Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:8]=2[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].C(=O)(O)[O-].[Na+]>ClCCl>[Br:41][CH2:2][C:3]1[CH2:4][CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:8]=2[CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(CO)CCO3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CBr)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Into a solution of 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (320 mg) in dichloromethane (10 ml) were added triphenylphosphine (378 mg) and carbon tetrabromide (597 mg), and the resulting mixture was stirred at room temperature for 2 hours. Thereto were additionally added triphenylphosphine (157 mg) and carbon tetrabromide (249 mg), and the resulting mixture was stirred further for 30 minutes, was then mixed with an aqueous solution of sodium bicarbonate under ice cooling and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/hexane=1/9) and further to washing with diethyl ether/hexane to obtain 4-bromomethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (286 mg) as a white powder.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH3:17])[CH:14]=1)OCCC)#[N:2].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH3:17])[CH:14]=1)=[N:27][CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])#[N:2]
Reactant: NCCc1ccccc1Cl
Reactant: CCCOC(=NC#N)c1cncc(NCC)c1
Solvent: CO
Product: CCNc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Reaction time: 1.75 h
Yield: 81 %

Procedure:
To a solution of propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (98 mg, 0.42 mmol) in methanol (3 ml) was added 2-(2-chlorophenyl)ethylamine(79 mg, 0.51 mmol), and the mixture was stirred for 105 minutes. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=100:1) and further crystallized from diethyl ether to give the title compound (110 mg, 0.34 mmol) as colorless crystals in the yield of 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][O:22][C:21]2=[O:30])[CH2:16][CH2:15]1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C(C)=CC=CC=1C>ClCCl>[CH3:9][CH:8]([NH:7][C:5](=[O:6])[C:4]1[CH:11]=[CH:12][C:13]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH2:23][O:22][C:21]3=[O:30])[CH2:18][CH2:19]2)=[C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[CH:3]=1)[CH3:10]
Reactant: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from the product of example 160 (0.1 g) and methanesulphonylchloride (0.02 ml) in dichloromethane (10 ml) at 0° C. in the presence of 2,6-lutidine (0.085 ml). The reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated, dissolved in ethyl acetate, washed with water, dried, and evaporated under reduced pressure. Purification was by chromatography eluting with (3:1) ethyl acetate/isohexane. Yield 0.066 g as a solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([CH3:26])[CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([CH3:26])[C:12]([CH2:16]/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(Br)cc(C)c1C/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1C/C=C/C(=O)O
Reaction time: 4 h
Yield: 100.3 %

Procedure:
TFA (10 mL) was added to a solution of 53B (2.35 g) in CH2Cl2 (20 mL) at 0° C. and stirred for 4 h. The reaction mixture was concentrated to yield 53C (1.95 g, 99%) as an off-white solid. MS (ESI) m/z 267.2/269.2 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:12])([CH3:1])[C:3]1=[O:11]
Reactant: ClCCCBr
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCCCl)c2ccccc21
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 3,3-dimethylindolin-2-one (1.843 g, 11.43 mmol, 1 equiv) in N,N-dimethylformamide was cooled to 0° C. Sodium hydride (60% dispersion) (503 mg, 12.58 mmol, 1.1 equiv) was slowly added and the reaction was stirred as such until all bubbling had stopped. 1-bromo-3-chloropropane (3.37 ml, 34.3 mmol, 3 equiv) was added to the reaction mixture in one portion. The reaction was allowed to warm to ambient temperature and stirred as such for 16 h. The crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as a light orange oil (2.38 g, 87%); 1H NMR (400 MHz, DMSO-d6): δ 1.26 (s, 6H); 1.98-2.14 (m, 2H); 3.65 (t, 2H, J=6 and 6.8 Hz); 3.77-3.81 (m, 2H); 7.02-7.07 (m, 2H); 7.24-7.28 (m, 1H); 7.33-7.35 (m, 1H); MS for C13H16ClNO m/z 237.99 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][C@@H:24]([CH3:28])[NH:23]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:25][C@H:24]([CH3:28])[NH:23][C@H:22]([CH3:21])[CH2:27]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H](C)N1
Yield: 66.8 %

Procedure:
A mixture of 280 mg of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 542 mg of cis-2,6-dimethylpiperazine and 10 ml of pyridine was heated under reflux for 2.5 hours. The solvent was evaporated under reduced pressure. To the residue was added a 1N aqueous solution of sodium hydroxide, and the insoluble matter was removed by filtration. A 10% aqueous solution of acetic acid was added to the filtrate to adjust its pH to 8. The solution was then extracted with chloroform. The chloroform layer was dried with sodium sulfate, and concentrated under reduced pressure. Acetonitrile was added to the residue, and the mixture was cooled with ice. The crystals were collected by filtration, and recrystallized from aqueous ammonia to give 250 mg of 5-amino-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 253°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH3:31].Cl[CH2:33][C:34](=[O:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:34]([CH2:35][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[C:25]5[CH3:31])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1)(=[O:36])[CH3:33]
Reactant: CC(=O)CCl
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(CC(C)=O)CC1
Temperature: 70 °C

Procedure:
A mixture of 6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quinazoline (0.2 g), chloroacetone (0.046 ml), potassium carbonate (0.1 g) and DMF (6 ml) was stirred and heated to 70° C. for 1 hour. The mixture was cooled to ambient temperature, the precipitate was removed by filtration, the solvent was removed by evaporation under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with dichloromethane and ending dichloromethane/methanol (93/7). Evaporation of the solvents gave a foam which was triturated under ether/pentane (70/30) to give a solid which was collected by filtration and dried under vacuum to give 7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (0.074 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(F)cc1
Product: O=C(O)Cc1ccccc1Nc1ccc(F)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-fluoroaniline to yield 2-[(4-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[F:13]>C1COCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[F:13]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ˜15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of −60° C. to −50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ˜20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as a pale yellow oil, which was directly used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.OS(O)(=O)=O.[CH3:20]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:20])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(O)ccc2c1
Yield: 95 %

Procedure:
To a 1-L round bottomed flash equipped with a nitrogen inlet and magnetic stir bar was added 50 g (0.27 mol) of 6-hydroxy-2-naphthoic acid and 400 mL of methanol. The suspension was treated slowly with 1 mL of con. H2SO4 and stirred at room temperature overnight. The resulting solution was evaporated, taken up in 500 mL of ethyl acetate and washed sequentially with 3×300 mL of saturated NaHCO3, 2×300 mL of water and brine. The pale yellow solution was dried over MgSO4, reduced in volume to about 100 mL and slowly treated with hexane. The resulting crystalline precipitate was collected and dried under a stream of nitrogen to yield 52 g (95%) of the title compound as fine, white plates, mp 196° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])=[CH:10][CH:9]=1>>[F:5][CH:6]([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15]([Cl:3])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)[C@H](C(=O)Cl)c1ccc(OC(F)F)cc1
Yield: 91.8 %

Procedure:
Add 32.8 g (0.275 mole) of thionyl chloride to 42 g (0.17 mole) of the obtained (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid, heat with stirring under reflux for 1 hour, and then distill off the unreacted thionyl chloride to give 41 g of (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]1([C:23]([O:25]C)=O)[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C([Mg]Cl)(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][C:11]2([N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][CH2:14][CH2:15]2)[C:23]1=[O:25]
Reactant: COC(=O)C1(CCNc2ccccc2Cl)CCCN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC12CCN(c1ccccc1Cl)C2=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1-tert-Butyl 2-methyl 2-{2-[(2-chlorophenyl)amino]ethyl}pyrrolidine-1,2-dicarboxylate, was dissolved in anhydrous THF (4 mL) and cooled to 0° C. To this cooled solution was added isopropylmagnesium chloride in THF (2.0 M, 2 mL). The reaction vial was then sealed and heated to 64° C. and stirred for 18 h. The reaction mixture was then diluted with EtOAc and quenched by the addition of water. The crude mixture was filtered through a pad of diatomaceous earth and the filter pad was washed several times with EtOAc. The organic and aqueous layers of the filtrate were separated. The aqueous phase was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (2×5 mL), then dried (NaSO4), filtered, and concentrated in vacuo to afford the desired product. LC-MS: 251.1 (M−Boc+2H)+ and 295.1 (M−t-Bu+2H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26].[C:28]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[F:1][C:2]1[C:3]([O:27][CH3:28])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.1 g, 0.3 mmol, see Example 23), and K2CO3 (0.04 g, 0.3 mmol) in 4 mL ACN stirred at room temperature, was treated with MeI (0.06 g, 0.4 mmol), and the resulting mixture was stirred for 12 hours, M+Na=416. The mixture was concentrated in vacuo and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 98 mg of the title compound as a white solid. MS (m/z)=416 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:62][N:63]1[C:67]([NH2:68])=[CH:66][CH:65]=[N:64]1>CN(C=O)C>[CH2:1]([N:3]1[C:7]2[NH:8][CH2:9][CH2:10][S:11][CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:68][C:67]4[N:63]([CH3:62])[N:64]=[CH:65][CH:66]=4)=[O:19])=[CH:15][C:14]=3[CH3:22])[C:6]=2[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)O)cc1C
Reactant: Cn1nccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(C(=O)Nc2ccnn2C)cc1C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
To a solution of 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoic acid (0.60 g, 1.521 mmol, Preparation # V.1) and DIEA (0.80 mL, 4.56 mmol), in DMF was added HATU (0.64 g, 1.67 mmol). The reaction mixture was stirred for about 30 min and 1-methyl-1H-pyrazol-5-amine (0.22 g, 2.28 mmol, Aldrich) was added. The reaction mixture stirred for about 5 h and was concentrated under reduced pressure. The residue was dissolved in DCM (15 mL) and washed with saturated NaHCO3 (5 mL). The organic layer was separated and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (Table 2, Method e), to afford 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide (0.30 g, 0.64 mmol, 42%) as a white solid. LC-MS (Table 1, Method g) Rt=2.01 min, m/z 474 (M+H)+; 1H NMR (DMSO-d6) δ 10.11 (s, 1H), 8.52-8.48 (m, 1H), 7.87-7.81 (m, 1H), 7.76-7.70 (m, 2H), 7.62 (dd, J=8.1, 1.8 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.24-7.18 (m, 1H), 6.89 (s, 1H), 6.19 (d, J=1.9 Hz, 1H), 5.83 (d, J=4.6 Hz, 1H), 4.31-4.00 (m, 2H), 3.76-3.68 (m, 1H), 3.65 (s, 3H), 3.06-2.95 (m, 1H), 2.77-2.62 (m, 2H), 2.60 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.C([Mg]Cl)(C)C.[NH:17]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[C:18]1=[O:19]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[OH:21][C:20]1([C:9]2[C:8]([OH:11])=[CH:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[CH:10]=2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:17][C:18]1=[O:19]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Cc1nc2cc(O)ccc2s1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2cc(O)c(C3(O)C(=O)Nc4ccccc43)cc2s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.1 %

Procedure:
To a cooled (0° C.) solution of 2-methylbenzo[d]thiazol-5-ol (4.0 g, 24.0 mmol) in anhydrous tetrahydrofuran (50 mL) was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 12.0 mL, 24.0 mmol). The resultant suspension was stirred at 0° C. for 0.5 h and isatin (3.1 g, 21.2 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 48 h and was diluted with a saturated aqueous solution of ammonium chloride (80 mL) and ethyl acetate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with boiling ethyl acetate (10 mL), filtered and dried in vacuo to afford 3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one (4.11 g, 62%) as an off-white microcrystalline solid: 1H NMR (300 MHz, DMSO-d6) δ10.34 (s, 1H), 10.02 (br s, 1H), 8.85 (br s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.18-7.10 (m, 1H), 7.01-6.74 (m, 4H), 2.77 (br s, 3H); MS (ES+) m/z 313.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].O([CH2:28][C:29]([F:32])([F:31])[F:30])S(C(F)(F)F)(=O)=O>CN(C)C=O.ClCCl>[CH3:17][O:16][C:15]1[C:8]([O:7][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:9]([CH:12]=[CH:13][C:14]=1[O:18][CH3:19])[C:10]#[N:11]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1ccc(C#N)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(OCC(F)(F)F)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
Potassium carbonate (6.91 g, 0.05 mol) was added to a stirred solution of 2-hydroxy-3,4-dimethoxybenzonitrile (from Example 10(c), 5.61 g, 0.031 mol) in dimethylformamide (30 ml). This was followed by the addition of a solution of 2,2,2-trifluoroethyl triflate (23.2 g, 0.10 mol) in dichloromethane (100 ml) and the reaction was stirred at room temperature for 18 hours. The reaction was partitioned between 2N hydrochloric acid and ethyl acetate, the organic layer separated, washed sequentially with saturated aqueous brine and water, dried (MgSO4) and evaporated under reduced pressure. Trituration with diethyl ether followed by filtration afforded the subtitle compound as a colourless solid (7.67 g, 94%). Rf 0.76 (dichloromethane:methanol 95:5, v/v). MS m/z 279 (MNH4)+
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23]>>[NH2:24][C:22]1[S:23][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\OC1CCCCCCC1)C(=O)CBr
Product: CCOC(=O)/C(=N\OC1CCCCCCC1)c1csc(N)n1
Yield: 72 %

Procedure:
Ethyl 4-bromo-(Z)-2-(cyclooctyloxyimino)-3-oxobutyrate (2.8 g) was treated with thiourea as described in Example 4d. Crystallisation from cyclohexane gave the title compound as colourless needles (1.9 g, 72%), m.p. 117°-8° C. [Found, C: 55.66, H: 7.16, N: 12.45. C15H23N3O3S requires C: 55.36, H: 7.12, N: 12.91%]. νmax (KBr) 3428, 2926, 1718, 1610, 1541 cm-1 : δH (CDCl3) 1.35 (3H, t) 1.4-2.0 (14H, m), 4.36 (3H, q+m) 5.65 (2H, br s, exch D2O), 6.66 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH2:20][CH2:19]1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:21]3[CH2:20][CH2:19][O:18][CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(N2CCOCC2)nc1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.24 mmol) was used in general procedure 2 with 6-morpholinonicotinic acid (0.30 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-morpholinonicotinamide. MS (Q1) 437.0 (M)+
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][OH:11].CCN(CC)CC>C(Cl)Cl>[CH:1]1([CH:7]=[N:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=CC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ON=CC1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of cyclohexanecarbaldehyde (4 ml, 33.02 mmol) in CH2Cl2 (100 ml) at room temperature was added hydroxylamine hydrochloride (2.76 g, 39.62 mmol) followed by Et3N (5.52 ml, 39.62 mmol) and the reaction was stirred overnight. The resulting mixture was partitioned between CH2Cl2 and H2O and the layers were separated. The organic layer was dried over Na2SO4, concentrated in vacuo and used directly for the next step. 1H NMR (CDCl3) δ 1.0-2.0 (m, 10H), 3.0 (m, 1H), 6.6 (d, 0.5H), 7.4 (d, 0.5H), 8.2 (bs, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[CH:16][NH:17]3)=[CH:9][C:6]=1[C:7]#[N:8]>C(O)CCC>[NH:17]1[C:18]2[C:14](=[C:13]([C:10]3[CH:9]=[C:6]4[C:5](=[CH:12][CH:11]=3)[NH:3][N:2]=[C:7]4[NH2:8])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2ccc(-c3cccc4[nH]ccc34)cc12
Temperature: 25 °C
Yield: 83.2 %

Procedure:
Hydrazine hydrate (0.4 mL, 12.7 mmol) was added to a solution of 2-fluoro-5-(1H-indol-4-yl)benzonitrile (1.2 g, 5.08 mmol) in n-butanol (25 mL). The mixture was heated to reflux under nitrogen for 3 days. The reaction was cooled to room temperature and the solvent was removed. The residue was purified on a silica gel column eluting with DCM: MeOH (95:5) to give 1.05 g (83%) of 5-(1H-indol-4-yl)-1H-indazol-3-ylamine as a white foam.