) and concentrated. The residue was dissolved in MeOH (10 mL), and hydrogen chloride (2M in diethyl ether, 2 mL, 4 mmol) was added and the resulting mixture was stirred at r.t for 2.5 h. The mixture was concentrated in vacuo and purified on a silica gel column eluted with 0-5% 0.1M NH3 in MeOH in DCM to afford 0.39 g (95% yield) of the title compound: MS (ES+) m/z 411, 413 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CO[C:11](OC)([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:12][C:11]1([CH3:13])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: O=C1CCC(CO)N1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
A mixture of 5-hydroxymethyl-2-pyrrolidone (0.3 g) and 2,2-dimethoxypropane (2 ml) in dichloromethane was refluxed in the presence of a crystal (ca. 10 mg.) of p-toluenesulfonic acid for 20 hours. Aqueous extractive work up followed by solvent evaporation produced 0.18 g of (R)-tetrahydro-3,3-dimethyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one as an oil (TLC showed a single spot at Rf =0.6 (ethyl acetate)).
Reaction SMILES: [CH:1]1([C:6]#[CH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.C([Li])CCC.CCCCCC.C1(C#C)CCCC1.[Li].O(C1C=CC=CC=1)[C:33]#[N:34]>>[CH:1]1([C:6]#[C:7][C:33]#[N:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#COc1ccccc1
Reactant: C#CC1CCCC1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC#CC1CCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
To a oven dried 500 mL 3-neck round bottom flask equipped with a stir bar, a nitrogen inlet, a 125 mL addition funnel and a thermocouple, cyclopentylacetylene (7, 15.0 g, 0.143 mol) and anhydrous tetrahydrofuran (THF, 170 mL, 2.10 mol) were added at room temperature. The resulting solution was then cooled to −78° C. before a solution of 2.5 M n-butyllithium in hexane (63.1 mL, 0.158 mol, 1.1 equiv) was added dropwise over 25 min. The resulting lithium cyclopentylacetylene solution was stirred at −78° C. for 15 minutes before a solution of crude cyanatobenzene (6, 25.0 g, 0.210 mol, 1.5 equiv) in anhydrous tetrahydrofuran (THF, 30.0 mL, 0.400 mol) was added dropwise via a canula at −78° C. The resulting reaction mixture was stirred at −78° C. for an additional 10 min before the cooling batch was removed and the reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for 1-2 h. When the reaction was deemed complete, the reaction mixture was quenched with a 6 N aqueous sodium hydroxide solution (NaOH, 200 mL) and a 20% aqueous brine solution (200 mL). The aqueous solution was treated with ethyl acetate (EtOAc, 200 mL) before the two layers were separated. The organic layer was dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0 to 5% ethyl acetate/hexane gradient elution) to afford 3-cyclopentylpropiolonitrile (8, 14.3 g, 17.0 g theoretical, 84% yield for two steps) as a yellow to orange oil. For 8: 1H NMR (DMSO-d6, 400 MHz) δ 2.97 (m, 1H), 1.97 (m, 2H), 1.64 (m, 4H), 1.56 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]([NH:13][CH:14]=[O:15])=[CH:11][CH:10]=[N:9]1)(=O)=O.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH:14]([N:13]1[C:12]2[N:8]([N:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1)=[O:15]
Reactant: CS(=O)(=O)OCCn1nccc1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CN1CCn2nccc21
Reaction time: 3 h
Yield: 107.3 %

Procedure:
To a solution of 1-(2-methylsulfonyloxyethyl)-5-formamidopyrazole (6.2 g) in N,N-dimethylformamide (60 ml) was added 62% sodium hydride (1.03 g) under ice-cooling. The mixture was stirred at the same condition for 3 hours. The reaction mixture was poured into ethyl acetate (300 ml) and the insoluble material was filtered off. The filtrate was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (100 g) using a mixture of diisopropyl ether and ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated in vacuo to give 1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (3.91 g) as crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>[Pd]>[OH:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: [Pd]
Product: Nc1ccc(F)c(F)c1O
Reaction time: 12 h
Yield: 100.2 %

Procedure:
2,3 difluoro 6-nitrophenol (2 g, 11 mmol) was treated with 10% Pd/C(1 g) at 23° C. The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afforded the title compound (1.6 g, 97%). EI-MS m/z 146(M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].N1C=CC=CC=1>O>[NH2:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[I:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(c1ccccc1)c1ccc(I)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(C(=O)c2ccccc2)ccc1I
Temperature: 40 °C

Procedure:
A mixture of 5.0 g (14 mmol) of 4-iodo-3-nitro-benzophenone, 7.5 g (42 mmol) of sodium dithionite, 40 ml of pyridine and 15 ml of water is heated to 40° C. for 2 hours. Then the mixture is concentrated in vacuo, combined with ice water and extracted with ethyl acetate. The organic phase is dried with sodium sulphate and the solvent is distilled off in vacuo.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:13][N:12]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[CH:34]([NH:37][C:38]1[CH:43]=[N:42][CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[N:39]=1)([CH3:36])[CH3:35].N#N>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:34]([NH:37][C:38]1[N:39]=[C:40]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[S:13][N:12]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:3]=2)[CH:41]=[N:42][CH:43]=1)([CH3:36])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(NC(C)C)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Temperature: 90 °C
Yield: 80.9 %

Procedure:
A mixture of tert-butyl (3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.6 g, 1.0 mmol) and N-isopropyl-6-(tributylstannyl)pyrazin-2-amine (0.429 g, 1.0 mmol) in DMF (10 mL) was bubbled N2 gas for 15 min. To the mixture was added CuI (95 mg, 0.5 mmol.) and Pd(PPh3)4 (12 mg, 0.1 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 90° C. for 1 h. The mixture was quenched with H2O (10 mL) and extracted with CHCl3 (2×25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by neutral alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give tert-butyl (3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.49 g, 81%). MS (ESI, pos. ion) m/z: 606.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:38])([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-hydroxy-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 86, 5.29 g, 11.3 mmol) in CH2Cl2 (100 mL) at 0° C. was added DAST (1.8 mL, 1.2 eq.). The reaction mixture was stirred for 30 minutes before it was quenched by addition of saturated NaHCO3 solution (20 mL). The organic phase was separated and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=2:3) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.2 Hz), 7.35 (1H, s), 7.10 (2 H, d, J=9.2 Hz), 5.22 (2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s), 2.05˜2.32 (4 H, m), 1.46 (9H, s).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C1C(=O)N(Br)C(=O)C1.[OH-].[Na+]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C1=NCCc2ccccc21
Temperature: 25 °C

Procedure:
9.4 ml of 1,2,3,4-tetrahydroisoquinoline are dissolved in 200 ml of DCM and 14.7 g of NBS are gradually added. The mixture is left stirring at RT, cooling slightly in order to maintain a temperature of less than 40° C. for 30 minutes, after which 50 ml of 10N NaOH are added and the mixture is left stirring for 1 hour at RT. The organic phase is separated out after settling of the phases has taken place and is washed with 100 ml of water and then twice with 100 ml of 4N HCl. The aqueous phases are washed with DCM and then brought to pH=9 by addition of concentrated NH4OH. This mixture is extracted with DCM, dried over Na2SO4 and evaporated to dryness. The oil obtained is distilled off. 7.16 g of the expected compound are obtained, b.p.=50-54° C. at 0.05 mbar.
Reaction SMILES: [C:1]([O:9][C@:10]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH2:24][CH2:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)[C:11](=[O:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([O:13][CH2:12][C:11](=[O:14])[C@:10]1([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH2:24][CH2:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)(=[O:38])[CH3:37]
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(OC(=O)c2ccccc2)C(=O)CO)[C@@]2(C)CCC(=O)C=C12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)c2ccccc2)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Analogously to Example 9, 2.2 g of 17-benzoyloxy-11β,21-dihydroxy-6α-methyl-4-pregnene-3,20-dione is reacted with acetic anhydride and worked up as usual. The crude product is purified on 350 g of silica gel with a methylene chloride-acetone gradient (0-8% acetone), thus isolating 1.6 g of 21-acetoxy-17-benzoyloxy-11β-hydroxy-6α-methyl-4-pregnene-3,20-dione, mp 210° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH:20]1([N:26]([CH3:35])[C:27](N2C=C[N+](C)=C2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:27](=[O:28])[N:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:35])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)C1CCCCC1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(cyclohexyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (80%, white crystals). HPLC-MS m/z=395.2 (M+1), Rt: 5.7 min.