Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31]([OH:33])=[O:32]>>[CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([C:35]5[C:36]([O:37][CH3:38])=[CH:28][CH:29]=[C:30]([C:31]([OH:33])=[O:32])[CH:34]=5)[CH:21]=[CH:22][CH:23]=4)=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2ccc(OCc3cccc(B(O)O)c3)cc2sn1C1CCCC1
Reactant: COc1ccc(C(=O)O)cc1I
Product: COc1ccc(C(=O)O)cc1-c1cccc(COc2ccc3c(=O)n(C4CCCC4)sc3c2)c1

Procedure:
A mixture of 3-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)phenylboronic acid (0.050 g, 0.14 mmol), 3-iodo-4-methoxybenzoic acid (0.053 g, 0.20 mmol) were coupled according to the general procedure to afford the title product. The crude residue was purified using automated prep-HPLC to yield the desired compound as pale yellow solid (0.013 g, over two steps 10%). 1H NMR (400 MHz, CDCl3): δ 7.80-7.66 (m, 2H), 7.60-7.34 (m, 5H), 7.23-7.21 (m, 2H), 6.79 (d, 1H, J=8.5 Hz), 5.02 (s, 2H), 4.44-4.30 (m, 1H), 3.61 (s, 3H), 1.93-1.91 (m, 2H), 1.78-1.45 (m, 6H), LC-MS (ESI) Calcd for C27H25NO5S [M+H]+: 475.14. Found: 475.80.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>S(=O)(=O)(O)O.CO>[CH:5]1[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]1[C:2]([NH:1]2)=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:12])=[O:11])=[CH:5][C:4]=3[C:3]2=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:12])=[O:11])=[CH:5][C:4]=3[C:3]=12
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(O)c1ccc2[nH]c3c4[nH]c5ccc(C(=O)O)cc5c4c4c5cc(C(=O)O)ccc5[nH]c4c3c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
1.07 g of the indole-5-carboxylic acid trimer synthesized in Example 12 was suspended in 30 ml of 10% aqueous sulfuric acid-methanol solution, and the suspension was agitated for 2 hours at the temperature of 25° C. The suspension was suction-filtered with a perforated funnel, washed with methanol and dried to obtain 1.00 g of 6,11-dihydro-5H-diindolo [2,3-a:2′,3′-c] carbazole-2,9,14-tricarboxylic acid (indole-5-carboxylic acid trimer) with a light green color. The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.55 S/cm. The result of elemental analysis was: <C9.00H4.90N1.09O1.98Cl0.03(SO4)0.12>3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.[BrH:11]>O>[Br:11][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Br
Reactant: OCCc1ccc(O)cc1
Solvent: O
Product: Oc1ccc(CCBr)cc1
Yield: 92 %

Procedure:
(4-Hydroxyphenethyl) alcohol (1.50 g, 0.01086 mol) and 48 wt. % hydrobromic acid (10 ml) were heated at 100° C. for 1.5 h. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate 9:1) gave a pure product (2.01 g, 92%). 1H NMR (400 MHz, DMSO-d6): 2.99 (2H, t, 3J=7.4 Hz), 3.63 (2H, t, 3J=7.4 Hz), 6.68 (2H, d, 3J=8.5 Hz), 7.05 (2H, d, 3J=8.3 Hz), 9.24 (1H, s, —OH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:16]([NH:15][S:12]([C:4]1[CH:3]=[C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:26])=[O:27])[CH:33]=2)[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=1)(=[O:14])=[O:13])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCCNS(=O)(=O)c1cc(Br)c(OC)c(C=O)c1
Product: CCCCNS(=O)(=O)c1cc(C=O)c(OC)c(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)c1
Yield: 89.1 %

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-N-butyl-5-formyl-4-methoxy-benzenesulfonamide (0.65 g, 1.72 mmol) and N-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (0.64 g, 1.90 mmol, 1.1 eq.), gave N-butyl-N′-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (0.74 g) as on orange oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]1[CH:26]=[C:27]([B:31]([OH:33])[OH:32])[CH:28]=[CH:29][CH:30]=1>CC(C)=O>[CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:24][C:25]4[CH:26]=[C:27]([B:31]([OH:33])[OH:32])[CH:28]=[CH:29][CH:30]=4)[CH:12]=3)[C:7]2=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1cccc(CBr)c1
Reactant: O=C1c2ccc(O)cc2CN1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccc(OCc3cccc(B(O)O)c3)cc2CN1C1CCCC1
Yield: 72.1 %

Procedure:
To a solution of 2-cyclopentyl-5-hydroxyisoindolin-1-one (500 mg, 2.3 mmol) in acetone (20 mL), K2CO3 (1.2 g, 8.7 mmol) and 3-(bromomethyl)phenylboronic acid (650 mg, 3.0 mmol) were added and refluxed for 3 h. The reaction mixture was filtered and solvent was evaporated in vacuo to obtain 3-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)phenylboronic acid as a white solid (582.7 mg, 72%). The crude product was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.86 (s, 1H), 7.75-7.69 (m, 2H), 7.55-7.32 (m, 4H), 7.19 (s, 1H), 7.09-7.07 (m, 1H), 5.15 (s, 2H), 4.55-4.49 (m, 1H), 4.37 (s, 2H), 1.84-1.56 (m, 8H). LRMS calcd. for C20H22BNO4 [M+H]+ 352 found: 352.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N=C=N.Cl.Cl.[NH:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][NH:26]/[C:25]/1=[N:34]\[C:35]([C:37]1[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=1)=[O:36].CN1CCOCC1>CN1C(=O)CCC1>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([N:31]3[CH2:32][CH2:33][C:28]4([NH:24]/[C:25](=[N:34]/[C:35]([C:37]5[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=5)=[O:36])/[NH:26][CH2:27]4)[CH2:29][CH2:30]3)=[O:17])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2)cc1
Agent: Cl
Agent: N=C=N
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carboxylic acid (0.023 g, 0.085 mmol) in NMP (850 l) is added to PS-carbodiimide (190 mg of 1.3 mmol/g loading, 0.24 mmol), followed by a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (0.08 mmol) and N-methyl morpholine (8 l, 0.08 mmol) in NMP (1 ml), and the resulting reaction mixture is shaken at room temperature. The reaction mixture is filtered and the resin is washed with NMP (1 ml). The collected filtrate is concentrated in vacuo and the residues are purified by mass-directed preparative HPLC. The purified fractions are evaporated under vacuum to afford the title compound; [M+H]+ 572.08
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[O:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[F:44])[O:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:44][C:35]1[CH:36]=[C:37]([C:40]([F:43])([F:41])[F:42])[CH:38]=[CH:39][C:34]=1/[CH:33]=[CH:32]/[C:29]1[O:30][CH:31]=[C:27]([CH2:26][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[O:10][CH:11]=[C:7]([CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:8]=3)=[CH:13][CH:14]=2)[N:28]=1
Reactant: Oc1ccc(-c2nc(Cn3ccnc3)co2)cc1
Reactant: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(CCl)co1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: Fc1cc(C(F)(F)F)ccc1/C=C/c1nc(COc2ccc(-c3nc(Cn4ccnc4)co3)cc2)co1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A mixture of 0.121 g (0.50 mmol) 4-[4-(imidazol-1-ylmethyl)-oxazol-2-yl]-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.153 g (0.50 mmol) 4-chloromethyl-2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazole and 0.083 g (0.50 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 221 mg raw material which was purified on silica. Elution with ethyl acetate/methanol 5:1 yielded 101 mg (40%) 2-[(E)-2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-4-[4-(4-imidazol -1-ylmethyl-oxazol-2-yl)-phenoxymethyl]-oxazole as off-white crystals melting at 150-153° C.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:10]([OH:12])=[O:11].[CH:13]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO.ClCCl>[ClH:1].[CH3:13][O:11][C:10]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:3]1[NH2:2])=[O:12]
Reactant: N[C@H]1CCCCC[C@H]1C(=O)O
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
cis-2-Amino-cycloheptanecarboxylic acid hydrochloride (0.75 g, 3.89 mmol) was dissolved in methanol (5 mL). Benzene (7.5 mL) was added followed by the dropwise addition of a 2.0 M solution of (trimethylsilyl)diazomethane in dichloromethane (3.5 mL). The yellow solution continued to stir at 25° C. for 20 min. The solution was concentrated in vacuo to afford a yellow powder. The powder was suspended in methanol (20 mL) and concentrated in vacuo to afford the desired product, cis-2-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (0.8 g, 3.86 mmol, 99%), as a white powder. 1H NMR (400 MHz, D2O) δ: 1.33-1.86 (8H, m), 2.60-2.62 (1H, m), 2.75-2.78 (1H, m), 3.27-3.30 (1H, m), 3.39-3.44 (1H, m), 3.62 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([OH:19])=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[N+:66]([CH:69]([C:71]1([OH:75])[CH2:74][NH:73][CH2:72]1)[CH3:70])([O-:68])=[O:67]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([N:73]2[CH2:74][C:71]([CH:69]([N+:66]([O-:68])=[O:67])[CH3:70])([OH:75])[CH2:72]2)=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: CC([N+](=O)[O-])C1(O)CNC1
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC([N+](=O)[O-])C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (150 mg, 0.35 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), N,N-diisopropylethylamine (300 μL, 1.74 mmol), PyBOP (180 mg, 0.35 mmol) and 3-(1-nitroethyl)azetidin-3-ol hydrochloride (76 mg, 0.42 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was then partitioned between 5% aqueous lithium chloride, and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 20% aqueous citric acid, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with 5% methanol in dichloromethane, the isolated product was concentrated in vacuo to afford 195 mg, 0.35 mmol (100%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol as a yellow foam. 1H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 7.23 (br s, 1H), 6.55-6.51 (m, 1H), 6.02 (br s, 1H), 4.79 (q, 1H), 4.45-3.96 (4H), 1.56 (d, 3H). MS (EI) for C20H19ClFIN6O4: 560 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.O.[BH4-].[Na+].Cl>C(O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (2 gm.) was suspended in n-propanol (80 ml) & water (12 ml) and then added sodium borohydride (0.253 gm.) at 35° C. and the reaction mixture was stirred for 1 hr. To the reaction mixture was added hydrochloric acid (12 ml). Than the reaction mixture was stirred for 1 hour. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (1.65 gm).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[O:10]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1oc2ccccc2n1CCCCl
Temperature: 55 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 2-benzoxazolinone (2.0 g, 14.8 mmol) and potassium carbonate (3.07 g, 22.2 mmol) in N,N-dimethylformamide (20 mL), was added 1-bromo-3-chloropropane (4.4 mL, 44.4 mmol, d=1.6). After stirring at 55° C. for 18 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4 and concentrated to obtain 3-(3-chloropropyl)benzo[d]oxazol-2(3H)-one (3.1 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[CH:24](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][CH:24]=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnco2)cc2[nH]cnc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.048 g, 0.144 mmol) is suspended in 3 mL absolute EtOH and HC(OEt)3 (0.60 mL, 3.54 mmol) is added followed by catalytic pTsOH.H2O. The reaction mixture is heated to reflux under N2. After 2 hours, the reaction mixture is cooled to room temperature and concentrated under reduced pressure. Purification by flash column chromatography (97:3 ethyl acetate:MeOH) provides 36 mg (73%) desired product as a light yellow solid. LC/MS ESI (+) m/z 344, 346 (M+Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ13.10 (bs, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.10 (bs, 1H), 7.78 (bs, 1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.41 (bs, 1H), 2.18 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:19][C:20]1[N:21]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)[CH:22]=[CH:23][N:24]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C)(C)C.Cl.CCOCC>CO>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([Cl:32])[CH:29]=1)[CH2:25][N:21]1[CH:22]=[CH:23][N:24]=[C:20]1[CH2:19][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:9][CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCCN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
{2-[[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-ethyl}-carbamic acid tert-butyl ester, (see Example 6) (455 mg, 0.899 mmol) was dissolved in MeOH (7 mL) and treated with 4N HCl/ether (2 mL). The solution was stirred at ambient temperature for 4 h. then heated to 40° C. for 3 h. The solvent was evaporated in vacuo providing N1-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-N1-(3-fluoro-benzyl)-ethane-1,2-diamine (341 mg, 93%). ESI MS m/z 407 [C20H21Cl2FN4+H]+.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:21][O:22]C1C=C(B(O)O)C=CC=1>>[CH3:21][O:22][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1nc2c(-c3cccc(C(F)(F)F)c3)cccn2n1
Product: COc1cccc(-c2cccn3nc(N)nc23)c1

Procedure:
Made by following the procedure described for the preparation of 8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine but substituting 3-methoxyphenyl boronic acid and making non-critical variations.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CC(C)=O.O>[CH2:12]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 4-hydroxybenzotrifluoride (8.55 g, 52.78 mmol) in acetone (200 ml) was treated with benzyl bromide (9.87 g, 6.86 ml, 58.05 mmol) and potassium carbonate (10.94 g, 79.16 mmol). The mixture was stirred and heated to reflux under nitrogen for 3 h. After cooling, diethyl ether (400 ml) and water (400 ml) were added and the aqueous phase re-extracted with diethyl ether (100 ml). The combined organic layers were washed with water, dried (MgSO4) and the solvent removed in vacuo to leave the title compound as a white solid. (12.71 g, 95%)
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.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[S:87]1[CH:91]=[CH:90][CH:89]=[C:88]1[S:92]([NH:95][CH2:96][C:97](O)=[O:98])(=[O:94])=[O:93]>>[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:97](=[O:98])[CH2:96][NH:95][S:92]([C:88]1[S:87][CH:91]=[CH:90][CH:89]=1)(=[O:93])=[O:94])[CH2:19][CH2:18]2
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
Reactant: O=C(O)CNS(=O)(=O)c1cccs1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CNS(=O)(=O)c3cccs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 31 %

Procedure:
The title compound was prepared in 31% yield 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 same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(thiophene-2-sulfonamido)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 733.6 (M+H)+, 2.06 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.73 (dd, J=1.4, 5.0 Hz, 1H), 7.66 (dd, J=1.2, 3.7 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.16 (dd, J=3.8, 5.0 Hz, 1H), 6.88 (s, 1H), 5.32-5.26 (m, 1H), 4.78 (d, J=1.5 Hz, 1H), 3.58-3.45 (m, 2H), 2.63-2.57 (m, 1H), 2.56-2.50 (m, 1H), 2.42 (dd, J=8.2, 12.2 Hz, 1H), 2.13 (dd, J=6.3, 17.2 Hz, 1H), 1.98-1.88 (m, 1H), 1.87-1.76 (m, 2H), 1.73 (br. s., 1H), 1.72 (s, 3H), 1.70-1.66 (m, 1H), 1.63-1.53 (m, 3H), 1.53-1.46 (m, 4H), 1.45-1.37 (m, 3H), 1.37-1.30 (m, 2H), 1.28-1.22 (m, 1H), 1.14 (s, 3H), 1.10 (d, J=3.1 Hz, 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.94 (s, 3H), 0.94 (br. s., 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=1)[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(COc2cc3c(cc2Br)C(C(C)C)=CCC3(C)C)cc1
Yield: 100 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.14 g, 0.49 mmol) was reacted with 4-methylbenzylbromide to afford 0.19 g (100%) of the title compound as a yellow oil. PNMR (300 MHz, CDCl3) δ 1.22 (d, 6 H, J=4.5 Hz), 1.28 (s, 6 H), 2.22 (d, 2 H, J=4.7 Hz), 2.45 (s, 3 H), 5.22 (s, 2 H), 5.78 (t, 1 H, J=4.5 Hz), 7.02 (s, 1 H), 7.22 (d, 2 H, J=8.8 Hz), 7.38 (d, 2 H, J=9.3 Hz), 7.60 (s, 1 H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[C:8]1([CH:4]2[C:3]3[N:15]=[C:16]([NH2:18])[S:17][C:2]=3[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc2c(s1)CCCC2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 2-bromo-6-phenyl-cyclohexanone (4.32 g, 17 mmol) and thiourea (1.18 g, 16 mmol) in EtOH (150 mL) was heated to reflux for 12 hours. The solvent was evaporated, diethyl ether was added to the residue and stirred at room temperature for 1 hour, the solid filtered off and washed with diethylether. The solid was dissolved in ethyl acetate and the organic phase was washed three times with sodium carbonate solution. The organic phase was dried over sodium sulfate, the solvent was evaporated to give the title compound as a white solid (3.46 g, 88%). MS ISP (m/e): 231.1 [(M+H)+].