Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[Cl:27]C1C=C2C(=CC=1)NC(=O)C2>>[Cl:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:26])[C:17]2=[CH:16][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:8][NH:9]2)=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccccc2C1=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc2c(-c3cccnc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-((3-(pyridin-3-yl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-chlorooxindole (5.3 mg, 0.031 mmol) the title compound was prepared as a yellow solid (6.5 mg, 54%). A mixture of (E)- and (Z)-isomers (68:32 by NMR) was obtained. 1H NMR (400 MHz, d6-DMSO) δ 13.77 (br s, 1H), 10.80 (br s, 1H), 9.24 (d, J=1.5 Hz, 1H), 8.63 (dd, J=4.8, 1.8 Hz, 1H), 8.41 (dt, J=7.8, 1.8 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.21-8.16 (m, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.57 (t, J=4.5, 1H), 7.55-7.52 (m, 1H), 7.31 (dd, J=8.3, 2.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H); MS ESI 373.1 [M+H]+, calcd for [C21H13ClN4O+H]+ 373.08.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH3:22]O>>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: CO
Reactant: CN1CCN(c2ccc(CC(=O)O)cc2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(N2CCN(C)CC2)cc1

Procedure:
Thionyl chloride (0.32 g, 2.77 mmol) was added dropwise to a suspension of 2-(4-(4-methylpiperazin-1-yl)phenyl)acetic acid (2.60 g, 11.1 mmol) in MeOH (30 ml) at 0° C. and refluxed for 5 h. The reaction mixture was concentrated and the residue was dissolved in water, made alkaline with saturated sodium bicarbonate solution up to pH˜8 and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to get the crude compound. The crude was purified by column chromatography over neutral alumina using 4% MeOH in DCM as eluent to afford 250 mg of methyl 2-(4-(4-methylpiperazin-1-yl)phenyl)acetate as brown color solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3]1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:20]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH2:3]1)[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCNC2)cc1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCN1CCCC(COS(=O)(=O)c2ccc(C)cc2)C1
Temperature: 65 °C
Yield: 4.1 %

Procedure:
A mixture of 1 g (3.2. mmol) toluene-4-sulfonic acid piperidin-3-ylmethyl ester, hydrochloride, 1.02 g (7 mmol) ethyl iodide (commercially available) and 0.6 g (10 mmol) sodium carbonate in 20 mL acetonitrile was shaken at 65° C. over night. Sodium hydrogencarbonate aq. was added and the mixture was extracted with DCM. The combined organic fractions were evaporated to dryness and the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to yield 40 mg (4%) of the title compound as yellow oil. MS(m/e): 298 (MH+).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH2:5]1[CH2:15][C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[C:13]1(=[O:14])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:15][NH:1]1
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCCc2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
With cooling with ice, 2.6 g of sodium azide was added to a concentrated hydrochloric acid (60 mL) solution of 5 mL of alpha-tetralone, and stirred at room temperature for 15 hours. The reaction liquid was poured into ice water, and neutralized with potassium carbonate. This was extracted with chloroform, and the organic layer was washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the crude product was purified through silica gel column chromatography (chloroform/methanol) to obtain 2.3 g of the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16]C=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1
Reactant: O=CNc1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(C2CCN(CC(F)(F)F)CC2)cc1

Procedure:
A solution of the formamide in MeOH (20 mL) is stirred at rt and HCl (conc., 1 mL) is added. The deep purple solution is heated at reflux for 1 h, cooled and the MeOH is evaporated. The residue is stirred with water (20 mL) and NaHCO3 (sat. aq.) is added until bubbling ceases. The mixture is extracted with DCM (20 mL, 2×10 mL) and the combined extracts are dried over MgSO4 and evaporated under reduced pressure to afford the title compound as an orange solid (870 mg).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.N([O-])=[O:13].[Na+]>C(O)=O.C(O)(=O)C.Cl.O>[CH3:11][C:7]1[C:5]2[NH:6][C:2](=[O:13])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1cccc2sc(N)nc12
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Solvent: O
Product: Cc1cccc2sc(=O)[nH]c12
Temperature: 25 °C

Procedure:
5.00 g (30.5 mmol) 2-amino-4-methylbenzothiazole in 15.0 mL formic acid, 6.10 mL glacial acetic acid and 112 mL conc. hydrochloric acid were cooled to −5° C. with stirring and slowly combined with a solution of 2.10 g (30.5 mmol) sodium nitrite in 5.0 mL water. The reaction mixture was stirred for 20 min at this temperature, then heated to RT and then refluxed overnight. The cooled mixture was then mixed with water and extracted several times with EtOAc. The combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulphate, filtered and the filtrate was evaporated down.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=[O:25])CCC1C=CC=CC=1.[Li].C(O[PH+](CC(OCC)=O)OCC)C.[Br-].[Na].C(OCC)(=O)CC(OCC)=O>O1CCCC1>[CH3:16][O:25][C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2][CH:3]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C(O)CC/C=C/CCc1ccccc1
Agent: CCOC(=O)C[PH+](OCC)OCC
Agent: [Br-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(=O)CC(=O)OCC
Product: COc1ccc(CC/C=C/CCC(=O)O)cc1

Procedure:
E-7-(4-Methoxyphenyl)hept-4-enoic acid was prepared in the same fashion as E-7-phenylhept-4-enoic acid by substituting 3-(4-methoxyphenyl) propional for dihydrocinnamaldehyde as the starting material in the synthetic sequence. 3-(4-methoxyphenyl)propional was combined with the lithium salt of ethyl diethoxyphosphonioacetate in tetrahydrofuran at room temperature. The resulting unsaturated ester, ethyl 5-(4-methoxyphenyl)pent-2-enoate, was purified by chromatography. The unsaturated ester was then reduced with excess diisobutylaluminum hydride in tetrahydrofuran at −78° C. The purified alcohol was then converted to the bromide, E-1-bromo-5-(4-methoxyphenyl)pent-2-ene, by reaction with triphenylphosphine and carbon tetrabromide in methylene chloride at 0° C. The purified bromide was then used to alkylate the sodium salt of diethyl malonate to provide the diester, methyl E-1-carbomethoxy-5-(4-methoxyphenyl)hept-4-enoate. The diester was purified by chromatography and then subjected to saponification using methanolic sodium hydroxide. The diacid was purified by acid/base extraction and then used directly in the next step of the reaction sequence. Heating the neat diacid at 170° C. (under Ar) for 30 minutes effected decarboxylation. The product, E-7-(4-methoxyphenyl)hept-4-enoic acid, was obtained in greater than 95% purity. Any residual diacid was removed by dissolving the acid in hexane and filtering. All compounds in the reaction sequence were fully characterized by spectral analysis and new compounds were analyzed by combustion analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][N:46]([CH2:48][C:49]([CH3:52])([OH:51])[CH3:50])[CH:47]=2)=[CH:38][C:37]=1[CH3:53].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:37]([CH3:53])=[CH:38][C:39]([C:43]3[CH:44]=[N:45][N:46]([CH2:48][C:49]([OH:51])([CH3:50])[CH3:52])[CH:47]=3)=[CH:40][C:41]=2[CH3:42])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(-c2cnn(CC(C)(C)O)c2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnn(CC(C)(C)O)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 1-(4-(4-bromo-3,5-dimethylphenyl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.23 min; Mass spectrum (ESI+): m/z=585 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[F:15][CH:16]([F:34])[N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:18]1=[O:33].[H-].[Na+]>CN(C=O)C.CO>[F:34][CH:16]([F:15])[N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:28][CH:27]=2)[C:18]1=[O:33]
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C(F)F
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c(=O)n(C(F)F)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 28.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (124 mg) and NaH (25.6 mg) in DMF (3 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(difluoromethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg) as white crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A140) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.[NH:33]1[C:37]([NH2:38])=[N:36][N:35]=[N:34]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:38][C:37]3[NH:36][N:35]=[N:34][N:33]=3)=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(N(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Reaction time: 21 h

Procedure:
To a solution of the product of Example 5 Step A (0.14 mmol, 64 mg), 1H-tetraazol-5-amine monohydrate (0.28 mmol, 29 mg), HOBt (0.35 mmol, 53 mg) and EDC (0.56 mmol, 108 mg) in 1 mL of DMF was added DIEA (0.7 mmol, 122 μL). The reaction was allowed to stand at ambient temperature for 21 h, then concentrated under reduced pressure. The residue was taken up in ca. 2:1 dioxane/H2O and acidified with TFA, then purified by reverse-phase chromatography (Condition A). The product was lyophilized, affording a white solid. 1H NMR (500 MHz, CD3OD): δ 8.01 (d, 2H), 7.52-7.62 (overlapping m, 3H), 7.35-7.50 (overlapping m, 3H), 3.87 (s, 3H), 3.76 (m, 1H), 2.16 (m, 2H), 1.99 (m, 2H), 1.84 (m, 2H), 1.30 (m, 2H), 1.14 (m, 1H), 0.92 (s, 9H). MS (ESI): m/z 487 (M+H). HPLC A: 1.97 min.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CC)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (6.0 gm., 0.02 mole), ethyl bromoacetate (4.0 gm., 0.025 mole) and potassium carbonate (8.3 gm., 0.06 mole) in dimethyl-formamide (35 ml.) is heated at 50° C. and stirred for one hour. The mixture is cooled and poured into water (300 ml.). The solid product that separates is removed by filtration, then washed with water followed by benzene (10 ml.).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[N:14]=[CH:13]2)=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.CS(C)=O.[C:39]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52](ON1C(=O)CCC1=O)=[O:53])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C)C=O>[C:42]([O:41][C:39]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([NH:1][CH:2]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[N:14]=[CH:13]2)=[O:9])[C:3]([OH:5])=[O:4])=[O:53])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NC(CNC(=O)c1ccc2c(cnn2CCCNc2ncc[nH]2)c1)C(=O)O
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
2-Amino-3-((1-(3-(imidazol-2-ylamino)propyl)(1H-indazol-5-yl))carbonylamino)propanoic acid (0.050 g, 0.103 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (43.1 μL, 0.309 mmol) was added and the reaction was stirred for 5 minutes. A precipitate formed so methyl sulfoxide (1 mL) was added. Succinimidyl N-boc-6-aminohexanoate (0.0406 g, 0.124 mmol) was added and the reaction was stirred under N2 for 18 h. The reaction was then concentrated to an oil under high vacuum. The oil was purified by the following method (Preparative HPLC Method A) to give 39.9 mgs (66%) of product. ESMS: Calcd. for C28H40N8O6, 584.31. Found, 585.2 [M+H]+1. Analytical HPLC, Method B, Rt=18.72 min, Purity=98% Preparative HPLC Method A:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[C:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:16]=3)=[CH:3][N:4]=[C:5]2[C:10]=1[F:11]
Reactant: Fc1c(Cl)ccn2c(Br)cnc12
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Product: Fc1ccc(-c2cnc3c(F)c(Cl)ccn23)cc1-c1cccnc1
Yield: 79.7 %

Procedure:
3-Bromo-7-chloro-8-fluoroimidazo[1,2-α]pyridine (45 mg, 0.18 mmol) was coupled with 4-fluoro-3-(pyridin-3-yl)phenylboronic acid (49 mg, 0.19 mmol), as described in Example 1, to afford the title compound as a white amorphous solid (49 mg, 80%): δH (400 MHz, DMSO) 7.10 (1H, t, J 7.0), 7.54-7.61 (2H, m), 7.77-7.81 (1H, m), 7.92 (1H, dd, J 2.3, 7.4), 7.94 (1H, s), 8.09-8.12 (1H, m), 8.52 (1H, dd, J 1.0, 7.2), 8.65-8.66 (1H, m), 8.88 (1H, s); m/z (ES+) 342 (100%, [MH]+).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17]2[CH2:23][CH:24]4[NH:28][CH:27]([C:16]3=2)[CH2:26][CH2:25]4)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br>C(O)(=O)C>[ClH:1].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17]2[CH2:23][CH:24]4[NH:28][CH:27]([C:16]3=2)[CH2:26][CH2:25]4)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc3c(c2)c2c(n3C)CC3CCC2N3)cc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccc(O)cc4)ccc31)C1CCC(C2)N1
Temperature: 60 °C
Yield: 12.3 %

Procedure:
A mixture of the product of Example 31, step B (18 mg, 0.04 mmol) and 33% HBr in acetic acid (10 mL) was heated at 60° C. for 4 days. The reaction mixture was concentrated in vacuo and the resulting residue neutralized with saturated sodium bicarbonate solution before extracting with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by semi-preparative HPLC and the free base treated with 1.25 M HCl methanol solution (0.5 mL) to give 2-(4-hydroxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (2 mg, 12%, AUC HPLC 97.2%) as an off-white solid: mp 210-212° C.; 1H NMR (CD3OD, 300 MHz) δ 8.18-8.23 (m, 1H), 7.73-7.81 (m, 2H), 7.69 (dd, J=9.0 Hz, 1.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 6.82-6.90 (m, 2H), 5.25-5.36 (m, 1H), 4.53 (br s, 1H), 3.71 (s, 3H), 3.40-3.55 (m, 1H), 3.46-3.55 (m, 1H), 3.01-3.11 (m, 1H), 2.23-2.51 (m, 2H), 1.92-2.11 (m, 1H); ESI MS m/z 369 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[B:27](OC)([O:30]C)[O:28]C.Cl>C(OCC)(=O)C.C1COCC1.C1CCCCC1.CCCCCC>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[B:27]([OH:30])[OH:28]
Reactant: COB(OC)OC
Reactant: CCCCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](COc2ccc(B(O)O)c(F)c2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound (58) (13.9 g) and THF (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. sec-Butyllithium (1.00 M, in a n-hexane and cyclohexane solution; 51.6 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. Subsequently, trimethyl borate (5.6 g) in a THF solution (50 ml) was added dropwise thereto in the temperature range of −74° C. to −65° C., and the mixture was stirred for 8 hours while allowing the temperature to come to 25° C. The reaction mixture obtained was poured into a vessel containing an aqueous 1N—HCl solution (100 ml) and ice-water (500 ml), and mixed. Then, ethyl acetate (300 ml) was added thereto and the mixture was allowed to be separated into organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 14.2 g of 2,3-difluoro-4-(trans-4-pentylcyclohexylmethoxy)phenylboronic acid (59). The yield based on the compound (58) was 89.0%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[C:39]([O-:42])(=[O:41])[CH3:40].[Cs+].C(OCC)(=O)C>CN(C=O)C>[C:39]([O:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)[O-]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 74.8 %

Procedure:
10.0 g of 4-(bromomethyl)-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl and 3.5 g of cesium acetate are suspended in 300 ml of anhydrous DMF and stirred at 45° C. for 24 h. The solvent is evaporated off under reduced pressure and the residue is taken up in water, to obtain a solid which can easily be filtered. After drying, the solid is triturated with an hexane: ethyl acetate mixture (4:1) to obtain 7.2 g of a beige powder (Yield: 75%).
Reaction SMILES: [C:1]([C:6]1[CH:29]=[C:28]([C:30]([CH2:33][CH3:34])([CH3:32])[CH3:31])[CH:27]=[CH:26][C:7]=1[O:8][CH:9]([CH2:24][CH3:25])[C:10]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N+:20]([O-])=O)=[CH:15][C:14]=1[OH:23])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:6]1[CH:29]=[C:28]([C:30]([CH2:33][CH3:34])([CH3:31])[CH3:32])[CH:27]=[CH:26][C:7]=1[O:8][CH:9]([CH2:24][CH3:25])[C:10]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([NH2:20])=[CH:15][C:14]=1[OH:23])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [Pd]
Solvent: CCO
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)cc1O

Procedure:
In 100 ml of ethanol was dissolved 30 g (61×10-3 mole) of 2-{2-(2,4-di-t-amylphenoxy)butanamido}-4-chloro-5-nitrophenol and hydrogenation was effected by using 1.5 g of Pd-C as a catalyst. The color of the nitro derivative disappeared in 2 hours, and the Pd-C was removed by filtration and ethanol was evaporated from the filtrate, followed by extraction of the residue with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium hydrogen carbonate solution and then with water, and after drying over magnesium sulfate, ethyl acetate was evaporated. 28 g of the crude product was used as such for the following reaction.