Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[O:14])[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH2:8]1.Cl[CH2:16][C:17](=[O:19])[CH3:18].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[OH:13][C:9]1[CH2:10][CH2:11][CH2:12][C:7](=[O:14])[C:8]=1[CH2:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)CCl
Reactant: O=C1CCCC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)CC1=C(O)CCCC1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a slurry of powdered K2CO3 (4.34 Kg, 31.4 moles) in chloroform (8.5 l), 1,3-cyclohexanedione (3.5 Kg, 31.2 moles) was added with stirring. To this mixture, at an ice-bath temperature, chloroacetone (2.9 Kg, 28.2 moles based on 90% purity) was added over a 1 hour period under a N2 atmosphere with stirring. The reaction temperature was raised slowly to room temperature and it was then allowed to stay at room temperature for 3 days. As the reaction proceeded, stirring became more and more difficult. Distilled water (2 l) was added slowly and the mixture was then transferred to an aqueous sodium hydroxide solution (1 l 50% NaOH to 6 l H2O) with stirring. Additional water (1 l) and chloroform (1 l) were used to rinse the remainer of the mixture from the reaction flask. The pH of the solution was less than 10 and additional sodium hydroxide (1 l of 50% solution) was added to bring the pH of the solution to approx. 10. After stirring for 20 minutes, the mixture was allowed to settle and the organic layer was separated. The aqueous layer was acidified with conc. hydrochloric acid solution (15 lb) and then ethyl acetate (9 l) was added. The mixture was stirred for 20 minutes, allowed to settle, and the organic layer was separated. This organic layer was washed with brine (2 l), dried over Na2SO4, and the filtrate was concentrated under reduced pressure to yield a brown oily product (approx. 4.5 l ). This material can be crystallized from ether, but may be used directly in the next step without further purification, mp 80°-81° C. (crystals obtained from ether crystallization).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH:16]=[C:15](C=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:21][OH:22].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH2:16][C:15](=[N:21][OH:22])[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1cn(CC)c2sc(C=O)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2c(c1=O)CC(=NO)S2
Yield: 80 %

Procedure:
In 50 ml of warm ethanol was dissolved 0.5 g of 4,7-dihydro-7-ethyl-2-formyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. The solution was cooled to room-temperature, then 0.2 g of hydroxylamine hydrochloride was added followed by 2 ml of a 5%-solution of sodium hydroxide. After filtration, 4,7-dihydro-7-ethyl-2-hydroxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was obtained in a yield of 80%.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]Br>C(O)(=O)C>[CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH2:23][Br:25])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=NOCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CON=C(C(=O)O)C(=O)CBr)OCc1ccccc1
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
To a solution of tert-butyl 2-benzyloxycarbonylmethoxyimino-3-oxobutyrate (32.3 g) in acetic acid (32 ml) was slowly added bromine (16 g) at 45° to 48° C. with stirring, and the stirring was continued at the same temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, followed by washing six times with a saturated aqueous sodium chloride. The solution was evaporated under reduced pressure to give 2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyric acid (35 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH3:13][CH:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:48]=[C:39]([C:40]3[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:11][CH:12]=1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 10.0 g (56.2 mmol) of 4-(2-methylpropyl)benzoic acid, 10.8 g (56.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.6 g (56.2 mmol) of 1-hydroxybenzotriazole hydrate in 70 mL of DMF was stirred at rt for 30 min. N-Hydroxy-4-(hydroxymethyl)benzamidine (9.3 g, 56.2 mmol, from Step A) was added to the reaction mixture at rt and the resulting slurry was stirred at 140° C. for additional 2 h. The reaction was cooled to rt and quenched with 50 mL of water. The aqueous layer was extracted with 200 mL of ethyl acetate. The organic layer was washed with 0.5 N HCl solution, saturated NaHCO3 solution and water and then was concentrated to dryness to afford 16.5 g of the title compound: 1H NMR (400 Mhz, CD3OD) δ 0.95 (d, J=6.7, 6H), 1.96 (m, 1H), 2.61 (d, J=7.3, 2H), 7.42 (d, J=8.0, 2H), 7.54 (d, J=8.2, 2H), 8.13 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: Oc1c(Cl)ccnc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Cl)ccnc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
2-bromo-4-chloropyridin-3-ol (8.15 g, 39.1 mmol), potassium carbonate (10.5 g, 76 mmol) and iodomethane (3.65 ml, 58.6 mmol) were added to acetone (300 ml) and stirred for 18 h at room temperature under inert conditions. The reaction mixture was evaporated to dryness, dissolved in ethyl acetate (100 mL), filtered over silica gel and the filter washed with ethyl acetate (3×100 mL). The filtrate was evaporated to dryness to obtain crude product which was purified over silica gel using 0:1 to 1:0 ethyl acetate in heptane to obtain 2-bromo-4-chloro-3-methoxypyridine as a white crystalline solid (6.8 g, 78%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:13]12>>[OH:10][C:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]([C:15](=[O:16])[C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=2[NH:12][CH3:11])[N:2]=1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: O=c1[nH][nH]c2cccnc12
Product: CNc1ccccc1C(=O)n1nc(O)c2ncccc21
Yield: 84.8 %

Procedure:
Pyrazolo[4,3-b]pyridine-3(2H)-one was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 84.8% yield; m.p. 221°-223° C.,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([O:15]C(C)C)[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([OH:15])[CH:3]=1
Reactant: CC(C)Oc1cc(F)ccc1-n1nnn(C)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1nnn(-c2cc([N+](=O)[O-])c(F)cc2O)c1=O
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A solution of 1-(4-fluoro-2-isopropoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (3.50 g, 13.9 mmol, 1 equiv) in H2SO4 (35 mL) was cooled in ice/water bath. To the cooled solution, was added HNO3 (fuming >90%; 715 uL, 15.3 mmol, 1.1 equiv) dropwise, and the cooled reaction mixture was allowed to warm to RT over 2 h. The reaction mixture was quenched with ice, and extracted with EtOAc 3×. The organic layer was then extracted with saturated NaHCO3 3×. The basic aqueous layer was acidified to pH <3 with 6N HCl. Then, the acidic layer was extracted with EtOAc 3×, and the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 1-(4-fluoro-2-hydroxy-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.94 g, 83%) as brown solid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 12.5 (bs, 1H), 8.41-8.44 (d, 1H, J=8.7 Hz), 7.04-7.08 (d, 1H, J=13 Hz), 3.59 (s, 3H); 19F NMR (282 MHz; d6-DMSO) δ −111.3 (q); m/z=256 (M+H)+.
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH2+]1CCCCC1>O>[C:13]([C:15](=[C:9]1[CH2:10][CH2:11][CH:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCOC(=O)CC#N
Reactant: CCC/C=C/C1CCC(=O)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC/C=C/C1CCC(=C(C#N)C(=O)OCC)CC1

Procedure:
A mixture of 33.3 g of 4-(1E-pentenyl)cyclohexanone (prepared in accordance with EP-A-168683), 42 ml of ethyl cyanoacetate, 300 ml of toluene and 2.9 g of piperidinium acetate is boiled for 1.5 hours on a water separator. After cooling the reaction mixture is washed with three 50 ml portions of water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on 750 g of silica gel with hexane/ethyl acetate (vol. 19:1) gives ethyl cyano-[4-(1E-pentenyl)cyclohexylidene]-acetate.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:11]=1)(=[O:9])=[O:8].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[O:28]1[CH2:29][CH2:30][CH:25]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:8])=[O:9])=[CH:11]3)[CH2:26][CH2:27]1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4C4CCOCC4)cccc3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(C3CCCN3C3CCOCC3)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (0.038 g, 0.065 mmol) was dissolved in DCM (1 mL) and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, triturated with diethyl ether, and filtered. The solids were washed with diethyl ether and vacuum dried overnight to afford 5-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.79 (br. s., 1H), 9.65 (br. s., 1H), 8.55 (br. s., 1H), 8.43 (d, J=9.1 Hz, 1H), 8.27 (d, J=7.2 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.82-7.72 (m, 1H), 7.27 (d, J=4.6 Hz, 1H), 6.85 (d, J=4.5 Hz, 1H), 5.61 (d, J=6.1 Hz, 1H), 3.91-3.68 (m, 5H), 3.63-3.45 (m, 3H), 3.13 (t, J=11.3 Hz, 3H), 2.71-2.57 (m, 2H), 2.20 (br. s., 2H), 1.98 (br. s., 1H), 1.84 (d, J=10.5 Hz, 1H), 1.65 (br. s., 2H), 1.51 (br. s., 1H). m/z (ESI) 444.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23]>C(Cl)Cl.C(C(O)=O)(F)(F)F>[O:1]=[C:2]1[C:10]2([CH2:11][CH2:12][N:13]([CH2:16][C:17]([F:20])([F:18])[F:19])[CH2:14][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21

Procedure:
A solution of the tert-butyl 2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetate from Step B (3.19 g, 8.01 mmol) in CH2Cl2 (16 mL) and CF3CO2H (5 mL) was stirred at ambient temperature for 17 h. Added CF3CO2H (1 mL) and stirred 1 additional hour. The mixture was concentrated in vacuo. To the resulting solid was added an HCl solution (10 mL, 2.0 M in Et2O) and the solution concentrated in vacuo. Repeated two more times to produce the hydrochloride salt of the title compound as a white solid. MS: m/z=343 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])O.[Na+].Cl[CH2:20][C:21](Cl)=[O:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[O:13]1[C:3]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=2[NH:1][C:21](=[O:22])[CH2:20]1
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cccc(N)c1O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc2c1OCC(=O)N2
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of ethyl 3-amino-2-hydroxybenzoate (500 mg), sodium hydrogen carbonate (927 mg) and benzyltributylammonium bromide (983 mg) in chloroform (10 ml) was added dropwise chloroacetyl chloride (374 mg) in chloroform (3 ml) under ice bath cooling. The reaction mixture was stirred at ambient temperature for 1 hour and at 60° C. for 2 hours. To the reaction mixture was added dropwise chloroacetyl chloride (312 mg) in chloroform (3 ml) under ice bath cooling and stirred at 60° C. for 2 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo to give ethyl 2H-1,4-benzoxazin-3-one-8-carboxylate (460 mg).
Reaction SMILES: [C:1]([O:9][CH:10]([C:18](=[O:20])[CH3:19])[C:11](=[O:17])[CH:12]=[CH:13]N(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC.C(O)(=O)C(O)=O.Cl.S(=O)(=O)(O)O>C(O)(=O)C.C(O)=O>[C:1]([O:9][C:10]1[C:11](=[O:17])[CH:12]=[CH:13][O:20][C:18]=1[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCC(=O)O
Solvent: O=CO
Product: Cc1occc(=O)c1OC(=O)c1ccccc1

Procedure:
said 4-benzoyloxy-1-dimethylamino-1-hexene-3,5-dione is heated in an acid chosen from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, dilute hydrochloric acid and dilute sulfuric acid to form 3-benzoyloxy-2-methyl-4-pyrone, and,
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[CH:9][N:8]=1)[CH:3]([CH3:5])[CH3:4].[I:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1>>[I:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[CH:12]=[C:7]([O:6][CH2:2][CH:3]([CH3:5])[CH3:4])[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:27])[CH:21]=1
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Reactant: Cn1nc(C(=O)O)cc1I
Agent: Cl
Product: CC(C)COc1cc(N2CCN(C(=O)c3cc(I)n(C)n3)CC2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Example 3 using 4-isobutoxy-6-(piperazin-1-yl)pyrimidine hydrochloride and 5-iodo-1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:51])[NH:7][C@H:8]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:19][CH2:18]2)=[CH:13][N:12]([CH2:32][C:33]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:34]=2[F:43])[C:11]1=[O:44])([CH3:4])([CH3:3])[CH3:2].[N:52]([Sn](CCCC)(CCCC)CCCC)=[N+:53]=[N-:54]>C1(C)C=CC=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:51])[NH:7][C@H:8]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:54][N:53]=[N:52][N:31]=4)[CH:25]=3)[CH2:19][CH2:18]2)=[CH:13][N:12]([CH2:32][C:33]2[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=2[F:43])[C:11]1=[O:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc(C#N)c3)CC2)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc(-c4nnn[nH]4)c3)CC2)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
{(R)-2-[5-[4-(3-cyano-benzyl)-piperazin-1-yl]-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (35 mg, 0.049 mmol), and azidotributyl tin (IV) (16 μl, 0.059 mmol) were dissolved at 120° C. for 10 hrs in toluene (1 mL) with stirring. The solution was cooled to room temperature, followed by the addition of azidotributyl tin (IV) (20 μl, 0.074 mmol) thereto and stirring at 120° C. for an additional 2 hrs. The solution was cooled to room temperature, diluted in dichloromethane, and washed with an aqueous saturated ammonium chloride solution and an aqueous saturated sodium chloride solution in the order. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 6/1) and dried in a vacuum to afford 20 mg of the compound as a colorless oil (yield 54%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[CH3:38][CH:39]1[O:44][CH2:43][CH2:42][NH:41][CH2:40]1.[OH-].[Na+].Cl>C(O)(C)C>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[N:7]=[C:3]([CH2:2][N:41]5[CH2:42][CH2:43][O:44][CH:39]([CH3:38])[CH2:40]5)[S:4][CH:5]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Reactant: CC1CNCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1CN(Cc2nc(C(=O)Nc3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)cs2)CCO1
Temperature: 90 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
2-(Chloromethyl)-N-[6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.091 mmol) and 2-methylmorpholine (0.5 mL, 0.091 mmol) were put in a 0.5-2 mL vial then heated in the microwave at 90° C. for 15 min. The solvent was blown down under nitrogen. Isopropanol (2 mL) and 2M NaOH (2.000 mL) were added and the reaction mixture was stirred for 3 hr at 25° C., then neutralised with 2M HCl aqueous solution until pH=7 (checking with pH paper). The solvent was removed under nitrogen. The mixture was dissolved in 2 mL of DMSO and passed through a hydrophobic frit. Purification was carried out by MDAP to afford the title compound (10 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20](=[O:25])[C:19]=1[CH2:26][NH:27][C:28](=[O:54])[C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:30]=1[CH3:53].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:7]([C:6]1[CH:9]=[C:2]([C:33]2[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[C:30]([CH3:53])=[C:29]([C:28]([NH:27][CH2:26][C:19]3[C:20](=[O:25])[NH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])=[O:54])[CH:34]=2)[CH:3]=[CH:4][C:5]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:8]
Reactant: CCN(c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: N#Cc1cc(Br)ccc1CN1CCOCC1
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)c(C#N)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 5.9 %

Procedure:
To a stirred solution of 5-bromo-2-(morpholinomethyl)benzonitrile (190 mg, 0.68 mmol) and N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (200 mg, 0.45 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (0.81 mL, 1.63 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (52 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (16 mg, 6%). LCMS: 598.20 (M+1)+; HPLC: 89.15% (@254 nm) (Rt; 4.039; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (bs, 1H), 8.20 (t, 1H), 8.15 (s, 1H), 7.94 (d, 1H, J=6.8 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.51 (s, 1H), 7.31 (s, 1H), 5.86 (s, 1H), 4.29 (m, 2H), 3.84-3.82 (m, 2H), 3.66-3.58 (m, 6H), 3.32 (m, 5H), 3.11-3.03 (m, 4H), 2.25 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.65-1.51 (m, 4H), 0.82 (t, 3H, J=6 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC)=O)[CH2:19][CH2:18]3)=[N:13][NH:14]2)=[CH:10][CH:9]=1.O>O1CCCC1>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 68.1 %

Procedure:
To a stirred suspension, under nitrogen, of 4.7 g of lithium aluminum hydride (50°-55% oil dispersion) in 90 ml of tetrahydrofuran was added, dropwise, 8.9 g of 6-fluoro-3-(1-methoxycarbonyl-4-piperidinyl)-1H-indazole, dissolved in 50 ml of tetrahydrofuran. After the addition was complete, the reaction was heated under reflux for 2 hr. The reaction was cooled in an ice-salt bath and water was carefully added. The mixture was filtered and the filter cake was washed with tetrahydrofuran and twice with hot methanol. The filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to yield 5.1 g (68%) of product, mp 217°-220°. Recrystallization from ethanol (twice) provided the analytical sample, mp 218°-220° C.
Reaction SMILES: [C:1]1([CH3:30])[CH:6]=[CH:5][C:4]([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:3][CH:2]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]1([CH3:30])[CH:6]=[CH:5][C:4]([CH:7]([NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(N[C@H](C)c2cccc3ccccc23)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(N[C@H](C)c2cccc3ccccc23)c2cccc(N)c2)cc1
Yield: 100.3 %

Procedure:
Following a procedure similar to that described in Example (1B), 1.51 g of N-[p-tolyl-(3-nitrophenyl)methyl]-N-[(R)-1-(naphthalen-1-yl)ethyl]amine [prepared as described in step (a) above], 2.08 g of nickel chloride hexahydrate and 607 mg of sodium borohydride were reacted, separated and purified, to obtain 1.40 g of the title compound as a yellow oil.