Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.O>CN(C)C=O>[N+:34]([C:31]1[CH:32]=[CH:33][C:28]([O:1][C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=2)[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[O:6])=[CH:29][CH:30]=1)([O-:36])=[O:35]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
To a suspension of 3-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide (5.62 g, 20.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol) in N,N-dimethylformamide (20 mL) was added 1-fluoro-4-nitrobenzene (3.10 g, 22.0 mmol), and the mixture was stirred at 60° C. for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (6.75 g, 84%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:44][N:43]=[CH:42][CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.2 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.2 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C25H32FN5O6S, 550. found, 550.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1([CH3:22])[O:10][C@@H:9]([C@H:11]2[O:15][C@@H:14]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:13]3[C@H:12]2[OH:21])[CH2:8][O:7]1.C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl>[CH3:5][C:6]1([CH3:22])[O:10][C@@H:9]([C@H:11]2[O:15][C@@H:14]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:13]3[C:12]2=[O:21])[CH2:8][O:7]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)C(=O)[C@H]2O1
Temperature: 25 °C
Yield: 112.6 %

Procedure:
To a stirred solution of DMSO (10.65 mL, 150.1 mmol) in CH2Cl2 (300 mL) at -78° C under argon was added trifluoroaeetie arthydride (16.00 mL, 113.3 mmol) dropwise. The resulting white suspension was stirred at -78° C. for 10 min before a solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (20.0 g, 76.7 mmol) in CH2Cl2 (200 mL) was slowly added by cannula. The resulting mixture was stirred at -78° C. for 1 h before triethylamine (30.4 mL, 218 mmol) was slowly added and the reaction mixture allowed to warm to room temperature. Saturated aqueous NH4Cl (100 mL) was added and the organic phase was separated and washed with cold 1M aqueous HCl (2×100 mL), H2O (100 mL), saturated aqueous NaHCO3 (100 mL), H2O (100 mL), and saturated aqueous NaCl (100 mL). The organic phase was dried, filtered and concentrated to give the crude ketone (22.3 g) as a pale yellow oil. This material was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12.[CH3:20]I.O>CN(C=O)C>[CH3:20][NH:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12
Reactant: CI
Reactant: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: O
Solvent: CN(C)C=O
Product: CNc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 80 °C

Procedure:
0.084 g of 1-amino-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of DMF, and 0.5 mL of methyl iodide were added. The reaction mixture was heated to 80° C., allowed to react at that temperature for 6 h, cooled, and 100 mL of water were added. The reaction solution was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with 30 mL of and 30 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to yield a solid (0.033 g). MS (m/z): 292 (M−1)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]([N:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:20][CH3:21])[CH:17]=2)[N:12]=[CH:11]1)[C:7](O)=[O:8])(=[O:3])[NH2:2]>C(OC(=O)C)(=O)C.C(Cl)(=O)C>[CH3:21][O:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([CH:6]1[CH2:5][CH2:4][C:1](=[O:3])[NH:2][C:7]1=[O:8])[CH2:19]2
Reactant: COc1ccc2c(c1)CN(C(CCC(N)=O)C(=O)O)C=N2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: COc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C=N2
Reaction time: 1 h

Procedure:
A solution of 1.20 g of the crude product from stage 4 in 7 ml of acetic anhydride and 7 ml of acetyl chloride was stirred for 5 hours at 70° C. and then concentrated by evaporation in vacuo. The residue was taken up in 20 ml of methanol and stirred for 1 hour with Amberlyst A-21 ion exchanger. After filtration the filtrate was concentrated by evaporation in vacuo and the residue was purified by flash chromatography with chloroform/methanol (4/1) as eluent. The free base of the title compound thereby obtained was dissolved in 4 ml of methanol and 0.5 ml of a saturated solution of HCl gas in diethyl ether followed by 150 ml of diethyl ether were added to the solution. The salt formed was separated and dried in vacuo, 0.29 g (23% of theory referred to L-glutamine in stage 4) of the title compound being obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:22](Br)([CH3:24])[CH3:23]>CN(C=O)C>[CH:22]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1)([CH3:24])[CH3:23]
Reactant: CC(C)Br
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(n2ccc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To a solution of 1-(piperidin-4-yl)-indole (0.5 g, 2.5 mmol) in dry DMF (3 m) was added anhydrous potassium carbonate (360 mg, 2.6 mmol). After stirring for 15 minutes at ambient temperature, i-propyl bromide (0.84 mL, 9 mmol) was added. The reaction mixture was refluxed for 2 days with stirring, quenched with water, extracted with ethyl acetate (2×), dried, and evaporated. The remaining residue was chromatographed on silica gel eluting with a toluene/acetone gradient (90:10 to 70:30). Evaporation of the eluting solvent gave the title compound as an oil. (220 mg, 36% yield).
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:19](Cl)(=[O:23])/[CH:20]=[CH:21]/[CH3:22]>>[C:19]([N:9]1[C@H:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:23])/[CH:20]=[CH:21]/[CH3:22]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: C/C=C/C(=O)Cl
Agent: [Li]CCCC
Product: C/C=C/C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
reacting (R)-4-(phenylmethyl)-2-oxazolidinone (5) with n-butyllithium and (E)-crotonyl chloride to produce (4R)-3-((E)-2-butenoyl)-4-(phenylmethyl)-2-oxazolidinone (6),
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[C:33](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.ClCCl>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[O:24])[CH2:19][CH2:18]4)[CH2:15][CH2:16]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN([C@H]2CC[C@H](c3ncc4c(Cl)nccn43)CC2)CC1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccn2c1cnc2[C@H]1CC[C@H](N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 100 °C

Procedure:
To benzyl trans-4-(4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)piperazine-1-carboxylate (0.66 mmol, 300 mg) and potassium carbonate (0.991 mmol, 137 mg) in dioxane (2 ml). was added trimethylboroxine (1.982 mmol, 0.559 ml, 50 wt % solution in tetrahydrofuran) and nitrogen was bubbled through the suspension for a couple of minutes. Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, complex with dichloromethane (0.066 mmol, 53.4 mg) was added and the reaction was stirred at 100° C. After two hours the reaction was cooled, filtered through decalite and rinsed with ethyl acetate and the filtrate concentrated under reduced pressure. The residue was purified using column chromatography (silica gel; dichloromethane/methanol 9/1) to give 224 mg of benzyl trans-4-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH3:30])[C:9]=2[C:8]1=[O:20]
Reactant: COc1ccccc1B(O)O
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1ccccc1-c1ccnc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 85.7 %

Procedure:
In a similar manner to Reference Example 5, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 3; 2.00 g) was reacted with 2-methoxyphenylboronic acid (690 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (1.65 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.Cl[C:27]1[N:28]=[N:29]C(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)=CC=1.C(NN)=O>C(O)CCC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:27]=[N:28][N:29]=3)[N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: O=c1ccc(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F
Agent: NNC=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(-c2ccc3nncn3n2)cc1C(F)(F)F

Procedure:
A mixture of 7.0 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone and 80 ml. of phosphorus oxychloride is heated on a steam bath for 18 hours. The solvent is removed and ice water added to the residue. Filtration gives 7.2 g. of 3-chloro-6-[4-nitro-3-(trifluoromethyl)phenyl]pyridazine as tan crystals, m.p. 129°-135° C. Recrystallization from dichloromethane-hexane gives cream colored crystals, m.p. 151°-155° C. The preceding compound is reacted with formylhydrazine in refluxing n-butanol for 24 hours to give the product of the example.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+].CO.O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][OH:13])=[NH:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(Cc1ccc(Br)cc1)NO
Yield: 85.6 %

Procedure:
4-Bromophenylacetonitrile (5.0 g, 25.5 mmol), hydroxylamine hydrochloride (3.9 g, 56.1 mmol), and sodium bicarbonate (5.1 g, 61.2 mmol) were dissolved in MeOH (250 mL, 6.2 mol) and water (40 mL, 2 mol). The mixture was heated at reflux overnight, cooled, and then concentrated to ˜50 mL. The residue was dissolved in DCM, washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to yield 2-(4-bromophenyl)-N-hydroxyacetamidine (5.0 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:8][C:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12])[CH3:7].[H-].[Na+]>>[CH2:6]([O:8][C:9](=[O:13])[CH2:10][CH:11]([CH3:12])[O:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH3:7]
Reactant: C/C=C/C(=O)OCC
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C)OCCCCl

Procedure:
The 7-iodo-3-methyl-4-exaheptanoic acid ethyl ester was obtained in the following manner: The 3-chloropropanol was added to the crotonic acid ethyl ester in the presence of sodium hydride to obtain the 7-chloro-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point1 : 74° - 82° C). Then the 7-iodo-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point0.05 : 62° - 65° C) was obtained in acetone with sodium iodide according to Finkelstein.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH:7]=[CH:6]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([N:28]1[CH2:29][CH2:30][N:25]([C:23](=[O:24])[C:22]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:26][CH2:27]1)=[O:17])[CH:7]=[CH:6]2
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Reactant: COc1cc2ccc(C(=O)O)cc2cc1OC
Product: COc1cc2ccc(C(=O)N3CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)CC3)cc2cc1OC

Procedure:
In a manner as that described in Example 62, 6,7-dimethoxy-2-naphthoic acid and 1-(3,4,5-trimethoxybenzoyl)piperazine are subjected to amidation to give 1-(6,7-dimethoxy-2-naphthoyl)-4-(3,4,5-trimethoxybenzoyl)piperazine. This product is recrystallized from ethyl acetate to give colorless needles, m.p. 224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21].[BrH:29].[OH-].[Na+]>CS(C)=O>[Br:29][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[CH:4][C:3]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:21])=[C:2]([Cl:1])[CH:7]=2)=[C:10]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:11]=1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2COCCO)cc1Cl
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Compound 156 (3.8 g, 9.6 mmol) was dissolved in DMSO (115 mL). The solution was cooled on an ice bath and 48% aqueous HBr (32 mL, 285 mmol) was added slowly. The solution was stirred in a closed vessel at room temperature for 5 days. The reaction mixture was cooled on an ice bath and 27% aqueous NaOH (30 mL) was added to give a basic solution. The water phase was extracted three times with EtOAc, the combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:1 as the eluent to afford the title compound as a slightly coloured crystalline compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:37]3[CH:42]=[N:41][C:40]([N:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)=[CH:39][CH:38]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (90 mg, 0.202 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (88 mg, 0.303 mmol). The final product was collected as a white solid (91 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.65 (d, J=2.53 Hz, 1H) 8.61 (t, J=4.80 Hz, 1H) 8.36 (s, 1H) 8.03-8.07 (m, 2H) 7.83 (s, 1H) 6.92 (d, J=9.09 Hz, 1H) 5.92 (s, 1H) 5.14 (quin, J=6.63 Hz, 1H) 4.42 (br. s., 1H) 4.41 (br. s., 1H) 3.45-3.51 (m, 4H) 2.75-2.84 (m, 4H) 2.54 (m, 2H) 2.14 (s, 3H) 1.51-1.58 (m, 2H) 1.50 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=528.0 [M+H]
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH:32]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CC(O)=O.[BH3-]C#N.[Na+]>C1COCC1.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCn1c(-c2ccccc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Reactant: CN(C)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)CCn1c(-c2ccccc2CNCCN(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-cyclohexyl-2-(2-formylphenyl)-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in THF (0.1 M), N,N-dimethylethane-1,2-diamine (10 eq) was added and the pH adjusted to pH=6 with HOAc. The solution was stirred at RT for 1 h, before the THF was concentrated in vacuo and the residue taken up in MeOH. To the methanolic solution (0.1 M) NaBH3CN (2 eq) was added and the mixture stirred at RT overnight. The reaction mixture was diluted with EtOAc. The organic phase was washed with NaHCO3 (s.s.), H2O and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The title compound was used as crude in the next step; MS (ES+) m/z 520 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][N:6]2[N:5]=1.C(OC([NH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CCOC(C)=O.O.CN(C=O)C>[NH2:40][C:41]([CH3:46])([CH3:45])[C:42]([NH:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][N:6]2[N:5]=[C:4]([CH3:3])[C:16]([C:17]3[S:18][C:19]([C:28]4[N:32]=[CH:31][NH:30][N:29]=4)=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=3)=[C:7]2[CH:8]=1)=[O:43]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Cc1nn2ccc(OCCN)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn2ccc(OCCNC(=O)C(C)(C)N)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.8 %

Procedure:
A mixture of 2-({2-methyl-3-[4-phenyl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridin-5-yl}oxy)ethanamine di-hydrochloride (100 mg, 0.20 mmol) obtained in Example 73-B(i), TEA (1.5 mL), 2-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (75 mg, 0.37 mmol), HOBT (50 mg, 0.37 mmol), EDCI (210 mg, 1.1 mmol) and DMF (20 mL) was stirred at rt for 14 h. To the reaction mixture were added water (200 mL) and EtOAc (200 mL) and the mixture was stirred for 30 min. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the above residue in MeOH (10 mL) and THF (15 mL) was added 6N hydrochloric acid (3 mL), and the mixture was stirred at 70° C. for 1 h. The reaction mixture was allowed to cool to rt and then the solvent was evaporated. To the reaction mixture were added EtOAc (100 mL), 8N aqueous sodium hydroxide solution (3 mL) and water (100 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether and dried to give the title compound (46 mg, 45%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:15][C:16]4[CH2:22][C:21](=[O:23])[CH2:20][CH:19]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:17]=4[N:18]=3)=[CH:9][C:8]=2[O:31][CH3:32])[CH:6]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:15][C:16]4[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:17]=4[N:18]=3)=[CH:9][C:8]=2[O:31][CH3:32])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(s2)CC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc3c(s2)CC(O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A mixture of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(4-fluorophenyl)-4,5-dihydrobenzo[d]thiazol-6(7H)-one (5.0 mg, 0.011 mmol, from example 75), sodium borohydride (1.2 mg, 0.032 mmol), and methanol (0.050 mL) were stirred at rt for 1 h. The crude reaction was quenched with brine solution and extracted with EtOAc. The organic layer was concentrated in vacuo to afford 4.0 mg (76% yield) of the titled compound as a brown oil. LC-MS (M+H)+ 471.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.82 (d, J=2.01 Hz, 1 H) 7.63 (d, J=1.51 Hz, 1H) 7.33 (s, 1 H) 7.17-7.24 (m, 3 H) 7.13 (d, J=8.56 Hz, 1 H) 7.02 (t, J=8.81 Hz, 2 H) 6.64 (dd, J=8.56, 2.27 Hz, 1 H) 4.00-4.23 (m, 3 H) 3.33 (s, 3 H) 3.04 (dd, J=15.23, 5.41 Hz, 1 H) 2.70 (ddd, J=15.30, 9.76, 3.15 Hz, 1 H) 2.29-2.42 (m, 1 H).