Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[C:11]2[C:6]=1[C:7](=[O:26])[C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:9]([CH3:19])[O:10]2)(=O)C.CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[OH:4][C:5]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:26])[C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:9]([CH3:19])[O:10]2
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(=O)c(-c3ccccc3)c(C)oc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc2cc(O)cc(O)c2c(=O)c1-c1ccccc1
Yield: 78.8 %

Procedure:
10 g of 5,7-diacetoxy-2-methyl-isoflavone of m.p. 177°-178° C. prepared by the method described in Example 5 are boiled for 10 minutes with 50 ml of methanol and with a solution of 5 g of sodium hydroxide in 30 ml of water. On acidifying the solution with a 10% aqueous sulphuric acid, the precipitated product is filtered, affording 6 g of 5,7-dihydroxy-2-methyl-isoflavone, m.p. 228°-229° C.
Reaction SMILES: [C:1](O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)S[C@H]1Br)(=[O:3])[CH3:2].[CH2:25]([C:27]1[CH:40]=[CH:39][C:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[OH:38])=[CH:29][CH:28]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]([O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][C:30]1[CH:39]=[CH:40][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1S[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2ccccc2O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Cc2ccccc2OC(C)=O)cc1
Temperature: 60 °C

Procedure:
2,3,4,6-Tetra-O-acetyl-5-thio-β-D-glucopyranosyl bromide (1) (Tetrahedron, vol. 49, p. 8977, 1993), 2-(4-ethylbenzyl)phenol (9), potassium carbonate and benzyl tri-n-butylammonium chloride were mixed in chloroform and heated at 60° C. However, it was completely impossible to obtain a glycosylation product. 2-(4-Ethylbenzyl)phenyl acetate was obtained as a by-product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN1CCCC1=O>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:6](=[O:8])[C:5]5[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:45]=[CH:44][CH:43]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: COc1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 42.5 %

Procedure:
Using 3-methoxybenzoic acid (48 mg, 0.32 mmol), oxalyl chloride (32 μL, 0.37 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (49 mg, 43%) was obtained as a white powder.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O>[CH2:18]([O:17][C:15]([NH:2][C@@H:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)CCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](CCCCC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To 30 g (166 mmol) of (S)-6-aminoheptanoic acid hydrochloride in 57 ml of water are added 57 ml of 4N aqueous sodium hydroxide solution and thereafter dropwise simultaneously at 10° 92 ml of 4N aqueous sodium hydroxide solution and 42 ml (294 mol) of benzyl chloroformate so that the pH value always lies between 10 and 12. After the precipitation of the product the mixture is stirred at 0° for a further 2 hours. Thereafter, 300 ml of water are added and the reaction mixture is extracted with ether. The aqueous phase is then acidified with 20 ml of concentrated hydrochloric acid and extracted with methylene chloride. The methylene chloride phase is dried over magnesium sulphate and evaporated. The crystals obtained are recrystallized from chloroform/hexane, whereby there are obtained 33.1 g (72%) of (S)-6-[1-(benzyloxy)formamido]heptanoic acid, m.p. 82°-83°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1Cc2ccc(OC)cc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Methyl 2-(t-butyloxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylate (0.615 g, 2.0 mmol) in DMF (7 mL) was added K2CO3 (0.304 g, 2.2 mmol) and iodomethane (0.137 mL, 2.2 mmol). The mixture was stirred for 18 hr at 25° C. Approximately 14% of the starting material remained. An additional amount of iodomethane (0.050 mL) was added and stirring continued for 18 hr. The DMF was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (30 mL). The ethyl acetate layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and evaporation in vacuo gave the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[C:12]([N+:22]([O-:24])=[O:23])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][C@H:9]3[CH3:25].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[CH3:25][C@@H:9]1[CH2:10][C:11]2[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:21])[C:12]=2[N+:22]([O-:24])=[O:23])[C@@H:18]2[C@@H:8]1[C@H:5]1[C@@:3]([CH2:20][CH2:19]2)([CH3:4])[C:2](=[O:1])[CH2:7][CH2:6]1
Reactant: C[C@@H]1CC2=C([N+](=O)[O-])C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)=O
Product: C[C@@H]1CC2=C([N+](=O)[O-])C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
A solution of 17β-hydroxy-7α-methyl-4-nitroandrost-4-en-3-one (4.2 g, 12.1 mM) in acetone (400 ml) is cooled to 0° C. and is treated with Jones reagent (4.0 ml). Any excess reagent is decomposed by addition of methanol. The solids are filtered off and the filtrate is concentrated to a green solid. This material is purified by flash chromatography on silica gel to give 7α-methyl-4-nitroandrost-4-ene-3,17-dione (aqueous acetone).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([CH3:17])=[CH:12][CH:11]=1>CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1ccc(N)cc1O
Solvent: CCO
Product: Cc1ccc(Nc2ccnc(N)n2)cc1O
Temperature: 90 °C
Yield: 94 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-amino-4-chloropyrimidine (70 mg, 0.5 mmol) and 5-amino-o-cresol (67 mg, 0.5 mmol) in 10% aqueous EtOH (2 mL) was heated at 90° C. for 18 h. The title compound was obtained in 94% yield a (110 mg) and used for the next step without additional purification.
Reaction SMILES: [O:1]1[C:5](=[O:6])[N:4]=[C:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[NH:2]1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1>N1C=CC=CC=1>[O:1]1[C:5](=[O:6])[N:4]=[C:3]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[NH:2]1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)Nc1ccc(-c2nc(=O)o[nH]2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Aniline derivative 16 (0.89 g, 5.0 mmol) was dissolved in pyridine (25 mL). Succinic anhydride (0.75 g, 7.5 mmol) was added together with 4-N,N,-dimethylaminopyridine (63 mg, 0.5 mmol) and the mixture was stirred overnight at 100° C. The solution was concentrated under reduced pressure and the pale brown solid was recrystallized from a mixture of EtOH/MeOH/H2O (60 mL, 5/35/1, v/v/v). After filtration, the mother liquid was concentrated to ˜10 mL to give carboxylic acid 17 as a solid which was dried under vacuum at 50° C. for 16 h. Yield 1.28 g (92%). Rf 0.3 (DCM/MeOH/AcOH, 100/10/1, v/v/v).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[C:32]([OH:42])(=O)[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:32](=[O:42])[CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(O)CCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (30 mg, 0.068 mmol, prepared as described in Step (A) of Example 28) and hydrocinnamic acid (10.3 mg, 0.068 mmol) in 0.68 ml of CH2Cl2 and 0.08 ml of DMF, 1,3-diisopropylcarbodiimide (9.5 mg, 0.075 mmol) was added. The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 20% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 80% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (18 mg, 46%) as a white solid, m.p. 110°-117° C. (amorphous).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[N+](=[CH2:30])=[N-]>ClCCl.CCOCC>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([O:19][CH3:30])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccccc2)c1=O
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(OC)c2cc(C)ccc2n(Cc2ccccc2)c1=O

Procedure:
A solution of 1-benzyl-3-ethoxycarbonyl-4-hydroxy-6-methyl-2(1H)-quinolinone obtained in Step (3) of Preparation A (12.4 g) in dichloromethane (50 ml) and methanol (10 ml) was treated with excess diazomethane in ether for 10 mins and was then evaporated. The crude methylation product, upon chromatography on silica gel, yielded 1-benzyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (11.5 g). This product (7.13 g) in dry toluene (80 ml) was cooled to -78° C. and a 1M solution of di-isobutyl aluminum hydride (30 ml) was added dropwise in 10 min. After 2.5 hours stirring at -78° C. the reaction mixture was worked up by stirring with aqueous ammonium chloride/1N hydrochloric acid followed by extraction with methylene chloride. The crude reduction product was chromatographed on silica gel and crystallized from ethyl acetate/hexane to give 1-benzyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone as a yellow solid (7.8 g). That the expected product was obtained was confirmed by the spectral data: NMR (CDCl3): δ2.40 (s, 3H, CH3), 4.18 (s, 3H, OCH3), 10.58 (s, 1H, CHO); MS (FAB): m/e 308 (M.+ +1).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([O:13]C)[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2].Cl.N1C=CC=CC=1>O>[N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: COc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1cccc(O)c1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A mixture of 28.8 g of 3-(2-nitrophenoxy)anisole and 68 g of pyridine hydrochloride was heated to 160°-170° C. to prepare a homogeneous solution, which was further heated at 195°-205° C. with stirring for one hour. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated and the residue was subjected to silica gel and eluted with chloroform to give 23.8 g of the title compound as a light brown oil.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]([Cl:14])[C:10]([Cl:13])=[N:11][CH:12]=1)(=O)C>O>[Cl:13][C:10]1[C:9]([Cl:14])=[CH:8][C:7]([OH:6])=[CH:12][N:11]=1
Reactant: CC(=O)Oc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., a solution of 13 g of sodium hydroxide in 80 ml of water was added to 16 g of 5-acetyloxy-2,3-dichloropyridine in 100 ml of ice-water. The mixture was subsequently initially stirred at 0° C. for one hour and then at approximately 20° C. for 17 hours, and the reaction mixture was then washed with 150 ml of ethyl acetate. The mixture was acidified up to a pH of 4-5 by addition of acetic acid and then extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and finally concentrated. Yield: 12.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=O)[CH:8]=O.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:8][NH:14][CH2:11][CH2:12][NH:13]1
Reactant: NCCN
Reactant: Cc1ccsc1C(=O)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccsc1C1CNCCN1
Reaction time: 3 h

Procedure:
A 5 g portion of the above aldehyde was dissolved in 100 ml of ethanol, cooled to 0°-5° C. and a solution of 2.14 g of ethylenediamine in 10 ml of ethanol was added dropwise with stirring. The mixture was allowed to come to room temperature over 3 hours, then 2.4 g of sodium borohydride was added and the mixture was stirred for 18 hours. Water was added, then the mixture was concentrated. The residue was dissolved in dichloromethane, cooled, extracted with water, dried, filtered and evaporated to an oil which crystallized, giving 4.6 g of 2-(3-methyl-2-thienyl)piperazine.
Reaction SMILES: CO.Cl.[N+:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[CH2:16][C:17]([OH:19])=O)([O-])=O.[H][H]>CCO.[Pd]>[NH2:13][C:11]1[CH:12]=[C:7]2[C:8]([CH2:16][C:17](=[O:19])[NH:4]2)=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Methanol (15 mL) and 1.25 M HCl in EtOH (10 ml) was added to 2,4-dinitrophenylacetic acid (837 mg, 3.7 mmol) and Pd/C (10%; 205 mg) under Argon. The argon balloon was replaced with a hydrogen balloon and it was stirred at RT for 12 h and at 50° C. for 24 h. It was cooled to RT and filtered through celite. The solvent was removed and the residue was purified by silica gel chromatography (DCM/methanol gradient) to give the title compound as a red solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=2[F:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=2[F:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)c1F
Yield: 85 %

Procedure:
To 5-bromo-3-(2-fluoro-3-methoxy-benzoyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (86, 350.0 mg, 0.78 mmol) in tetrahydrofuran (30 mL) and water (10 mL) were added 2-thiophene boronic acid (190 mg, 1.49 mmol), tetrakis(triphenyl-phosphine)palladium(0) (40.0 mg, 0.0346 mmol) and potassium carbonate (780 mg, 5.64 mmol) under an atmosphere of nitrogen. The reaction mixture was refluxed for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude compound (87, 0.30 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][NH:42]5)=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[F:47][C:48]([F:61])([F:60])[CH2:49][CH2:50][CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:52](O)=[O:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:59][O:58][C:56](=[O:57])[NH:55][CH:51]([C:52]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21]4[NH:20][C:19]([CH:15]5[CH2:16][CH2:17][CH2:18][N:14]5[C:12](=[O:13])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:46])[CH2:6][CH2:7][C:8]([F:9])([F:11])[F:10])=[N:23][CH:22]=4)=[CH:29][CH:28]=3)=[CH:31][CH:32]=2)=[CH:40][N:39]=1)=[O:53])[CH2:50][CH2:49][C:48]([F:47])([F:61])[F:60]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)O
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(CCC(F)(F)F)NC(=O)OC)[nH]4)cc3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a solution of crude [4,4,4-Trifluoro-1-(2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester (115 mg, 0.18 mmol) in dimethylformamide (0.5 mL) was added a solution of 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid (44 mg, 0.19 mmol) and HATU (72 mg, 0.19 mmol) in dimethylformamide (0.5 mL). Diisopropylethylamine (65 μL, 0.37 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield (4,4,4-Trifluoro-1-{2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester (35 mg, 23%). LCMS-ESI+: calculated for C40H44F6N8O6: 846.82; observed [M+1]+: 847.34.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:24]=[CH:23][C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=3[CH3:22])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:12]([CH2:11][C:10]1[CH:23]=[CH:24][C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH3:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(NCc2ccc(Oc3ccc(Br)cc3)cc2)cccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)cc3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 64B and benzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:38]=[C:39]([SH:44])[CH:40]=[CH:41][C:42]=1[F:43]>CN(C=O)C.C(OCC)(=O)C>[F:36][C:37]1[CH:38]=[C:39]([S:44][C:2]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[O:21][C:20]([CH3:22])=[N:19][CH:18]=5)=[C:13]([O:23][CH3:24])[CH:12]=4)=[N:9][N:10]=[C:3]23)[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Sc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (500 mg) and potassium carbonate (497 mg) in DMF (6.0 mL) was added 3,4-difluorobenzenethiol (0.133 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (491 mg).
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.C(O)(=O)C.Cl.[C:23]([NH:27][NH2:28])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([N:27]1[C:5]2[C:4](=[O:3])[CH2:9][CH2:8][CH2:7][C:6]=2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nn(C(C)(C)C)c2c1CCCC2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate 10 g (42.6 mmol) and acetic acid 5 ml in absolute ethanol (150 ml) at room temperature was added tert-butyl hydrazine hydrochloride 6 g (48 mmol). The mixture was stirred at 60° C. for 3 hours. The volatiles were removed under vacuum, the residue was diluted with DCM and washed with sat. aqueous solution of NaHCO3, and with brine. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane (1:2) to give ethyl 1-tert-butyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 90% yield. LC/MS (254 nm) HPLC method 2 Rt 6.08 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.18 (q, J=6.83 Hz, 2H) 2.93-2.30 (3 m, 6H) 1.58 (s, 9H), 1.16 (t, J=6.83 Hz, 3H). HRMS (ESI) calcd for C14H20N2O3 [M+H]+ 287.1366 found 287.1356.