Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:5].[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>O1CCOCC1.[Cl-].[Na+].O>[OH:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][OH:32])[C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:5]
Reactant: O=C(NCCCN1CCOCC1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: OCCNCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCCN1CCOCC1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N(CCO)CCO

Procedure:
2-Chloro-N-[3-(4-morpholinyl)propyl]-3,5-dinitrobenzamide (12h) (0.5 g, 1.34 mmol) was reacted with diethanolamine (0.5 g) in p-dioxane (10 mL) at room temperature for 3 h. The reaction mixture was poured into brine, extracted with EtOAc (3×70 mL), and the combined organic phases were dried and concentrated under reduced pressure to give crude 2-[bis(2-hydroxyethyl)amino]-N-[3-(4-morpholinyl)propyl]-3,5-dinitrobenzamide. This was dissolved in CH2Cl2 (100 mL), cooled in an ice-bath, and treated with Et3N (1.5 mL) followed by MsCl (0.7 mL) in one portion. After stirring for 10 min, sat. NaHCO3 (100 mL) was added and the mixture was stirred for a further 30 min, then the aqueous phase was extracted with CH2Cl3 (2×70 mL). The combined organic phases were dried and evaporated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc/MeOH (20:1 to 9:0) to give yield 2-[{2-[(methylsulfonyl)oxy]ethyl}-2-({[3-(4-morpholinyl)propyl]amino}carbonyl)-4,6-dinitroanilino]ethyl methanesulfonate (13h) (0.75 g, 93%) as a foam;
Reaction SMILES: ClC1C=CC([N:8]([CH2:30][CH3:31])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[O:22])[C@@H:13]([CH3:29])[CH2:12]2)=[O:10])=CC=1.FC(F)(F)[C:34]1[CH:42]=[CH:41][C:37](C([Cl:40])=O)=[CH:36][CH:35]=1.N1C=C(C(O)=O)C=NC=1.C(Cl)(=O)C([Cl:57])=O>C(Cl)Cl.CN(C)C=O>[N:25]1[CH:24]=[C:23]([C:21]([Cl:40])=[O:22])[CH:28]=[N:27][CH:26]=1.[Cl:57][C:34]1[CH:42]=[CH:41][C:37]([CH2:31][CH2:30][NH:8][C:9]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[O:22])[CH:13]([CH3:29])[CH2:12]2)=[O:10])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2cncnc2)c2ccccc21)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cncnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CC(C(=O)NCCc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1cncnc1
Product: O=C(Cl)c1cncnc1

Procedure:
(±)-trans-2-Methyl-1-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting pyrimidine-5-carbonyl chloride for 4-trifluoromethyl-benzoyl chloride. Pyrimidine-5-carbonyl chloride was prepared by reaction of pyrimidine-5-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. The crude 2-methyl-1-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (2% methanol/methylene chloride) yielded (±)-trans-2-methyl-1-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (44%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.65-1.75 (m, 1H), 2.50-2.60 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 4.98-5.10 (m, 1H), 6.40 (d, 1H), 6.70 (d, 1H), 6.90-7.00 (m, 2H), 7.20 (d, 2H), 7.50 (d, 2H), 8.85 (s, 2H), 9.15 (s, 1H). MS m/z: 435/437 (M+1).
Reaction SMILES: ClCCl.[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[O:11].[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:14])[CH3:13].CC1[C:27](C)=[C:26](N)[C:25](C)=[C:24](C)[C:23]=1[NH2:32]>CO>[N:4]1[C:5]([CH:10]=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[C:12]([C:15]1[N:16]=[C:17]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:32]=2)[CH:18]=[CH:19][CH:20]=1)(=[O:14])[CH3:13]
Reactant: Cc1c(C)c(N)c(C)c(C)c1N
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1ccccn1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cccc(-c2ccccn2)n1
Product: O=Cc1cccc(-c2ccccn2)n1

Procedure:
The electrospray (ES) mass spectra were recorded using a micromass Quattra LC mass spectrometer with dichloromethane or methanol as the matrix [Masslynx software. open-access autosampler injection]. The infrared spectra were recorded with Universal ATR sampling accessories on a Perkin Elmer Spectrum One FTIR instrument. 1H and 13C NMR spectra were recorded on a Bruker ARX spectrometer 250/300 MHz at ambient temperature; chemical shifts (ppm) are referred to the residual protic solvent peaks. The reagents 2-pyridinecarboxaldehyde, the 2-acetylpyridine, 2,3,5,6-tetramethyl-benzene-1,4-diamine were purchased from Aldrich Chemical Co. and used without further purification. Formic acid (98%) was purchased from Fisons PLC and used without further purification. The compounds 2,2′-bipyridinyl-6-carbaldehyde [J. Uenishi, T. Tanaka, K. Nishiwaki, S. Wakabayashi, S. Oae and H. Tsukube, J. Org. Chem., 1993, 58, 4382], 6-acetyl-2,2′-bipyridine [J. Uenishi, T. Hiraoka, S. Hata, K. Nishiwaki and O. Yonemitsu, J. Org. Chem., 1998, 63, 2481] were prepared according to the indicated journal articles. All other chemicals were obtained commercially and used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][C:28]=2[F:33])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CP(C)(=O)c1ccc(N)c(F)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2F)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-fluoroaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][O:8][C:9]2[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=[C:11]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](B5OC(C)(C)C(C)(C)O5)[CH:26]=4)[N:21]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:20]=3)[CH:10]=2)=[CH:5][CH:4]=1.Br[C:47]1[CH:52]=[N:51][CH:50]=[C:49]([CH:53]2[CH2:55][CH2:54]2)[N:48]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[CH:53]1([C:49]2[N:48]=[C:47]([C:25]3[CH:26]=[C:27]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH:20]=[C:19]4[C:11]3[CH:10]=[C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=4)[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=3)[CH:52]=[N:51][CH:50]=2)[CH2:55][CH2:54]1
Reactant: COc1ccc(COc2cc(-c3cn(C(=O)OC(C)(C)C)c4ccc(B5OC(C)(C)C(C)(C)O5)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: Brc1cncc(C2CC2)n1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COc2cc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5cncc(C6CC6)n5)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 28.4 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (150 mg, 0.236 mmol) and 2-bromo-6-cyclopropylpyrazine (70.5 mg, 0.354 mmol, CombiPhos) in p-dioxane/H2O (4:1, 2.0 mL) followed by potassium phosphate (100 mg, 0.472 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (8.36 mg, 0.012 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 20 min. The mixture was diluted with DCM and washed with water. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20-60% EtOAc in hexanes) to give tert-butyl 5-(6-cyclopropylpyrazin-2-yl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole-1-carboxylate (42 mg, 0.067 mmol, 28.3% yield) as a solid: MS (ESI, pos. ion) m/z: 628.0 (M+1), and 5-(6-cyclopropylpyrazin-2-yl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole (28 mg, 0.053 mmol, 22.49% yield) as a solid. MS (ESI, pos. ion) m/z: 528.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[NH:12][N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:20][C:21]1[CH:22]=[N:23][C:24]([C@@H:27]([NH2:29])[CH3:28])=[N:25][CH:26]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[NH:12][N:11]=2)=[N:4][C:5]([NH:29][C@H:27]([C:24]2[N:25]=[CH:26][C:21]([F:20])=[CH:22][N:23]=2)[CH3:28])=[N:6][CH:7]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 60 %

Procedure:
A mixture of 5-bromo-2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 13, 150 mg, 0.45 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 88 mg, 0.5 mmol) and DIPEA (0.12 ml) in n-BuOH (2 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (20-60% EtOAc in hexanes) to give the titled compound as solid (118 mg, 60%). NMR: 11.98 (s, 1H), 9.36 (s, 1H), 8.82 (s, 2H), 8.10 (s, 1H), 7.96 (s, 1H), 5.56 (s, 1H), 5.13 (s, 1H), 4.66 (m, 1H), 1.48 (m, 3H), 1.26 (m, 6H); m/z 437.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:2]([S:7]([NH:10][C:11](=[N:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)SC)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:29][O:30][NH2:31]>O1CCOCC1>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:2]([S:7]([NH:10][C:11]([NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)=[N:31][O:30][CH3:29])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC(=Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: CON
Solvent: C1COCCO1
Product: CON=C(Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 63.3 %

Procedure:
4.12 g of 1-(2-biphenylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)2-methylisothiourea was dissolved in 50 ml of dioxane, 2.35 g of O-methylhydroxylamine was added to the solution, and the mixture was heated under reflux for 5 hours. After cooling the reaction mixture, the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 2.6 g of the desired N-(2-biphenylsulfonyl)N'-(4,6-dimethylpyrimidin-2-yl)N"-(methoxy)guanidine of the following formula, mp. 190°-192° C.: ##STR21##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[N:9]=1.C(N(CC)CC)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:26])=[CH:22][CH:21]=2)[N:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.0 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid (Example 5) and 1.25 ml of 1-chloro-N,N-2-trimethyl-1-propen-1-amine [CAS-Reg.-No. 26189-59-3] are stirred for 2 h in 50 ml of tetrahydrofuran. 2.2 ml of triethylamine and 0.8 ml of morpholine are added and the mixture is stirred at room temperature for 18 h. It is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, {4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-phenyl}morpholin-4-yl-methanone remains as colorless crystals of m.p. 157-160° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([OH:29])=O.[CH2:36]([NH:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:37][CH:38]([CH3:40])[CH3:39]>C1COCC1.C(Cl)(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27]([N:41]([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])=[O:29]
Reactant: CC(C)CCNCCC(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
1-hydroxybenzotriazole (HOBt) (8 g, 1.1 eq) in solution in THF (60 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (ED)C) (11.4 g, 1.1 eq) in solution in chloroform (60 ml) are added successively to 3-fluoro-4-nitrobenzoic acid (10 g, 1 eq) in solution in anhydrous THF (60 ml). The mixture is stirred for 2 hours at a temperature of approximately 20° C. then diisoamylamine (12.2 ml, 1.1 eq) is added. After stirring for 4 hours at a temperature of approximately 20° C., the reaction mixture is concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (300 ml) and water (100 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: heptane 100% to heptanel ethyl acetate 70:30) produces the expected compound (12.36 g; 71% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C#CCCO)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(CCCCO)c1

Procedure:
A solution of 3-(4-hydroxybut-1-ynyl)phenyl acetate (4.47 g) was hydrogenated over 5% Pd on carbon in ethyl acetate (100 mL) and ethanol (100 mL) over 20 h. The reaction mixture was filtered through celite under nitrogen, and the filtrate was concentrated in vacua. The residue was purified by chromatography (SPE, gradient from cyclohexane to EtOAc) to give the title compound. LCMS RT=2.64 min
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:37][N:38]1CCOC[CH2:39]1.C(OC(Cl)=O)C(C)C.CNC>ClCCl.C1COCC1>[CH3:37][N:38]([CH3:39])[C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:26]2([CH3:34])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:30]([C:29]=3[CH2:28][CH2:27]2)([CH3:33])[CH2:31][CH2:32][C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C:10]4([CH3:36])[CH3:35])=[CH:16][CH2:17]1)[CH3:25]
Reactant: CN1CCOCC1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)N(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: -15 °C
Reaction time: 8 h

Procedure:
3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.30 g) is dissolved in 10 ml of dry dichloromethane. After cooling to −15° C., 0.07 ml of N-methylmorpholine and 0.084 ml of isobutylchloroformate is added and the mixture is stirred at −15° C. for 20 minutes, whereupon 1.74 ml of a 2.0 M solution of N,N-dimethylamine in THF) is added. The mixture is stirred overnight and the temperature is slowly elevated to room temperature. After aqueous work-up and crystallization from methanol, 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid-N,N-dimethyl amide (0,231 g) is obtained. M.p. 143-145° C. 1H-NMR (CDCl3, 400 MHz)): δ=5.35 (1H, s); 3.20 (1H, m); 3.03 (3H, s); 2.95 (3H, s); 0.90 (9H, s); 0.05 (6H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O1CCOCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]3([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: COC(=O)C1(CC(=O)c2ccc(Br)cc2)CCCC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C1(CC(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)CCCC1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
To a 150 mL 3-neck flask fitted with a reflux condenser was added methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentanecarboxylate (1.58 g, 4.64 mmol), 4-nitro phenyl boronic acid (0.93 g, 5.6 mmol), toluene (45 mL), and dioxane (13 mL), followed by the addition of a saturated aqueous sodium carbonate solution (13 mL). The mixture was degassed using argon and 1,2-bis[(diphenylphosphino)ferrocene]dichloropalladium(II) (0.19 g, 0.23 mmol) was added, followed by an additional 15 minutes of degassing, and the deep red reaction mixture was heated to 85° C. for 16 h. The very darkly colored reaction mixture was allowed to cool, and then was diluted with ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL). The layers were separated and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and filtered under reduced pressure through 2 cm Celite®/2 cm silica. The filtrate was concentrated under reduced pressure, leaving a dark red-brown oil, that was purified by flash chromatography (4:1/hexane:ethyl acetate, then 3:1/hexane:ethyl acetate, then 2:1/hexane:ethyl acetate) to afford methyl 1-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate (1.65 g, 93%). LC-MS ret. time 3.56 min, m/z 368.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.56-1.85 (overlapping signals, 6H), 2.23-2.37 (m, 2H), 3.45 (s, 2H), 3.67 (s, 3H), 7.70 (d, 2H), 7.77 (d, 2H), 8.06 (d, 2H), 8.34 (d, 2H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12](Br)[S:13][C:9]=2[CH:8]=1)(=O)=O.[NH:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18]1.[C:26](=[O:29])([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:17]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]3[N:11]=[C:12]([NH:11][C@@H:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C@H:26]4[OH:29])[S:13][C:9]=3[CH:8]=2)[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18]1
Reactant: CS(=O)(=O)OCc1ccc2nc(Br)sc2c1
Reactant: O=C([O-])[O-]
Reactant: c1cnc2nc[nH]c2c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ncccc43)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2-bromobenzo[d]thiazol-6-yl)methyl methanesulfonate (900 mg, 2.79 mmol) from Step 3 of Example 2 and 1H-imidazo[4,5-b]pyridine (365 mg, 3.07 mmol) in DMF (8 mL) was added potassium carbonate (560 mg, 3.14 mmol) at rt. The reaction mixture was stirred at rt overnight. It was then diluted with 80 mL of EtOAc and the resulting mixture was washed with water and brine. The organic layer was separated and dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of MeOH—CH2Cl2 (1:20, v/v) as eluent to give three isomers:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C.O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:10]1[CH:11]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: O=c1[nH]cc(-c2cccs2)c(=O)[nH]1
Reactant: ClCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCCl)cc1-c1cccs1
Yield: 21.8 %

Procedure:
The solution of 5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep22, 2.5 g, 12.9 mmol), 1-bromo-4-chlorobutane (2.2 g, 12.9 mmol) and potassium carbonate (1.8 g, 12.9 mmol) in DMF (150 ml) was stirred at room temperature for 5 hours. Water was added and the solution was adjusted to pH=6 with 3N hydrochloride acid. Ethyl acetate was added and the aqueous layer was extracted three times, the combined organic layer was dried and concentrated, the residue was purified by FC(P:E=3:1) to give the title compound (800 mg, y=22%).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C)C=O>[C:5]([O:9][C:10]([N:12]([CH3:3])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
A procedure similar to that described in Preparation 7 was repeated, except that 0.46 g of sodium hydride (as a 55% w/w dispersion in mineral oil), 15 ml of dehydrated dimethylformamide, 0.66 ml of methyl iodide and a solution of 1.9 g of N-t-butoxycarbonyl-4-methoxy-2-nitroaniline (prepared as described in Preparation 22) in 15 ml of dehydrated dimethylformamide were used, to give 2.0 g of the title compound having an Rf value=0.34 (on thin layer chromatography on silica gel; developing solvent: a 1:5 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[F:11].[Cl-].[NH4+:13]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:13])=[CH:4][C:3]=1[F:11]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c(F)c1
Temperature: 60 °C
Yield: 43 %

Procedure:
Iron powder (28.1 g, 0.502 mol) was added as small portions to 1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol-(200 ml) and heated to 60° C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml) was added drop wise and the reaction mixture refluxed for 5 hr. The reaction mixture was filtered over Celite and washed with methanol. Methanol was removed, and the aqueous layer was extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentrated to yield 1,2-difluoro-4-aminobenzene (7 g, 43%).