Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14]1([C:19]2([CH3:39])[CH2:27][C:26]3[C:21](=[C:22]([Cl:37])[C:23]([Cl:36])=[C:24](OS(C(F)(F)F)(=O)=O)[CH:25]=3)[C:20]2=[O:38])[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>CN(C)C=O.C(Cl)Cl>[CH:14]1([C:19]2([CH3:39])[CH2:27][C:26]3[C:21](=[C:22]([Cl:37])[C:23]([Cl:36])=[C:24]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:25]=3)[C:20]2=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of sodium hydride (2.88 g., 120 mmole) in dry dimethylformamide (20 ml), under dry nitrogen and cooled in an ice-bath is added dropwise, a solution of diethyl malonate (19.2 g., 120 mmole) in dimethylformamide (30 ml). The mixture is stirred for one hour in the ice-bath and another hour at room temperature, then is cooled in the ice-bath again and 2-cyclopentyl-6,7-dichloro-2-methyl-5-trifluoromethylsulfonyloxy-1-indanone (12.93 g., 30 mmole) in dimethylformamide (25 ml) is added dropwise over 1-1/2 hours. The mixture is stirred at room temperature overnight and then poured into a mixture of ice-water (750 ml), methylene chloride (200 ml) and 6 N hydrochloric acid (20 ml). The methylene chloride layer is separated and the aqueous layer extracted with methylene chloride (50 ml). The combined extract is washed with water (500 ml), dried (MgSO4) and evaporated under vacuum, finally at 70°/0.05 Torr, to give an oil (18.28 g.). This is purified by chromatography on Merck silica gel (1.04 Kg) using 1,1,1-trichloroethane as the solvent. The product is accompanied by some diethyl malonate which is removed at 125°/0.05 Torr to give a viscous oil, 10.25 g. (77%),
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:59]1[CH:64]=[CH:63][C:62]([CH2:65][NH2:66])=[CH:61][CH:60]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([NH:66][CH2:65][C:62]3[CH:63]=[CH:64][N:59]=[CH:60][CH:61]=3)=[O:26])[CH2:22][CH2:23]2)=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccncc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (97 mg, 0.504 mmol), and 1-Hydroxybenzotriazole (68 mg, 0.504 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (88 μL, 0.504 mmol) and pyridin-4-ylmethanamine (0.051 ml, 0.504 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified in silica gel using the gradient 60% ethyl acetate:hexanes to 100% ethyl acetate. After purification, pure white solid was obtained. Yield: 79.5 mg (White solid)
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH3:13])[O:9]2)[CH2:5][O:4]1.Br[CH2:16]C1OCC(O)C(O)CO1.CC(C=C)=O>>[Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH:13]=[CH2:16])[O:9]2)[CH2:5][O:4]1
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Reactant: OC1COC(CBr)OCC1O
Agent: C=CC(C)=O
Product: C=CC1(C)OC2COC(CBr)OCC2O1
Yield: 54 %

Procedure:
4-Bromomethyl-9-methyl-9-vinyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane was prepared in a similar way to 4-bromomethyl-9,9-dimethyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane starting from 220 mmol (50 g) of 2-bromomethyl-5,6-dihydroxy-1,3-dioxepane and from 1.36 mol (95.5 g) of methylvinyl ketone, fractional distillation giving 33.2 g of 4-bromomethyl-9-methyl-9-vinyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane (54% yield) with a boiling point from 94° to 101° C. (0.2 mbar).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7](N)([NH2:10])(=[O:9])=[O:8]>COCCOC>[N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1COCCN1
Solvent: COCCOC
Product: NS(=O)(=O)N1CCOCC1
Temperature: 100 °C
Yield: 17 %

Procedure:
To a solution of morpholine (1 eq) in DME (0.3 M), 5 eq of sulfamide were added and the solution was heated at 100° C. overnight. The volatiles were removed in vacuo, the residue taken up in EtOAc and the organic phase washed with H2O and then brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (17%); MS (ES+) m/z 167 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C(Cl)=O.CN(C)C=O.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of 3,5-difluorobenzoic acid (10 gm, 63.2 mmol) in dichloromethane (100 mL) was added oxalyl chloride (11.96 gm, 94.9 mmol) at 0° C. followed by addition of dimethylformamide (2 mL). The resulting reaction mixture was stirred for about 3 hours at room temperature. Methanol (100 mL) was added to the reaction mass and stirring was continued further for 20-30 minutes. Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford colorless methyl 3,5-difluorobenzoate (10 gm, 91.91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[C:6]([CH3:17])[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.ClC1C([N+]([O-])=O)=CC=C(C)C=1C(NC1C=CC=CC=1)=O.O>CCO>[NH2:18][C:5]1[C:6]([CH3:17])=[C:7]([C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: Cc1c([N+](=O)[O-])ccc(Cl)c1C(=O)Nc1ccccc1
Agent: Cc1ccc([N+](=O)[O-])c(Cl)c1C(=O)Nc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1c(N)ccc(Cl)c1C(=O)Nc1ccccc1

Procedure:
To a stirred mixture of 6-chloro-2-methyl-3-nitro-N-phenylbenzamide 9 and 2-chloro-6-methyl-3-nitro-N-phenylbenzamide I-9′ (33.6.8 g, 116 mmol, 1.0 eq) in EtOH (400 mL), SnCl22.H2O (105 g, 464 mmol, 4.0 eq) was added and the resulting mixture was stirred at reflux for 3 h. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was poured into water (500 mL) and the mixture was extracted with ethyl acetate (5×500 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% ethyl acetate-petroleum ether) to afford the regio-isomer, 3-amino-6-chloro-2-methyl-N-phenylbenzamide I-10. The remaining mixture of 3-amino-6-chloro-2-methyl-N-phenylbenzamide I-10 and 5-amino-6-chloro-2-methyl-N-phenylbenzamide I-10′ was collected separately. Compound I-10′ was obtained by further column chromatography purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[NH:14][CH:15]=[C:16]2[C:21](=[O:22])OC(C)(C)OC2=O)[CH2:3][CH2:2]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:30][O:29][C:28]1[CH:27]=[C:26]2[C:13](=[CH:12][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[NH:14][CH:15]=[CH:16][C:21]2=[O:22]
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCCCN1CCOCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCOCC1
Yield: 39.2 %

Procedure:
A solution of 5-((3-(3-morpholinopropoxy)-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (700 mg, 1.66 mmol) in phenyl ether (5 ml) was heated at reflux for 2 minutes. After cooling, the residue was triturated with ether and acetone. The solid was collected by filtration, washed with acetone followed by ether and dried under vacuum to give 6-methoxy-7-(3-morpholinopropoxy)-1,4-dihydroquinolin-4-one (207 mg, 41%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)[C:21]([CH2:36][CH3:37])=[CH:22][C:23]1[CH:35]=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C:25]=2[CH:24]=1)C.Cl>C1COCC1.C(OCC)(=O)C.CO>[CH2:36]([C:21](=[CH:22][C:23]1[CH:35]=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C:25]=2[CH:24]=1)[CH2:20][OH:19])[CH3:37]
Reactant: CCOC(=O)C(=Cc1ccc2c(c1)Cc1ccccc1-2)CC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=Cc1ccc2c(c1)Cc1ccccc1-2)CO
Reaction time: 0.75 h
Yield: 98 %

Procedure:
Under an atmosphere of nitrogen a 1M solution of DIBAL-H in toluene (10.5 ml, 10.5 mmol) was added dropwise at −70° C. over 20 min. to a stirred solution of 2-ethyl-3-(9H-fluoren-2-yl)-acrylic acid ethyl ester (1.54 g, 5.3 mmol) in dry THF (75 ml) and the mixture stirred for 45 min. Methanol (2 ml) was added, followed by 1N HCl and ethyl acetate. The aqueous phase was separated and further extracted with ethyl acetate. The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo yielding 1.3 g of 2-ethyl-3-(9H-fluoren-2-yl)-prop-2-en-1-ol.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C@@H:6]([C:29]#[N:30])[NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9].[BH4-].[Na+]>CO.C(Cl)Cl>[C:29]([CH:6]([NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9])[CH2:5][CH2:4][CH2:3][OH:2])#[N:30]
Reactant: COC(=O)CC[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CCCO)cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.5 %

Procedure:
To a solution of (S)-4-cyano-4-({(1R,2S)2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid methyl ester (obtained from compound 3-8, 209 mg, 0.492 mmol), in 15 mL of MeOH and 15 mL of CH2Cl2, was added sodium borohydride (100 mg, 2.64 mmol). The reaction mixture was stirred at ambient temperature for 24 hours, concentrated, and purified by column chromatography (3:97, MeOH/CH2Cl2) to give 83 mg (43%) of 1-methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-(1-cyano-4-hydroxy-butylcarbamoyl)-cyclohexyl]-amide as an amorphous solid. MS: 397 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([Cl:34])[CH:33]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:30]1[CH:29]=[C:28]([Cl:27])[CH:33]=[C:32]([Cl:34])[CH:31]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
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: CCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cc(Cl)cc(Cl)c1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) wAas added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3,5-dichlorophenylboronic acid (0.24 g) in ethanol (1 ml). The mixture was heated under reflux for 3 hours, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:hexane (1:2). Combination and evaporation of suitable fractions followed by recrystallisation from ether/hexane gave the title compound as a white solid, m.p. 228-30° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([OH:16])[C@@H:9]([OH:17])[CH2:8][O:7]1)=O)C>CN(C=O)C>[C:13]([O:12][C@@H:11]1[C@H:10]2[O:16][C:4](=[O:3])[C@@H:6]1[O:7][CH2:8][C@@H:9]2[OH:17])(=[O:15])[CH3:14]
Reactant: CCOC(=O)[C@@H]1OC[C@H](O)[C@H](O)[C@H]1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@H]2OC(=O)[C@@H]1OC[C@@H]2O
Yield: 12 %

Procedure:
(2R,3R,4S,5S)-3-acetoxy-4,5-dihydroxy-tetrahydropyran-2-carboxylic acid ethyl ester (300 mg, 1.2 mmol) was dissolved in DMF (5 ml) and the solution was subjected to microwave irradiation at 150° C. for 4H. After cooling, the solvent was removed in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane to give (−)-(1R,4S,5S,8R)-8-acetoxy-4-hydroxy-2,6-dioxa-bicyclo[3.2.1]octan-7-one.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:12]=1[C:25]1[C:26]([CH3:31])=[N:27][O:28][C:29]=1[CH3:30])(C(C)(C)C)(C)C.B(F)(F)F.S(C)C>C(Cl)Cl>[CH3:31][C:26]1[C:25]([C:12]2[C:13]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)=[N:14][N:15]([CH3:16])[C:11]=2[CH2:10][CH2:9][OH:8])=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: COc1ccc(-c2nn(C)c(CCO[Si](C)(C)C(C)(C)C)c2-c2c(C)noc2C)cc1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1CCO
Yield: 96.8 %

Procedure:
To a solution of 4-(5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylisoxazole (41.5 mg, 0.094 mmol) in DCM (3 ml) was added BF3.Me2S (1 M solution in DCM, 0.5 mL, 0.5 mmol) and the mixture was stirred at room temperature over night. The DCM layer was discarded and the precipitate was washed with another 0.2 ml DCM. The raw product was purified on silica gel to give 4-(4-(3,5-dimethylisoxazol-4-yl)-5-(2-hydroxyethyl)-1-methyl-1H-pyrazol-3-yl)phenol (28.6 mg, 0.091 mmol, 97%) ES/MS m/z: 314.22 (M+H), 312.31 (M−H); 1H NMR (MeOD, 500 MHz): 7.15 (m, 2H), 6.70 (m, 2H), 3.88 (s, 3H), 3.54 (t, 2H, J=6.8 Hz), 2.70 (t, 2H, J=6.8 Hz), 2.16 (s, 3H) and 1.87 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][F:15])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N+:12]=[N-:13])=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[Cl:23][CH:24]([Cl:30])[C:25](OCC)=[O:26]>CO>[N:11]([C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@H:2]([NH:1][C:25](=[O:26])[CH:24]([Cl:30])[Cl:23])[CH2:14][F:15])=[CH:10][CH:9]=1)=[N+:12]=[N-:13]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](N)CF)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To the stirred solution of (1R,2R)-2-Amino-1-(4-azido-phenyl)-3-fluoro-propan-1-ol (600 mg, 2.83 mmol) in methanol (6.5 mL) is added triethyl amine (0.57 g, 5.64 mmol) and ethyl dichloroacetate (0.88 g, 5.60 mmol). Resulting reaction mixture is stirred under nitrogen at room temperature for 16 hours. Solvent is evaporated in vacuo to get the crude material purified by column chromatography eluting in 0.5% methanol in dichloromethane to afford the title compound (150 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 4.40-4.41 (m, 1H), 4.24-4.26 (m, 0.5H), 4.36-4.38 (m, 0.5H), 4.52-4.54 (m, 0.5H), 4.64-4.66 (m, 0.5H), 4.84 (t, 1H, J=3.64 Hz), 5.96 (d, 1H, J=4.24 Hz), 6.49 (s, 1H), 7.05 (d, 2H, J=8.48 Hz), 7.38 (d, 2H, J=8.44 Hz), 8.58 (d, 1H, J=8.98 Hz). LC-Ms (m/z): [M−H]=318.8.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([OH:17])[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1.[CH3:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[N:25]1[C:29]2=[N:30][CH:31]=[N:32][C:33](OC3C=CC=CC=3)=[C:28]2[CH:27]=[N:26]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:18])[C@@H:12]([O:17][C:33]2[N:32]=[CH:31][N:30]=[C:29]3[N:25]([C:21]4[N:20]([CH3:19])[CH:24]=[CH:23][N:22]=4)[N:26]=[CH:27][C:28]=23)[CH2:13][O:14][CH2:15][CH3:16])=[N:8][CH:9]=1
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1
Reactant: Cn1ccnc1-n1ncc2c(Oc3ccccc3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1nccn1C)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil) (29.2 mg, 0.73 mmol) was added to (S)—N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (149 mg, 0.61 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-(1-methyl-1H-imidazol-2-yl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AV1) (196 mg, 0.67 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with 1M citric (2 mL), extracted with EtOAc, the organic layer was washed with water ×2 and brine, dried (MgSO4), filtered and evaporated to afford orange oil. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents to afford the product (111 mg, 41.2%, 95% ee). 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t), 3.56-3.72 (5H, m), 4.03-4.15 (2H, m), 6.05 (1H, t), 7.02 (1H, d), 7.17 (1H, d), 7.65-7.71 (1H, m), 8.19-8.26 (2H, m), 8.43 (1H, s), 8.65 (1H, s), 8.78 (1H, s); m/z (ES+) (M+H)+=443.40; HPLC tR=1.92 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][CH2:16][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1cc(C=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Indole-3-carbaldehyde (1 eq.) was dissolved in DMF (0.15 M). Sodium hydride was added (1.3 eq.) and the resulting solution was stirred at RT for 20 min. Tetrabutylammonium iodide (1 eq.) and tert-butyl 3-bromopropylcarbamate (2 eq.) were then added and the reaction solution was allowed to stir at RT for 18 h. The reaction mixture was subsequently quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a light pink solid.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([NH:20][O:21]C3CCCCO3)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7].[ClH:29]>CO>[ClH:29].[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([NH:20][OH:21])=[O:19])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: CN(C)CCCC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Agent: Cl
Solvent: CO
Product: CN(C)CCCC(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 35 mg 2-[4-(dimethylamino)butanoyl]-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 1 ml methanol and 1.5 ml 0.1N, aqueous HCl is stirred for 3 h at ambient temperature. Subsequently, the mixture is lyophilized. 40 mg of a colorless solid are obtained. MH+=306.1
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:11]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)[CH:17]=2)[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:11]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)c1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
3-(1H-Benzo[d]imidazol-2-yl)-5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (30 mg, 0.0755 mmol), 3-(methylsulfonyl)phenyl boronic acid (15 mg, 0.075 mmol) and triphenylphosphine (2 mg, 0.007 mmol) were dissolved in a mixture of THF (6 mL), and 1M sodium carbonate (8 mg, 0.075 mmol) and palladium (II) acetate (2 mg, 0.009 mmol) were added. The solution was heated overnight at reflux. After cooling to room temperature, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (20 mL), and washed with water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound (8 mg) as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.93 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 7.97 (d, 1H, J=8.0 Hz), 7.86 (m, 2H), 7.61 (t, 1H, J=7.6 Hz), 7.45 (m, 1H), 7.24 (m, 4H), 5.77 (dd, 1H, J=2.4 and 9.6 Hz), 4.04 (m, 1H), 3.75 (m, 1H), 3.07 (s, 3H), 2.59 (m, 1H), 2.12 (m, 2H), 1.76 (m, 3H); ESI-MS [M+H]+: 473.3.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCOC(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Product: c1ccc(C(OCCCCCN2CCNCC2)c2ccccc2)cc1
Yield: 93 %

Procedure:
Using 5-(dipenylmethoxy)pentyl chloride and piperazine, the procedure of Reference Example 16 was otherwise repeated to provide the title compound.