Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][C@H:17]([CH3:20])[CH2:18][OH:19].C(N(CC)CC)C.CO>>[OH:19][CH2:18][C@H:17]([N:16]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=2[N+:13]([O-:15])=[O:14])[C:8]1=[O:12])[CH3:20]
Reactant: C[C@@H](N)CO
Reactant: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A round bottom flask was charged with 6-methyl-5-nitro-1H-isochromen-1-one (260.00 mg, 0.0012673 mol), (2R)-2-aminopropan-1-ol (143 mg, 0.00190 mol), triethylamine (1.6 L, 0.011 mol) and methanol (5 mL, 0.1 mol) and the reaction was heated at 80° C. overnight. The solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as a light yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=3[Cl:23])[NH:14]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:23][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:24][CH3:25])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Yield: 89.6 %

Procedure:
A solution of [2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (160 mg, 0.43) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at 25° C. The solution was heated to reflux for 3 hours. Concentrate the solution in vacuo to afford crude 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (105 mg, 90%) as light yellow oil. The crude product was used directly for next step. MH+ 273.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]=[C:22]=[S:23]>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:22](=[S:23])[NH:21][CH3:20])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CN=C=S
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=S)SC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 0.8 g of methyl isothiocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 5 hours. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with cold ethanol and dried, thereby producing 3.5 g (yield of 94%) of the subject compound. Recrystallization from ethanol yielded white crystals, 112°-114° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21](O)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:51]5[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cc4c(s3)CCCC4O)no2)cc1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C2CCCc3sc(-c4noc(-c5ccc(CC(C)C)cc5)n4)cc32)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using 2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzothiophen-4-ol (92 mg, 0.26 mmol) that was obtained in Example 8 (8f), carbon tetrabromide (0.10 g, 0.31 mmol), triphenylphosphine (81 mg, 0.31 mmol), ethyl 3-azetidinecarboxylate hydrochloride (65 mg, 0.39 mmol), and N,N-diisopropylethylamine (0.14 ml, 0.78 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (44 mg) in a yield of 36% as a colourless oily product.
Reaction SMILES: Br[C:2]1[C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C([Li])CCC.CCCCCC.CN([CH:36]=[O:37])C>C1COCC1>[CH2:16]([C:3]1[C:2]([CH:36]=[O:37])=[CH:11][C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 5.43 g of 3-bromo-2-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 110 ml of THF was cooled to −78° C. with an acetone/dry ice bath and treated dropwise with 14.5 ml of butyllithium 1.6M in hexane (1.5 eq.). The mixture was kept at −78° C. for 1 hour. DMF (2.4 ml) was added at −78° C. The reaction mixture was stirred at −78° C. for 15 min. then was allowed to warm to room temperature for 2 hours. The mixture was quenched with water (100 ml) and the pH was adjusted to 2 with hydrochloric acid 25%. The mixture was extracted with 3 portions of 100 ml of ether. The combined organic extracts were washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (SiO2, hexane then 5% ethyl acetate/hexane) yielding 4.41 g of a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[NH:22][C:28]2=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g), CDI (668 mg), and DBU (1.2 mL) in THF (25 mL) was heated at 60° C. overnight. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=97/3 to 9/1) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (993 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)[CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:28]4([CH3:33])[O:32][CH2:31][CH2:30][O:29]4)[CH:27]=3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC1(c2cncc(Br)c2)OCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(C4(C)OCCO4)c3)ccc21
Temperature: 105 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (109 mg, 0.4 mmol), prepared as described in Example 3a, was added 3-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (CAS#59936-01-5, 107 mg, 0.44 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (182 mg, 0.02 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 105° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-5-[5-(2-methyl-[1,3]-dioxolan-2-yl)-pyridin-3-yl]-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 311.1395 (M+H)+; 1H NMR (400 MHz, CDCl3) δppm 1.73 (s, 3H), 3.28 (s, 3H), 3.62 (s, 2H), 3.82-3.88 (m, 2H), 4.08-4.16 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 7.49-7.58 (m, 2H), 7.97 (s, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[OH:23][C@@H:24]([CH2:37][NH2:38])[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(O)(=O)C>[OH:23][C@@H:24]([CH2:37][NH:38][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:9]=[C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][C:6]3=[O:8])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 18)(0.15 g, 0.47 mmol) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) (0.11 g, 0.47 mmol) were mixed in dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.15 mL). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was poured into a saturated aqueous sodium bicarbonate solution. The precipitate was collected and purified by column chromatography (eluent: methanol/methylene chloride) to give the title compound as a pale yellowish solid(0.16 g, 65%); mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.60-3.00 (m, 5 H), 3.05 (s, 3 H), 3.75-4.15 (m, 5 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d, J=8.7 Hz, 2 H), 7.38 (d, J=8.7 Hz, 2 H), 7.47 (s, 1 H), 10.56 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)2+, 100%); 522.9 (MH+, 75%); HRMS Calcd. for C26H31N6O4S (MH+): 523.2128. Found: 523.2142.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:19][CH2:20]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[CH2:12]([O:19][CH2:20][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCn2cccn2)cc1
Reaction time: 96 h

Procedure:
To a solution of pyrazole (2.0 g, 29 mmol) in DMF (20 mL) is added potassium carbonate (12.4 g, 90 mmol) and benzyloxymethylchloride (4 mL, 32.3 mmol). The reaction is stirred for four days, then poured into water and extracted with EtOAc . The organic layer is washed with 1 N NaOH, dried over MgSO4 and concentrated. The residue is purified by column chromatography using EtOAc as eluent to afford the title compound as a light yellow oil: (M+1)+=189.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[CH3:22][N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1>CCOCC>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH:24]2[CH2:25][CH2:26][CH2:27][N:23]2[CH3:22])=[CH:33][N:32]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CCCC1c1ccc(N)nc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCCC1c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(I)cc32)nc1
Temperature: 125 °C

Procedure:
A mixture of (E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (696 mg, 2.12 mmole), dimethylformamide (15 mL), and 5-(1-methylpyrrolidin-2-yl)pyridin-2-amine (375 mg, 2.12 mmole) is heated at 125° C. for four hours. The reaction mixture is cooled, diluted with ether, filtered, washed with fresh ether and dried to give a yellow solid, 580 mg, (58%), mp 174-206° C. dec; MS (ES+): m/z 475.0 (M+H).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:26](=[O:27])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([CH3:12])([CH3:11])[S:9](=[O:10])[C@H:5]12)=[O:2].[Cl:28]N1C(=O)CCC1=O.ClC(Cl)CCl>>[CH3:11][C:8](=[CH2:12])[CH:7]([N:6]1[C:26](=[O:27])[CH:4]([NH:3][CH:1]=[O:2])[CH:5]1[S:9]([Cl:28])=[O:10])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14]
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC=O)[C@H]2S1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCC(Cl)Cl
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC=O)C1S(=O)Cl

Procedure:
A solution of 1.43 g. of p-nitrobenzyl 6β-formamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 500 mg. of N-chlorosuccinimide in 40 ml. of dry 1,1,2-trichloroethane was refluxed for 90 minutes. The mixture was cooled, washed with water and brine, dried over MgSO4, and the solvent was evaporated. The nmr spectrum indicates conversion to the title compound.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[CH:23]=O.O>O1CCCC1>[CH3:19][C:20]1[CH:21]=[C:22](/[CH:23]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:25]=[CH:26][N:27]=1
Reactant: Cc1cc(C=O)ccn1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(/C=C/C(=O)OC(C)(C)C)ccn1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of tert-butyl diethylphosphonoacetate (12.4 g, 49 mmol) in tetrahydrofuran (30 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 2.3 g, 57 mmol) and tetrahydrofuran (100 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, a solution of 2-methylisonicotinaldehyde (5.0 g, 41 mmol) in tetrahydrofuran (20 ml) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:3, v/v) were collected and concentrated to give the titled compound (4.4 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:19]([Mg]Br)#[CH:20].O>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:10]([CH:11]([OH:12])[C:19]#[CH:20])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: Cc1ccoc1-c1nn2c(Cl)cccc2c1C=O
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2occc2C)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (11.56 g, 44.3 mmol) in tetrahydrofuran (200 mL) at −78° C. was added ethynylmagnesium bromide (133 mL, 0.5 M in tetrahydrofuran, 66.5 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated to a solid residue, 1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (12.29 g, 97%). 1H-NMR (CDCl3): δ 7.97 (d, 1H), 7.48 (d, 1H), 7.16 (t, 1H), 6.96 (d, 1H), 6.42 (d, 1H), 6.18 (m, 1H), 2.78 (m, 1H), 2.6 (d, 1H), 2.46 (s, 3H). MS m/z 287 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][O:11][C:12]2[N:13]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:14]=[C:15]([C:17](=[O:47])[NH:18][C@H:19]([C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=4)[CH2:33][CH2:32]3)=[O:30])[CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH:16]=2)=[CH:8][CH:9]=1)=[O:4]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][O:11][C:12]2[N:13]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:14]=[C:15]([C:17](=[O:47])[NH:18][C@H:19]([C:29]([N:31]3[CH2:32][CH2:33][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:44])[F:45])[CH:38]=4)[CH2:35][CH2:36]3)=[O:30])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:16]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(COc2cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)nn2-c2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2cc(C(=O)N[C@@H](CCC(=O)O)C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)nn2-c2ccccc2)o1

Procedure:
The crude 5-(5-{(S)-3-tert-Butoxycarbonyl-1-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-propylcarbamoyl}-2-phenyl-2H-pyrazol-3-yloxymethyl)-furan-2-carboxylic acid methyl ester was dissolved in a mixture of 2 ml of DCM and 1 ml of TFA. After 2 h at RT all volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:33][CH:34](Br)[CH3:35]>CN(C=O)C>[Br:33][CH2:34][CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:26]=[CH:25][C:16]4[C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(O)ccc34)ccc12
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of methyl 6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylate 121-D (2.4 g, 7.2 mmol) in DMF (20 ml) was added K2CO3 (5 g, 35.8 mmol) a dibromoethane (2.7 g, 14.3 mmol). The reaction mixture was stirred at room temperature overnight. Column chromatography gave methyl 6-{[7-(2-bromoethoxy)quinolin-4-yl]oxy}-2-methyl-1-benzofuran-3-carboxylate 121-E (1.5 g). A solution of compound 121-E (750 mg) and pyrrolidine (351 mg) in DMF (3 ml) was heated to 60° C. for 45 min. The reaction mixture was extracted with EtOAc. Methyl 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}benzofuran-3-carboxylate 121-F (110 mg) was purified by silica gel chromatography using 5-10% MeOH/CH2Cl2. Compound 121-F (110 mg) was treated with 20% NaOH (1 ml) in MeOH (1 ml) overnight. The reaction mixture was acidified with AcOH and extracted with EtOAc. The residue was purified by silica gel chromatography using 0-10% MeOH in CH2Cl2 to give 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxylic acid 121-G (100 mg).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O>[CH2:23]([O:22][C:20]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1cc(C)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To the suspension of crude 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid (250 mg, 1.126 mmol) in 2 ml H2O was added NaOH (90 mg, 2.25 mmol) in 6 ml H2O, followed by ethyl chloroformate (134.4 mg, 1.24 mmol) dropwise. The reaction mixture was stirred at room temperature for 20 min and acidified by 1N HCl to pH=5.0. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as an off-white powder (120.5 mg, yield: 34%, two steps). 1H NMR (400 MHz, DMSO) δ 12.37-12.36 (t, J=3.6 Hz, 1H), 9.29 (s, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 5.53-5.50 (m, 1H), 4.28-4.22 (m, 2H), 3.10-3.05 (m, 1H), 2.31 (s, 3H), 2.11-2.17 (m, 1H), 1.32-1.27 (m, 3H); MS (ESI) m/z=285 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[N:13]1[C:21]2[C:16](=[CH:17][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Clc1ccc2ccccc2n1
Product: c1ccc2nc(-c3ccc4[nH]ccc4c3)ccc2c1

Procedure:
2-(1H-indol-5-yl)quinoline was prepared using general procedure A from 2-chloroquinoline (32 mg, 0.2 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (51 mg, 0.2 mmol). The product was obtained as off-white solid (22 mg, 42%). MS (ESI): 245 (M+H+).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccccn1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.12 (s, 2H), 6.13 (t, 1H), 6.60 (d, 1H), 7.10 (br s, 2H), 7.22–7.41 (m, 9H); HPLC-MS: m/z=335.2 (M+1); Rt=2.97 min.