Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:41]=[C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH:39]=[CH:38][C:7]=1[O:8][CH:9]([CH2:34][CH2:35][CH2:36][CH3:37])[C:10]([NH:12][C:13]1[C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:21][C:16]2[NH:17]C(=O)[O:19][C:15]=2[CH:14]=1)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].C1(C)C(C)=CC=CC=1.[OH-].[Ca+2].[OH-]>C(O)CO>[NH2:17][C:16]1[CH:21]=[C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)[C:13]([NH:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:38]=[CH:39][C:40]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])=[CH:41][C:6]=2[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:14][C:15]=1[OH:19]
Reactant: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc2oc(=O)[nH]c2cc1Oc1ccc(C(C)(C)C)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: OCCO
Product: CCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(N)cc1Oc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
In a 250-ml flask inert with nitrogen, place 11.3 g (0.018 m) of 6-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-5-(4-t-butylphenoxy)-benzoxazol-2-one (2, Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl), 120 ml of xylene, 12 ml of ethylene glycol, and 8.0 g of calcium hydroxide. Heat under reflux collecting approximately 7 ml of water-ethylene glycol and 20 ml of xylene in a Dean-Stark trap. Detach the trap and heat under reflux for 5 hrs. Cool to 80° C. and add 100 ml of toluene, 100 ml of hot water, 25 ml of acetic acid, and 2 g sodium hydrosulfite. Stir the mixture at 60°-65° C. for 15 min and filter through a Celite pad to remove interlayer insolubles. Separate toluene-xylene solution, wash with 100 ml of hot water +12 ml of acetic acid +2 g sodium hydrosulfite and 100 ml of hot water twice, and concentrate under a reduced pressure to a thick oil. Dissolve the oil in 200 ml of heptane, add seed crystals, and stand at room temperature over night. Cool in an ice-water bath for 1 hr, collect solid, wash with heptane, and dry in a vacuum oven to give 9.2 g (85%) of 2-amino-5-{2-(2,4-di-t-pentylphenoxy)hexanoyl}amino-4-(4-t-butylphenoxy)-phenol (Formula I; Y=4-t-butylphenoxy and R′=1-(2,4-di-t-pentylphenoxy)pentyl).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[N:14]([CH3:25])[C:15]1[CH:20]=[N:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:25][N:14]([C:15]1[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1)[C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[NH2:8]
Reactant: [H][H]
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N

Procedure:
To a solution of (1S,2S)-1-N,1-N-dibenzyl-2-N-methyl-2-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (285 mg, 0.647 mmol) in ethyl acetate (2 ml) and ethanol (1 ml) was added palladium on carbon (10% wt, 50% wet, 100 mg, 0.094 mmol). The resulting mixture was stirred under a balloon of hydrogen gas for 18 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:54]1([C:59]([C:61]2[CH:69]=[CH:68][C:64]([C:65](O)=[O:66])=[CH:63][CH:62]=2)=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55]1>ClCCl>[C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][C@H:3]([NH:2][C:65](=[O:66])[C:64]1[CH:63]=[CH:62][C:61]([C:59]([N:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)=[O:60])=[CH:69][CH:68]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])#[N:24]
Reactant: N#Cc1cccc(OC[C@H](N)CC(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(OC[C@@H](CC(=O)OCc2ccccc2)NC(=O)c2ccc(C(=O)N3CCCC3)cc2)c1

Procedure:
1.8 g (5.2 mmol) of benzyl (3R)-3-amino-4-(3-cyanophenoxy)butyrate hydrochloride (the compound in step 2 in Example 52), 703 mg (5.2 mmol) of 1-hydroxybenzotriazole (hydrate), 997 mg (5.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, 526 mg (5.2 mmol) of triethylamine, and 1.14 g (5.2 mmol) of 4-(1-pyrrolidyl carbonyl)benzoic acid were stirred in dichloromethane overnight. The reaction solution was washed with 1 N hydrochloric acid, 1 N aqueous sodium hydroxide and saturated saline and dried over sulfate magnesium anhydride, and the solvent was distilled off. The resulting residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[OH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:41][CH2:42][NH:43]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:41][CH2:42][NH2:43]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)c(F)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Temperature: 150 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 28, 3.0 g, 10 mmol), 1,1′-azobis(N,N (3.5 g, 21 mmol), triphenylphosphine (5.4 g, 21 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (3.3 g, 21 mmol) and DCM (20 mL) were added. The mixture was heated at 150° C. for 20 minutes in a microwave heater. The reaction mixture was allowed to cool to room temperature and TFA (20 mL) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude material was filtered through a plug of silica gel using DCM as eluent. The solvent was removed under reduced pressure and the crude material was dissolved in ethyl acetate (10 mL) and the HCl salt of the title compound precipitated when 1 M HCl in diethylether (20 mL) was added. The solid was filtered off, dissolved in DCM (100 mL) and organic phase was washed with saturated aqueous NaHCO3 (40 mL) to give the title compound (2.0 g). MS m/z 335 [M+H]+.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])[CH:13]=2)[CH2:6]1)C.C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37].O.O.O.C([O-])(=O)C.[Na+]>CCO>[NH2:37][C:36]1[N:38]=[CH:4][C:5]2[CH2:6][N:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)=[O:19])[CH:13]=3)[CH2:8][CH2:9][C:10]=2[N:35]=1
Reactant: CN(C)C=C1CN(c2ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)CCC1=O
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ncc2c(n1)CCN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 80 °C
Reaction time: 23 h
Yield: 14.3 %

Procedure:
A solution of 4-[3-(dimethylamino)methylidene-4-oxopiperidin-1-yl]-N-[3-(trifluoromethyl)phenyl]pyridine-2-carboxamide (417 mg, 0.997 mmol) in EtOH (10 ml) was treated with guanidine carbonate (719 mg, 3.99 mmol), followed by adding sodium acetate trihydrate (1.09 g, 7.98 mmol). The reaction mixture was stirred at 80° C. for 23 hours and concentrated. The residue was partitioned between EtOAc and water resulting in the formation of a yellow, amorphous solid. The solid was collected, washed with water, EtOAc, MeOH, and dried to give the title compound (59 mg, 14%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1)[CH3:2]
Reactant: Brc1ccc(Br)nc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethylmagnesium bromide in dry ether (3M; 100 ml, 0.30 mol) was added dropwise to a stirred, ice-cooled solution of anhydrous zinc chloride (40.9 g, 0.30 mol) in dry tetrahydrofuran (500 ml) under nitrogen and the resulting solution stirred for a further 1 hour before the sequential addition of tetrakis (triphenylphosphine)palladium(0) (1.0 g, 0.87 mmol) and a solution of 2,5-dibromopyridine (50 g, 0.21 mol) in dry tetrahydrofuran (200 ml). The resulting yellow suspension was stirred at room temperature for 18 hours, quenched by the addition of water (200 ml) and evaporated under reduced pressure. The residue was partitioned between dichloromethane (500 ml) and a suspension of ethylenediaminetetraacetic acid (200 g) in water (1 l). The organic phase was separated, combined with a dichloromethane extract (500 ml) of the aqueous phase, dried (MgSO4) and evaporated under reduced pressure. Distillation under reduced pressure of the residue gave the title compound (28.8 g) as a colourless oil, b.p. 123-124° C./8 kPa (60 mm Hg). δ(CDCl3): 1.30(3H,t), 2.80(2H,q), 7.10(1H,d), 7.70(1H,dd), 8.60(1H,d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:8]([C@H:9]4[C@@:13]([CH2:16][CH2:17]3)([CH2:14][CH3:15])[C:12](=[O:22])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:23][N:24]([CH:26](N(C)C)OC(C)(C)C)[CH3:25]>C(O)C>[CH3:23][N:24]([CH:26]=[C:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:18]([CH2:17][CH2:16][C@:13]2([CH2:14][CH3:15])[C:12]1=[O:22])[C:19]1[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)[CH3:25]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: CCO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC(=CN(C)C)C2=O
Temperature: 160 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
A mixture of 10 g of 3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one and 15 g of bis(dimethylamino)tert.-butoxymethane is stirred for 3 hours at 160° C. After cooling the mixture is combined with 50 ml of ethanol and left at -5° C. for crystallizing purposes. After filtering off and drying, 10.6 g of 16-dimethylaminomethylene-3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one is obtained, m.p. 157°-159° C.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O-:33])=[O:32].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH:10][C:26]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[CH3:9])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](NC(=O)CCCCC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Yield: 49.5 %

Procedure:
24 mg of (1S,2S)-2-(4-biphenylyl)-3-(3,4-dichlorophenyl)-1-methylpropylamine obtained in Example 115, 14 mg of monoethyl adipate and 10 mg of 4-dimethylaminopyridine were dissolved in 2 ml of methylene chloride, and 15 mg of 1-ethyl-3-(3-dimethyaminopropyl)carbodiimide hydrochloride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl ether, then sequentially washed with a 10% citric acid aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel™ C-200, 1 g, hexane/ethyl acetate=2/1), and 28 mg of the obtained amide compound was dissolved in 1 ml of methanol. Then, 0.5 ml of a 2N sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was acidified with 1N hydrochloric acid and then subjected to liquid separation by an addition of ethyl ether and water. The organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off. The residue was treated with a liquid mixture of isopropyl ether and ethyl ether to obtain 16 mg (yield: 49%) of the above-identified compound as white crystalline powder having a melting point of from 123° to 124° C. and
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[Cl:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([Cl:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1Cl
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1Cl
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-5-chloro-3-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 160 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 20 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 50 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:33][CH:32]([N:34]2[CH2:41][C:38]3([CH2:40][CH2:39]3)[NH:37][CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:36][CH2:35][N:34]([CH:32]5[CH2:33][O:30][CH2:31]5)[CH2:41][C:38]54[CH2:39][CH2:40]5)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: C1CN(C2COC2)CC2(CC2)N1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC34CC4)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (183 mg, 0.47 mmol), 7-oxetan-3-yl-4,7-diazaspiro[2.5]octane (90 mg, 0.54 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was allowed to stir at r.t. for 6 h before the addition of sodium triacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture was allowed to stir for 16 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 5% then MeOH:DCM, 1-5%) followed by recrystallisation from Et2O affording 744 (156 mg, 61%). LCMS (method I): RT 2.53 min [M+H]+ 544.2. 1H NMR (DMSO, 400 MHz): δ 8.00-7.99 (1 H, m), 7.65-7.61 (1 H, m), 7.24-7.23 (2 H, m), 4.53 (2 H, t, J=6.46 Hz), 4.42 (2 H, t, J=6.05 Hz), 4.24 (4 H, brd s), 4.07 (2 H, s), 3.77 (4 H, t, J=4.61 Hz), 3.73 (3 H, s), 3.50-3.42 (1 H, m), 3.26 (2 H, q, J=7.44 Hz), 2.85-2.75 (2 H, m), 2.32 (2 H, t, J=4.72 Hz), 2.17 (2 H, brd s), 1.33 (3 H, t, J=7.44 Hz), 0.72-0.65 (2 H, m), 0.52-0.51 (2 H, m)
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C([Li])(C)(C)C.B(OC(C)C)(OC(C)C)OC(C)C.FC(F)(F)C([NH:40][C:41]1[N:42]=[C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][N:44]2[CH:50]=1)=O>C1COCC1.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>[CH3:17][C:13]1[N:12]=[C:11]([C:3]2[C:2]([C:46]3[CH:47]=[CH:48][C:43]4[N:44]([CH:50]=[C:41]([NH2:40])[N:42]=4)[CH:45]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Nc1cn2cc(I)ccc2n1)C(F)(F)F
Reactant: Cc1cccc(-c2nn3ccccc3c2Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccc3nc(N)cn3c2)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Stir 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (500 mg, 1.74 mmol) in THF (20 ml) at −60° C. and add t-butyl lithium (4 ml, 6.94 mmol, 1.7M in pentane). Stir for 1 hour, then add tri-isopropyl borate (1.2 ml, 5.2 mmol) and warm to 0° C. for 1 hour. Quench with 1M HCl (5 ml). Concentrate in vacuo and redissolve in a 2:1 toluene/methanol mixture (30 ml). Adjust to pH 8 with aqueous 2M Na2CO3. Add 100 mg Pd(PPh3)4 and 2,2,2-trifluoro-N-(6-iodo-imidazo[1,2-a]pyridin-2-yl)-acetamide (200 mg, 563 mmol) and heat to 90° C. for 18 hours. Acidify with 1M HCl and extract with ethyl acetate (3×100 ml). Neutralize aqueous layer with 5N NaOH and extract with ethyl acetate (3×100 ml). Concentrate organic layer in vacuo and purify on Silica gel (eluting with 70/30 Hexane/EtOAc). MS ES+ m/e 341.1 (M+1).
Reaction SMILES: [OH-].[Na+].CC(O)CC.[OH:8][C:9]1[C:14]([C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:13][C:12]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][C:10]=1[N:33]1[N+:37]([O-])=[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]2=[N:34]1>ClC1C(=O)C2C(C(=O)C=1Cl)=CC=CC=2.CC(=O)CC>[OH:8][C:9]1[C:14]([C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[CH:13][C:12]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:11][C:10]=1[N:33]1[N:37]=[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]2=[N:34]1
Reactant: CC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(c2ccccc2)c2ccccc2)c1
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(c2ccccc2)c2ccccc2)c1
Temperature: 82 °C
Yield: 96.7 %

Procedure:
To a 500 mL three-necked flask fitted with a mechanical stirrer, 3 g of sodium hydroxide pellets and 50 mL of 2-butanol are charged and heated to 82° C. To this solution, a slurry of 200 mL of 2-butanone, 15 g of the benzotriazole N-oxide prepared in Example 4, and 0.67 g of 2,3-dichloro-1,4-naphthoquinone is added over 40 minutes. The mixture is refluxed at 88° C. for five hours while distilling off 2-butanone. Additional 2-butanol (50 mL) is added to replace what is lost during distillation of the 2-butanone. After cooling the reaction mixture to ambient temperature, 25 g of water and 30 mL of ethyl acetate are added at which time the pH is reduced to 2 with 30% aqueous sulfuric acid. After splitting off the aqueous layer, the solvent is removed by distillation and the crude solid purified by silica gel chromatography using heptane/ethyl acetate as the eluent. After collecting the desired fractions and crystallization from methanol/toluene, 14 g of the title compound is obtained after drying as a light yellow solid melting at 172-173° C. The structure is confirmed by 1H nmr and mass spectroscopy.
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3]1>C(O)C.C1(C)C=CC=CC=1>[Cl:1][CH2:4][CH2:3][CH2:2][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6]
Reactant: Cl
Reactant: COC(=O)C(Cc1ccc(C(=O)C2CC2)cc1)C(=O)OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OC
Temperature: 68 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Bubble hydrogen chloride gas through a solution of [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dimethyl ester (315 mg, 1.1 mmol) in ethanol (3 mL) and toluene (9 mL) for 10 minutes. Heat the solution to 68° C. After 4 hours, cool the solution to room temperature and bubble nitrogen through the solution for 1 hour. Add ethyl acetate and water to the residue. Dry the organic phase over anhydrous magnesium sulfate and concentrate to give the title compound (321 mg, 91%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[C:18]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([CH:27]=1)[NH2:26])([OH:20])=[O:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([CH:27]=1)[NH:26][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)([OH:20])=[O:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(C(=O)O)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 5-carboxy-2-methoxyaniline (38 mg, 0.231 mmol), similar to Example 180 and was isolated as an off white solid (20 mg, 33%). 1H NMR (CDCl3): 9.99 (brs, 1H), 9.660 (d, J=1.5 Hz, 1H), 8.86 (m, 3H), 7.80 (d, 2H), 7.2 (m, 2H), 3.94 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]([NH:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1)=[O:16].[NH2:32][OH:33].[OH-].[Na+].Cl>CO>[OH:33][NH:32][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][CH2:19][CH2:18][NH:17][C:15]([C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][O:4][CH2:3][C:2]([F:31])([F:30])[F:1])=[O:16])=[CH:22][CH:23]=1
Reactant: NO
Reactant: O=C([O-])c1ccc(OCCNC(=O)c2oc3ccccc3c2COCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NO)c1ccc(OCCNC(=O)c2oc3ccccc3c2COCC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
4-{2-[3-(2,2,2-Trifluoroethoxymethyl)benzofuran-2-yl-carbonylamino]-ethoxy}-benzoate was dissolved in MeOH and excess aqueous hydroxylamine solution and NaOH(aq) were added to give pH 10-11. After stirring overnight, the reaction mixture was neutralized reaction to pH 7-8 with aqueous hydrochloric acid. The reaction mixture was concentrated in vacuo to give a solid which was collected and washed with water, then dissolved in acetonitrile and water and purified with prep HPLC to give the title compound (35 mg). 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.95 (t, J=5.6 Hz, 1H), 8.89 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.00 (d, J=9.2 Hz, 2H), 5.25 (s, 2H), 4.18 (m, 4H), 3.67 (m, 2H). EM (calc.): 452.1; MS (ESI) m/e (M+1H)+: 453.0, (M−1H)−: 451.0.