Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.5 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide (32 mg, 0.061 mmol) and TFA (0.9 ml, 11.7 mmol) were combined with dichloromethane (3 ml) to give an orange solution. The reaction mixture was stirred at room temperature until the consumption of starting material (2.5 h). The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (300 μl, 4.44 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (1:1 dichloromethane/heptane) to afford 14 mg (59%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=399; 1H NMR (300 MHz, DMSO-d6) δ: 9.11 (s, 1H), 8.53 (d, J=8.6 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 4.30-4.46 (m, 1H), 4.18 (s, 3H), 3.53 (dd, J=9.6, 5.1 Hz, 1H), 3.47 (dd, J=9.6, 4.5 Hz, 1H), 3.27 (s, 3H), 1.31 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH2:10][NH:11][CH:12]1[CH:19]2[CH2:20][C:15]3([C:22]([O:24]C)=[O:23])[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:26])[CH2:10][NH:11][CH:12]1[CH:19]2[CH2:20][C:15]3([C:22]([OH:24])=[O:23])[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CC3CC(C1)C(NCC(=O)OCc1ccccc1)C(C3)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CNC1C2CC3CC1CC(C(=O)O)(C3)C2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of methyl 4-{[2-(benzyloxy)-2-oxoethyl]amino}-adamantane-1-carboxylate thus obtained (3.30 g) in tetrahydrofuran (20 ml), methanol (10 ml) and 8M aqueous sodium hydroxide (10 ml) were added and stirred at room temperature for 3 hours. After the reaction mixture was concentrated, the resulting residue was diluted with 1M aqueous sodium hydroxide and washed with diethyl ether. The resulting aqueous layer was diluted with 12M aqueous hydrochloric acid and extracted with chloroform. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give 4-{[2-(benzyloxy)-2-oxoethyl]amino}-adamantane-1-carboxylic acid (2.95 g) as a light-brown viscous substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[C:3]([SH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1S
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1S

Procedure:
A solution of 3,4-dichloro-2-mercaptobenzoic acid (17.78 g) and concentrated sulphuric acid (3.75 ml) in ethanol was heated at reflux for 20 hours. After cooling the mixture was evaporated and the residue suspended in dichloromethane, washed with water, sodium bicarbonate, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with hexane to give ethyl 3,4-dichloro-2-mercaptobenzoate (7.96 g) as a yellow solid NMR (CDCl3) 1.3(t,3H), 4.25(q,2H), 6.75(s,1H), 7.15(d,1H), 7.8(d,1H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.CON(C)[C:22](=[O:24])[CH3:23].Cl>>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:22](=[O:24])[CH3:23])[CH:16]=[CH:15]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CON(C)C(C)=O
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc2cc(C(C)=O)ccc2c1
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
n-BuLi (1.6M in hexane, 73 ml) was added dropwise to a solution of 2-bromo-6-methoxynaphthalene (25.29 g) at −78° C. and the mixture was stirred for 15 minutes. A solution of N-methoxy-N-methylacetamide (11.03 g) was added to the mixture and stirred for 1 hour at −78° C. 1N-HCl was added, and the whole was extracted with ethyl acetate. The extract was concentrated and crystallized from cyclohexane to give the titled compound (17.50 g) as a colorless powder.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]2[CH3:18])=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=1)(C)(C)C.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:22]([O:21][C:19]([C:14]1[N:15]([CH3:18])[C:16]2[C:12]([CH:13]=1)=[C:11]([C:24]([F:25])([F:27])[F:26])[CH:10]=[C:9]([O:8][CH2:7][C:6]([OH:28])=[O:5])[CH:17]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cc(OCC(=O)OC(C)(C)C)cc2n1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C(F)(F)F)cc(OCC(=O)O)cc2n1C
Temperature: 25 °C
Yield: 104.6 %

Procedure:
Under nitrogen, ethyl 6-(2-tert-butoxy-2-oxoethoxy)-1-methyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (1.3 g, 3.24 mmol) was dissolved in acetic acid (20 ml), followed by adding thereto a 30% aqueous sulfuric acid solution (10 ml), and the resulting mixture was stirred at 50° C. for 1 hour. Crystals were precipitated and the reaction mixture became a white suspension. The reaction mixture was cooled to room temperature, followed by adding thereto water, and the crystals precipitated were collected by filtration, washed with water, and then dried under reduced pressure to obtain 1.17 g of [[2-(ethoxycarbonyl)-1-methyl-4-(trifluoromethyl)-1H-indol-6-yl]oxy]acetic acid as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:35][Si:36]([C:39]#[C:40][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1)([CH3:38])[CH3:37]
Reactant: Nc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cncc(N)c1
Temperature: 75 °C

Procedure:
To a mixture of 7.23 g (41.8 mmol) 5-bromo-3-amino-pyridine in 70 mL dry THF under argon atmosphere is added 239 mg (1.3 mmol) CuI, 880 mg (1.3 mmol) bis(triphenyl-phosphine)palladium(II) chloride, 1.1 g (4.2 mmol) triphenylphosphine and 70 mL (0.50 mol) triethylamin. Then 8.3 mL (59 mmol) trimethylsilylacetylene are added and the reaction mixture is heated at 75° C. over night. After cooling to RT, 100 mL DCM is added and the reaction mixture is extracted twice with 100 mL water. The organic layer is dried over MgSO4 and the product is purified by chromatography on silica gel. Yield: 5.26 g (66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:21][NH2:22])[CH2:18][CH2:17][O:16][C:15]([CH3:20])([CH3:19])[CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:40])([F:39])[C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])[N:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:21][NH:22][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([C:27]5[N:26]=[C:25]([C:24]([F:40])([F:39])[F:23])[O:29][N:28]=5)[CH:31]=4)[CH2:18][CH2:17][O:16][C:15]([CH3:19])([CH3:20])[CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC1(C)CC(CN)(c2nc(-c3ccc(F)cc3)cs2)CCO1
Product: CC1(C)CC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2nc(-c3ccc(F)cc3)cs2)CCO1
Yield: 17 %

Procedure:
This compound was synthesized from (4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (7 mg, yield 17%): 1H NMR (500 MHz, CD3OD) δ 8.41 (t, J=1 Hz, 1H), 8.23 (d, J=4 Hz, 1H), 7.96-7.90 (m, 3H), 7.76 (s, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.69-7.04 (t, J=8.8 Hz, 2H), 3.88 (m, 2H), 3.60 (s, 2H), 2.52 (m, 2H), 1.95 (m, 2H), 1.29 (s, 3H), 0.81 (s, 3H). MS (ESI) m/z: Calculated for C27H24F4N4O3S: 560.15. found: 561.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: CN
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Product: CNC(=O)c1cnc(CCc2c(-c3ccc(F)cn3)noc2C)s1
Yield: 48 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using methylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (33 mg, 48%) which was obtained as a white solid. MS: m/e=347.0 [M+H]+.
Reaction SMILES: C1CCCCC1.C([N-]C(C)C)(C)C.[Li+].[C:15]([O:26][CH:27]([CH3:29])[CH3:28])(=[O:25])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCCC1>[OH:37][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:18]([C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20])[CH2:17][CH2:16][C:15]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)OC(=O)CCCC(=O)OC(C)C
Reactant: O=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)c1ccccc1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
38 ml of a 1.5M lithium diisopropylamide cyclohexane solution was dissolved in 400 ml of tetrahydrofuran, and 20 ml of a tetrahydrofuran solution containing 10.3 g of diisopropyl glutarate was dropwise added at -78° C. in a nitrogen atmosphere. After stirring at the same temperature for 30 minutes, 10 ml of a tetrahydrofuran solution containing 3.9 g of benzaldehyde was dropwise added thereto, followed by stirring at -78° C. for 1.5 hours. 2N hydrochloric acid was added to the reaction solution, and the temperature was brought to room temperature. Then, the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1+3/1) to obtain 6.14 g of the above-identified compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(isobutyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C6) (5.28 g, 13.99 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a pale yellow solid (3.69 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([F:40])[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:37][C:36]1[CH:38]=[CH:39][C:33]([Br:32])=[CH:34][C:35]=1[F:40])=[O:5])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1sc2ccncc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2ccncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 64 %

Procedure:
A degassed solution of 3-(nonafluorobutane-1-sulfonyloxy)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (422 mg, 0.83 mmol), 4bromo -2-fluoroaniline (206 mg, 1.08 mmol), Pd2 dba3 (38 mg, 0.04 mmol), Xantphos (48 mg, 0.08 mmol) and DBU (316 μl, 2.08 mmol) in toluene (1 ml) was subjected to microwave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (30 ml). The resultant solution was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo to give a solid residue. The solid residue was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 90:10 to 70:30) to afford the title compound as a white solid (210 mg, 64%). LCMS (method B): RT=3.78 min, M+H+=395/397.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]4[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:13]=4[CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:32](=O)[CH3:33]>C1COCC1>[CH:32](=[C:20]1[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][C:13]=2[CH2:16][CH2:17][CH2:18][C:19]1=[O:21])[N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[N:8]=[CH:9]3)[CH3:33]
Reactant: CC=O
Reactant: O=C1CCCc2cc3c(cnn3-c3ccncc3)cc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=C1C(=O)CCCc2cc3c(cnn3-c3ccncc3)cc21
Temperature: -77 °C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with 1-(pyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (14.419 g, 52.0 mmol) and THF (200 mL). The solution was cooled to about −77° C. and then 1 M LiHMDS solution (54.6 mL, 54.6 mmol) was added over about 30 min, keeping the internal temp below about −75° C. After complete addition of the LiHMDS the mixture was stirred for about 5 min, the cold bath was removed and the mixture was allowed to warm to about 0° C. (over about 1 h). The mixture was re-cooled to about −65° C. then acetaldehyde (14.6 mL, 260 mmol) was added. The cold bath was removed and the mixture was allowed to warm to about 0° C. brine (50 mL) and water (50 mL) were added to the mixture, then collected the organic layer. Extracted the aqueous layer with EtOAc (2×50 mL). Combined organics and dried over MgSO4 and concentrated in vacuo. Purified by 120 g silica column, eluting with 20-100% EtOAc/DCM to provide 5-ethylidene-1-(pyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (83, R1=4-Pyridyl, R2′=Methyl) (12.3 g, 78%); LC/MS, method 3, Rt=2.17 min MS m/z 304 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.75-8.72 (m, 2H), 8.50-8.49 (m, 1H), 8.13 (s, 1H), 7.98-7.95 (m, 2H), 7.75 (s, 1H), 7.18-7.11 (q, J=7.3 Hz, 1H) 2.93-2.85 (m, 2H), 2.35-2.22 (m, 2H), 2.04-1.95 (m, 2H), 1.90-1.85 (d, J=7.4 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(N)cc1
Yield: 105.2 %

Procedure:
In 100 ml of absolute ethanol, 8.35 g of the compound of Example II was hydrogenated over 2 spatulas-full of 10% Pd/C in a Parr apparatus at ca 40 lbs/in2 for 3-4 hrs. Under a nitrogen blanket, the catalyst was filtered off through a Celite pad (sintered glass funnel), which was washed with two volumes of ethanol. Evaporation gave ca 7.2 g of a brown oil.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:9]=2[O:8][CH:7]=1)(=O)C.Cl>>[NH2:4][CH2:5][C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][C:9]=2[O:8][CH:7]=1
Reactant: CC(=O)NCc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Agent: Cl
Product: CS(=O)(=O)Nc1cc2occ(CN)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Acetylaminomethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was treated with 6N hydrochloric acid to obtain 3-aminomethyl-7-methylsulfonylamino- 6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:31][Si](C(C)(C)C)(C)C)=[C:5]([O:23][Si](C(C)(C)C)(C)C)[C:6](/[CH:9]=[CH:10]\[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:7][CH:8]=1)[CH3:2].[F-].[K+].CN(C)C=O>CO.C(O)(=O)C.C(OC)(C)(C)C>[CH2:1]([C:3]1[C:4]([OH:31])=[C:5]([OH:23])[C:6](/[CH:9]=[CH:10]\[C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O)c1O
Reaction time: 16 h

Procedure:
To a solution of 13 (0.15 g, 0.268 mmol) in methanol (2 mL), acetic acid was added acetic acid (0.032 mL, 0.563 mmol) followed by potassium fluoride (0.033 mg, 0.563 mmol). Dimethylformamide was then added (0.5 mL) and the mixture was stirred for 16 hours then more acetic acid (0.04 mL) and KF (0.033 mg) were added and the mixture stirred for 48 hours. The mixture was then diluted with tertbutylmethyl ether (50 mL) and washed with water (10 mL). The aqueous layer was re-extracted, the combined organic layers were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (cyclohexane:AcOEt 8:2+1% AcOH) to give 0.05 g of ZSB-76:
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([N:11]2[C@@H:15]([CH:16]([CH3:18])[CH3:17])[C@@H:14]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:13][C@@:12]2([CH2:32][CH:33]([CH3:35])[CH3:34])[C:25]([O:27]C(C)(C)C)=[O:26])=[O:10])=[CH:7][C:6]=1[O:38][CH3:39])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([N:11]2[C@@H:15]([CH:16]([CH3:18])[CH3:17])[C@@H:14]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:13][C@@:12]2([CH2:32][CH:33]([CH3:34])[CH3:35])[C:25]([OH:27])=[O:26])=[O:10])=[CH:7][C:6]=1[O:38][CH3:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](C(C)C)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](C(C)C)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1. Purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy. This afforded the title compound as a solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.C(N(CC)CC)C.Cl.Cl.[CH:46]1([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][CH2:47]1>ClCCl>[CH:46]1([N:49]2[CH2:54][CH2:53][N:52]([CH2:6][C:7]3[N:12]=[CH:11][C:10]4[N:13]=[CH:14][N:15]([C:16]5[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=6[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=5)[C:9]=4[CH:8]=3)[CH2:51][CH2:50]2)[CH2:48][CH2:47]1
Reactant: C1CN(C2CC2)CCN1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(C5CC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
100 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 205 mg triethylamine are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere 1-cyclopropylpiperazine dihydrochloride (184 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[O:6][C@@H:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[O:6][C@@H:7]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[CH:22]=[CH:21][C:19]([NH:20][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1
Reactant: COc1ccc(O[C@H](CCN2CCC(c3ccc(N)cc3)CC2)c2ccccc2)cc1OC
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(O[C@H](CCN2CCC(c3ccc(NC(=O)C(C)C)cc3)CC2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
A mixture of 4-{1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}aniline (5.31 mg, 0.0119 mmol), isobutyryl chloride (2.08 mg, 0.019 mmol), N,N-diisopropylethylamine (8.40 mg, 0.0650 mmol) in methylene chloride (1.0 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and chromatographed using a preparative TLC plate [2.5% of NH3 (2.0 M in methanol) in CHCl3] to give the product (3.5 mg, 56.5%) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H, J=8.6 Hz), 7.30-7.20 (m, 4H), 7.20 (m, 1H), 7.11 (d, 2H, J=8.6 Hz), 7.04 (s, 1H), 6.57 (d, 1H, J=8.3 Hz), 6.44 (d, 1H, J=2.6 Hz), 6.22 (dd, 1H, J=2.6, 8.3 Hz), 5.09 (apparent dd, 1H, J=4.4, 8.1 Hz), 3.72 (s, 3H), 3.70 (s, 3H), 3.08 (m, 2H), 2.57 (m, 2H), 2.43 (apparent sept, partially hidden, 2H, J=6.8 Hz), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 517.3 (M+H)+.