Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22](O)=[O:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:25][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:20])([CH3:21])[C:22]([C:30]3([C:29]([OH:28])=[O:35])[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:23])=[CH:14][CH:13]=2)=[O:10])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)C3(C(=O)O)CCCN3)cc2)c1

Procedure:
Using RSR13 acid (3.08 g, 9.0 mmol), proline methyl ester hydrochloride (1.5 g, 9.0 mmol) and 1-hydroxybenzotriazole hydrate (1.34 g, 9.9 mmol), N-methylmorpholine (1.37 g, 13.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.08 g, 10.8 mmol) in dimethylformamide (40 mL), the product was prepared in 3.9 g yield (99%).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:41])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](O)[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].[CH:42](=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[O:50]1CCCC1>>[CH3:9][O:10][C:11](=[O:41])/[C:12](/[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:50])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33])=[CH:42]/[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=Cc1ccccc1
Reactant: C1CCOC1
Reactant: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Product: COC(=O)/C(=C/c1ccccc1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
1,1,3,3-Tetramethylguanidine (20 μL, 0.16 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 132; 33 mg, 0.066 mmol) in tetrahydrofuran (1 mL) at room temperature. After 5 min, benzaldehyde (7 μL, 0.068 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by chromatography over silica gel. The column was eluted sequentially with chloroform, chloroform/methanol/water/acetic acid (600:30:10:6), chloroform/methanol/water/acetic acid (300:30:10:6) and chloroform/methanol/water/acetic acid (150:30:10:6). The appropriate fractions were combined and lyophilized to fuirnish (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-phenylpropenoic acid methyl ester (23 mg, 73% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:12])=O.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:2]=[C:1]([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: N#CCc1ccccc1
Product: N#CCc1cccc(C(Cl)c2ccccc2)c1
Reaction time: 1 h

Procedure:
9 g of 3-hydroxyphenylmethyl)phenylacetonitrile are dissolved in 150 ml of toluene and treated with stirring with 5.8 ml (80 mmol) of thionyl chloride. The reaction mixture is heated to reflux temperature and stirred for one hour. In the course of this, approximately 50 ml of toluene are removed in a water separator. The solvent is removed and 3-(chlorophenyl-methyl)phenylacetonitrile is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:26]>C(Cl)Cl>[F:26][C:10](=[O:11])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccsc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To (R)-2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)acetic acid in CH2Cl2 cooled to −10° C. was added pyridine and cyanuric fluoride. The solution was stirred for 1 hour at −10° C., quenched with ice and extracted with CH2Cl2 and ice cold water, dried (Na2SO4), filtered and evaporated to give (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[NH:9][C:10](=[O:14])[C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CS(C)=O>[CH2:22]([O:12][C:11](=[O:13])[C:10]([NH:9][C:3]1[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCBr
Reactant: O=C(O)C(=O)Nc1cccccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCOC(=O)C(=O)Nc1cccccc1=O
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A solution of [(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid (1.54 g, described in Example 30) and potassium carbonate (0.82 g) in dimethylsulfoxide (8 ml) is stirred at room temperature for 15 minutes. A solution of 5-bromopentane (1.52 ml) in dimethylsulfoxide (8 ml) is added and the resulting mixture is stirred at 80° C. for 40 minutes. The mixture is cooled to room temperature and poured over ice. The mixture is stirred for ten minutes and the precipitate is collected by filtration. The precipitate is dissolved in ether, treated with charcoal and crystallized by the addition of hexane to give the title compound, mp 87°-89° C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7](C(O)=O)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:13]([Cl:16])CCl.C1C=CC2N([OH:26])N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([Cl:16])(=[O:26])[CH2:2][CH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[CH:11][CH:12]=1
Reactant: ClCCCl
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
A mixture of 2-amino-2-methyl-t-propanol (4 ml, 42 mmol), CH2Cl2 (200 mL), 4-acetyl benzoic acid (1, 6.9 g, 42 mmol), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl, 12.1 g. 63 mmol), HOBT (N-hydroxybenzotriazole H2O, 6.4 g, 42 mmol), and Hunig's base (diisopropylethylamine, 22 mL, 126 mmol) was stirred at room temperature for 18 hours. Upon completion (TLC, LC/MS) the reaction mixture was concentrated, and the resulting residue was diluted with EtOAc (50 mL) and washed with NaHCO3 (2×40 mL) and brine (40 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated. The crude material was purified by flash column chromatography (4:1:1 hexanes:EtOAc:CH2Cl2:1:1:1 hexanes:EtOAc:CH2Cl2; EtOAc:CH2Cl2) to remove bisacylated material. Alcohol 2 was obtained in 54% yield (5.36 g). Tetrapropylammonium perruthenate (TPAP, 387 mg, 1.1 mmol) was added portion-wise to a solution of 2 (5.36 g, 22.8 mmol), CH2Cl2 (46 mL, 2 mL/mmol). 4-methyl-morpholine N-oxide (4 g. 34.2 mmol), and molecular sieves, 4 Å activated powder (11.4 g, 500 mg/mmol) at 0° C. under N2. The reaction was allowed to warm to r.t. after 15 minutes. After 1 hour the reaction was complete (TLC) and was filtered through silica, which was eluted with EtOAc (100 mL), and the filtrate was concentrated. This yielded 4.4 g of light pink solid (3). The material was recrystallized: 1:1 Flexanes:EtOAc (5 mL), CH2Cl2 (20 mL), and MeOH (10 mL) were added portion-wise with heating and sonication. This was brought to a boil after which hexane (100 mL) was added while cooling. Crystals immediately began to precipitate as the solution was cooled. The mixture was filtered and the crystals were washed with hexane (10 mL), affording 2.46 g (46%) of 3 as off-white fluffy crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]([CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].CCN(CC)CC>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]([CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[CH2:20][CH2:21][N:22]1[C:23](=[O:32])[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]1=[O:31])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C1c2ccccc2C(=O)N1CCNCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution chloroacetyl chloride (1.2 mL, 15.2 mmol) in DCM (65 mL) at 0° C. was added dropwise a solution of 2,2′-(iminodi-2,1-ethanediyl)bis(1H-isoindole-1,3(2H)-dione) (5 g, 13.7 mmol) [prepared according to Anelli, P. L.; et. al. J. Org. Chem. 1984 49, 4197.] and Et3N (2.5 mL, 17.9 mmol) in DCM (65 mL). After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 5% MeOH in DCM (NH4OH)) yielding the title compound (5.9 g, 98%) as a yellow foam: LCMS (ES) m/e 440 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH3:2].[CH3:15][O:16][C:17]([C:19]1[CH:36]=[CH:35][CH:34]=[CH:33][C:20]=1[CH2:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)=[O:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=1)[C:30](=[O:31])[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([S:22][CH2:21][C:20]2[CH:33]=[CH:34][CH:35]=[CH:36][C:19]=2[C:17]([O:16][CH3:15])=[O:18])=[CH:28][CH:27]=1)[CH3:2]
Reactant: CCNCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1CSc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Ethyl[4-(trifluoromethyl)benzyl]amine (284 mg, 1.40 mmol) and (4-{[2-(methoxycarbonyl)benzyl]thio}phenyl)acetic acid (443 mg, 1.40 mmol, See Example 2 b) were mixed in DMF (15 ml). TBTU (472 mg, 1.47 mmol) was added and then DIPEA (190 mg, 1.47 mmol) was added. The mixture was stirred at room temperature for 1 hour. EtOAc (20 ml) was added. The mixture was then washed with sodium hydrogencarbonate aqueous solution (sat.), 1% HCl, water (×2) and brine, dried with magnesium sulphate and evaporated. The title compound (663 mg) was left, yield 94%.
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH3:17])[C:11]=2[Cl:15])[CH:6]=1)=[O:4].[ClH:19].Cl.[CH2:21]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:15].[ClH:19].[CH2:21]([N:30]1[CH2:35][CH2:34][N:33]([CH:2]([C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH3:17])[C:11]=3[Cl:15])[CH:6]=2)=[O:4])[CH3:18])[CH2:32][CH2:31]1)[C:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:23]
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(CC(=O)c4ccccc4)CC3)ccc2c1Cl
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A mixture of 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (3.8 mmol), N-phenacyl piperazine dihydrochloride (0.89 g, 3.2 mmol) and K2CO3 (1.56 g, 11.2 mmol) in 30 ml of DMF are stirred at 50° C. for 10 h, then was treated according to the general preparation 2 to give compound(IV-19), 1.09 g (61%), M+ 451.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:29]=[C:28](C(Cl)(Cl)Cl)[O:27][N:26]=3)[CH:23]=2)[N:18]([S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:17]=1>C1COCC1>[I:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:29]=[C:28]([NH:4][C:1](=[O:3])[CH3:2])[O:27][N:26]=3)[CH:23]=2)[N:18]([S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[CH:17]=1
Reactant: CC(N)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)no1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a solution of acetamide (91.5 mg, 1.54 mmol in dry THF (10 mL) was added 1.0M lithium bis(trimethylsilyl)amide (LHMDS) (1.2 mL, 1.54 mmol) at −78° C. and the mixture was stirred for 45 min at −78° C. and 10 min at −10° C. Again the reaction was cooled back to −78° C. To the mixture at −78° C. was added 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (600 mg, 1.03 mmol) and the reaction was stirred at RT for 12 h. The solvent was then removed in vacuo and the residue was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with basic alumina column chromatography (eluent: 35% EtOAc in petroleum ether) to give N-(3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)acetamide (300 mg, 55.5%) as an off brown solid. MS (ESI, pos. ion) m/z: 523.0 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 12.22 (brs, 1H), 8.22 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.02-7.90 (m, 4H), 7.44 (d, J=8.0 Hz, 2H), 2.33 (m, 3H), 2.19 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C[O-].[Na+].Br[C@H:11]([CH2:15][CH3:16])[C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1.CO>[CH3:16][CH2:15][C@H:11]([N:1]1[C:2](=[O:6])[CH2:3][CH2:4][CH2:5]1)[C:12]([NH2:14])=[O:13]
Reactant: CC[C@@H](Br)C(N)=O
Reactant: O=C1CCCN1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine-2-one (85 mg, 1 mmol) in 6 ml of toluene is added sodium methoxide (0. 19 ml of a 30% solution in MeOH, 1 mmol, 1 equiv.). The mixture is heated to 40° C. and concentrated to dryness under reduced pressure. The solid residue is taken up in 3 ml of tetrahydrofuran, cooled to 0° C. and (R)-2-bromobutyramide (IId) (optical purity >98%) (166 mg, 1 mmol, 1 equiv.) is added. The mixture is stirred for 1 h at 0° C. and further 16 h at room temperature. The mixture is then concentrated to dryness under reduce pressure.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[Cl:23][CH2:24][C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)=[O:26].CC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:23][CH2:24][C@H:25]([C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)[OH:26]
Reactant: O=C(CCl)C1CCc2cc(F)ccc2O1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O[C@H](CCl)[C@H]1CCc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of (−)-B-chlorodiisopinocampheylborane [(−)-DIP-Chloride™] (2.10 g, 6.55 mmoles) in toluene (7 ml) is cooled to 0° C. under nitrogen atmosphere. On the magnetically stirred solution is added in 3 hours a solution of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanone (1.0 g, 4.373 mmoles) in toluene (3 ml). At the end of the addition, the mixture is stirred at 0° C. for further 20 hours. On the reaction mixture is added acetone (0.5 g), followed by a 10% w/w (5 ml) aqueous solution of sodium carbonate, and then demi water (5 ml). The reactive mixture is heated to 20° C. at the end of the additions and transferred in a separator funnel. The mixture is diluted with demi water (5 ml) and toluene (5 ml) and phases are separated. The organic layer is then washed with additional demi water (15 ml) and concentrated and anhydrified under vacuum to obtain crude (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol (98% de via GC). The product is purified by chromatography on silica using a toluene:ethyl acetate 9.5:0.5 eluting mixture. After separation, the product (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol is isolated as a colorless oil (0.31 g, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:28].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[NH:28][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][CH:9]=1)=[O:13]
Reactant: Nc1cccc(F)c1F
Reactant: O=C(O)c1c[nH]c2ncc(Br)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (950 mg, 3.94 mmol) in DCM (20 mL) and DMF (0.1 mL) was added oxalyl chloride (600 mg, 4.72 mmol) slowly. The mixture was stirred at RT for 1 h. To this suspension was then added a solution of 2,3-difluorophenyl amine (610 mg, 4.72 mmol) and triethylamine (800 mg, 7.91 mmol) in DCM (5 mL). The reaction was kept at RT for another 2 h. The solvent was then evaporated, the residue was washed water, and dried for direct use. MS (ES+): m/e=352 (M+H); LC: 3.5 min.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(OC([NH:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][N:23]=1)=S)=O)C>C(O)C>[Br:28][C:26]1[CH:25]=[CH:24][N:23]2[N:6]=[C:19]([NH2:18])[N:21]=[C:22]2[CH:27]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cc(Br)ccn1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1nc2cc(Br)ccn2n1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A mixture of hydroxylamine hydrochloride (20.0 g, 288 mmol) and N-ethyldiisopropylamine (30.1 ml, 173 mmol) in ethanol (367 ml) is stirred for a few minutes at room temperature and the mixture is added to 1-ethoxycarbonyl-3-(4-bromo-pyridin-2-yl)-thiourea (17.5 g, 57.5 mmol). The resulting mixture is refluxed for 1 day. The solvent is evaporated and 100 ml water is added to the residue. The suspension is stirred for 10 minutes, the solid is collected by filtration, washed with water and dried affording 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (10.71 g, 87.4%) as a light yellow solid. Mp.: 190-2° C. MS: m/z=213.0, 215.0 (M+H+).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[C:6]1[N:10]([C@@H:11]2[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1>C(Cl)Cl>[Cl:23][C:21]1[C:20]([Cl:24])=[CH:19][C:9]2[N:10]([C@@H:11]3[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[N:7][C:8]=2[CH:22]=1
Reactant: NC1CC1
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: C[C@H]1O[C@@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Yield: 50.8 %

Procedure:
Following General Procedure V, cyclopropyl amine (Aldrich, 5 mL, 71.28 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (250 mg, 0.65 mmol) reacted for 92 h. Purification on a silica gel column with 1:15 methanol:CH2Cl2 gave the title compound (120 mg, 0.33 mmol, 52%); MS (El): m/z (rel. intensity) 358 (0.08, M+); 1H NMR (DMSO-d6) δ7.48 (s, 1H, Ar—H), 7.35 (s, 1H, Ar—H), 7.13 (d, 1H, NH, J=2.0 Hz), 5.61 (d,1H, CH, J=6.6 Hz), 5.25 (m, 2H, 2 overlapping OH), 4.36 (m,1H, CH), 3.88 (m, 1H, CH), 3.79 (m, 1H, CH), 2.76 (m, 1H, CH), 1.36 (d, 3H, CH3, J=6.3 Hz), 0.70 (m, 2H, CH2), 0.53 (m, 2H, CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:36])[C:22]1=[O:37].C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:36][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:28]=1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[C:22]1=[O:37]
Reactant: COc1cccc(F)c1CN1CCCC(N)C1=O
Reactant: Cc1cc(-c2n[nH]c3ccc(C(=O)O)cc23)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CN1CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1=O
Temperature: 23 °C
Reaction time: 16 h

Procedure:
3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxylic acid (50 mg, 0.154 mmol), 3-amino-1-(2-fluoro-6-methoxybenzyl)piperidin-2-one (148 mg, 0.308 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44.4 mg, 0.231 mmol) and hydroxybenzo-triazole (23.62 mg, 0.154 mmol) were combined in a sealed vial. DMF (0.8 ml) and N,N-diisopropylethylamine (0.269 ml, 1.542 mmol) were added and the reaction mixture stirred for 16 hours at a temperature of 23° C. The residue was then purified by preparative HPLC Normal phase, eluting with dichloromethane/MeOH (0-20%) to give N-(1-(2-fluoro-6-methoxybenzyl)-2-oxopiperidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide as a colorless solid. MS ESI calc'd. for C27H26FN5O3 [M+H]+488, found 488. 1H NMR (600 MHz, CDCl3) δ 10.80-10.49 (m, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.53 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=4.9 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.46 (s, 1H), 6.75-6.65 (m, 3H), 5.00 (d, J=14.1 Hz, 1H), 4.51 (d, J=14.2 Hz, 1H), 4.49-4.42 (m, 1H), 3.84 (s, 3H), 3.35-3.21 (m, 2H), 2.65 (s, 3H), 1.95-1.82 (m, 2H), 1.65-1.55 (s, 2H).