Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4]([OH:6])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:1]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A stirred mixture of methyl 2-amino-4-chlorobenzoate (2.50 g, 13.5 mM) and dimethyl acetylenedicarboxylate (2.05 g, 14.4 mM) in t-butanol (22 mL) was refluxed for 7 hr under a nitrogen atmosphere. After adding additional dimethyl acetylenedicarboxylate (1.16 g, 8.13 mM) and refluxing another 2.5 hr, the reaction mixture was allowed to cool to room temperature and potassium t-butoxide (1.56 g, 13.9 mM) was added in one portion. A precipitate formed and the resulting mixture was refluxed for 1.5 hr. The mixture was cooled to room temperature and filtered to separate the solids, which were washed with t-butanol and ether. The solids were dissolved in water and acidified with 1N sulfuric acid to form a precipitate. The resulting mixture was extracted with methylene chloride and the combined extracts were washed with brine and water, dried (MgSO4), filtered and concentrated to give a green solid. Recrystallization of this material from methanol provided dimethyl 7-chloro-4-hydroxy-quinoline-2,3-dicarboxylate (1.15 g, 28.9%) as an off-white solid, mp 232°-233° C.; MS(CI): 296 (M+H).
Reaction SMILES: O=S(Cl)Cl.Br.[NH2:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8]([OH:10])=[O:9].[CH3:14]O>>[BrH:13].[CH3:14][O:9][C:8](=[O:10])[C@@H:7]([NH2:6])[CH2:11][CH2:12][Br:13]
Reactant: NC(CCBr)C(=O)O
Reactant: CO
Agent: Br
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCBr
Reaction time: 0.5 h

Procedure:
SOCl2 (7.0 mL) was added slowly to MeOH (100 mL) at −20° C. (bath temp), and stirred for 30 min. 2-Amino-4-bromo-butyric acid hydrobromide (5.0 g, 19 mmol) was then added and the reaction mixture was stirred O/N at rt. Concentration in vacuo gave the title compound as a viscous liquid which become solid on standing: yield 5.2 g (99%).
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)([CH3:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1>[CH3:15][C:2]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)([CH3:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(OCC(C)(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 60 °C

Procedure:
305 mg of 2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanol dissolved in 15 ml THF were treated with 338 mg of triphenylphosphine, 196 mg of methyl 4-hydroxybenzoate and 0.21 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was partitioned in 100 ml of 1:1 ethyl acetate/sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting oil was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), giving 160 mg of methyl 4-[2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propyloxy]-benzoate as a colorless oil. The ester (160 mg), dissolved in 4 ml THF/0.8 ml H2O, was treated with 50 mg of lithium hydroxide hydrate. The mixture was heated at 60° C. for two hours. The mixture was acidified to pH 2 with 1N hydrochloric acid then partitioned in 10 ml ethyl acetate/10 ml sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparation tlc (SiO2, 40% ethyl acetate/hexanes), giving a white foam. 1H NMR (CDCl3): 8.03 (d, J=8.8 Hz, 2H), 7.35 (d, J=2.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 2.1 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 3.96 (s, 2H), 1.67 (s, 4H), 1.46 (s, 6H), 1.27 (s, 12H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:21]([CH3:23])[CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[N-:24]=[C:25]=[O:26].[K+].Cl>>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[NH:24][C:25](=[O:26])[NH:2][C:3]=2[CH:21]([CH3:23])[CH3:22])[CH:7]=[C:8]([C:17]([CH3:20])([CH3:18])[CH3:19])[C:9]=1[OH:16])([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)C(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Product: CC(C)c1[nH]c(=O)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 21.3 %

Procedure:
By following the same procedure as in Example 6 using 1.7 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-1-butanone hydrochloride, 0.8 g of potassium isocyanate, and 1 ml of concentrated hydrochloric acid and recrystallizing the reaction product from aqueous isopropanol, 0.35 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-isopropyl-2-oxo-4-imidazoline was obtained.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:23]=[CH:22][C:15]([CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:25]>O1CCOCC1>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]2[O:25][C:17]2([C:20]#[N:21])[C:18]#[N:19])=[CH:22][CH:23]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#CC(C#N)=Cc1ccc(OCc2ccccc2)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: N#CC1(C#N)OC1c1ccc(OCc2ccccc2)cc1

Procedure:
5.3 ml of 1.2M aqueous sodium hypochloride solution were added dropwise to a suspension of 1.04 g (4 mmol) of 2-(4-benzyloxybenzylidene)-malononitrile in 12 ml of dioxan while stirring at pH 9-10, the mixture was stirred at room temperature for 1 hour and 2N sulphuric acid was added until a pH of 4.8 was reached. Extraction with ethyl acetate, drying with sodium sulphate and distillation of the solvent gave 1.22 g of 3-(4-benzyloxy-phenyl)-oxirane-2,2-dicarbonitrile as a yellow-brown oil, which was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>CN(C=O)C>[CH2:14]([NH:17][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: CCc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(CC)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
In 6 ml of DMF, 500 mg (2.1 mmol) of 2,4-dichloro-7-etylthieno[3,2-d]pyrimidine was dissolved, and then 269 mg (4.7 mmol) of allylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 483 mg (yield: 88.8%) of the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
To a solution of crude ethyl 9-{(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-[(acetyloxy)methyl]tetrahydro-2-furanyl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 64) (74.9 g, assumed 0.103 moles) in warm absolute ethanol (330 ml) was added sodium ethoxide (1.2 g, 0.018 moles) in portions over 23 hours. The resultant mixture was stirred for a further 3 hours and then glacial acetic acid (1.5 ml) was added. The mixture was concentrated in vacuo to give the crude product as a light brown foam (63.7 g) that was used as such for the next step. The crude product can be purified by flash chromatography on silica gel eluting with a gradient system of 5% v/v isopropanol in dichloromethane changing to 7.5% v/v isopropanol in dichloromethane changing to 10% v/v isopropanol in dichloromethane followed by crystallisation from tertiary-butyl methyl ether to give the title compound as colourless crystals, m.p. 118–120° C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[C:11]([F:13])[CH:12]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:30][C:29](=[O:31])[CH2:28]2)=[CH:22][CH:21]=1>CCCCCC.C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:28][C:29]([CH:14]([C:9]3[CH:8]=[C:7]([F:6])[CH:12]=[C:11]([F:13])[CH:10]=3)[C:15]([O:17][CH3:18])=[O:16])([OH:31])[CH2:30]2)=[CH:22][CH:21]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: COC(=O)Cc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(c1cc(F)cc(F)c1)C1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 2 mL of 1.6M butyllithium in hexane and 2 mL of dry THF was cooled to −78° C. under nitrogen. To this was added a solution of 0.626 g (3.2 mmol) of methyl (3,5-difluorophenyl)acetate in 4 mL of THF and the solution was stirred at −78° C. After 20 min, a solution of 0.600 g (1.95 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 4 mL THF was added and the solution was stirred at −78° C. After 1 h, the reaction was quenched by addition of 10 mL of saturated NH4Cl solution and 20 mL of ether. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was filtered through a plug of silica gel using 25% ether-hexane to afford the title compound; 1NMR(CDCl3) δ 2.91 (d, 1H J=8.3 Hz), 3.14 (d, 1H J=8.0 Hz), 3.17 (d, 2H, J=8.2 Hz), 3.32 (d, 1H J=7.8 Hz), 3.74 (s, 3H), 4.03 (s, br, 1H), 4.42 (s, 1H), 4.42 (s, 1H), 6.76 (m, 1H), 6.6.89 (m, 2H), 7.33 (m, 4H), 7.38 (m, 4H); Mass Spectrum: m/e=492 (M+1 35Cl, 35Cl ) and 494 (M+1 35Cl, 37Cl).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)([O-:3])=[O:2]>ClCCl.FC(F)(F)C(O)=O>[NH:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][NH:14][C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1

Procedure:
A solution of EXAMPLE 113A (0.8 g) in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours. The solvents were evaporated and the residue triturated with diethyl ether. The resulting solid was dissolved in 5% aqueous sodium carbonate solution (20 mL). The solution was concentrated to dryness and the resulting solid was triturated with a solution of 10% methanol in dichloromethane several times. Evaporation of the organic solvents gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:23]([C:29]2[N:33](COCC[Si](C)(C)C)[C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)(O)[C:24]([F:27])([F:26])[F:25])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(O)C(F)(F)F)=C2C(=C(C)C=1)[N:55](S(C1C=CC(C)=CC=1)(=O)=O)[CH:54]=C2)C.CN>CO.C(O)C>[CH2:1]([C:3]1[C:4]([C:23]([C:29]2[NH:33][C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)([NH:55][CH3:54])[C:24]([F:25])([F:27])[F:26])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:14])=[O:15])[CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CN
Solvent: CCO
Solvent: CO
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(NC)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F

Procedure:
The title compound was synthesized from a mixture of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 105-A, methylamine in MeOH was used instead of ammonia in ethanol. MS (ESI+) m/z 566.79 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(C)=O.[I-:15].[Na+]>C(Cl)Cl>[I:15][CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CC(C)CI

Procedure:
Mix ethyl 4-chloro-3-methylbutyrate (80 g), acetone (400 mL) and sodium iodide (100 g). Reflux for 8 hours, cool and add methylene chloride (400 mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200 mL) and water (200 mL). Separate the organic phase, dry (MgSO4) and evaporate to an oil. Purify by distillation to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:3]1[C:2]([CH3:13])([CH3:1])[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:19]
Reactant: CC1(C)CC(=O)c2ccccc2S1
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1C(=O)c2ccccc2SC1(C)C

Procedure:
3,4-dihydro-2-dimethylaminomethylene-3,3-dimethyl-4-thia-1(2H)-naphthalenone was prepared from 3,4-dihydro-3,3-dimethyl-4-thia-1(2H)naphthalenone (426 mg, 1.72 mmol) [Clayton, S E et al, Tetrahedron (1993), 49, 939], and N,N-dimethylformamide diethyl-acetal (1 ml) to give the compound as a yellow solid (113 mg). δH (CDCl3) 8.22 (1H, dd, J 1.6, 7.9 Hz), 7.32-7.14 (3H, m), 6.72 (1H, s), 2.89 (6H, s) and 1.63 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[I:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.CCOC(C)=O>CC1CCCO1>[C:13]([Si:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=1)([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cl)c(I)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of 4-chloro-3-iodophenol (2 g. 7.86 mmol) in anhydrous 2-methyltetrahydrofuran (10 mL) was added tert-butyldimethylsilyl chloride (1.25 g, 8.28 mmol) followed by imidazole (642 mg, 68.1 mmol) The resulting mixture was stirred at room temperature for 3 hours. EtOAc (10 mL) was added and the mixture washed with aqueous sodium hydroxide solution (2M, 3×10 mL), water (10 mL), and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane:EtOAc 90:10 to afford the title compound as colourless oil in 30% yield, 870 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:31][N:30]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Yield: 112 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (0.500 g, 1.69 mM) in ethanol (17 mL) was added 4-methoxyphenyl hydrazine hydrochloride (2.07 g, 11.83 mM). Triethylamine (1.88 mL, 13.52 mM) was added, and the mixture was heated to reflux for 40 hours. The resulting suspension was filtered hot, and the collected solids were washed with ethanol to give the 4-methoxyphenyl hydrazine salt of the title compound (0.700 g) as a light tan solid. This material was heated to reflux in glacial acetic acid (20 mL) for 2 hours to give a brown suspension. The suspension was cooled to room temperature. The solids were collected and washed with glacial acetic acid, methanol and ether to give the title compound (0.331 g, 53%) as a tan powder, mp 365° C. (decomp.); MS(CI): 370 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17]([O:19]C)=O)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:21])[O:4][N:3]=1.[CH:22]([Mg]Br)([CH3:24])[CH3:23]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17](=[O:19])[CH:22]([CH3:24])[CH3:23])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: COC(=O)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(=O)C(C)C)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C

Procedure:
Methyl 6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (100 mg, 0.35 mmol) was dissolved in 5 mL of THF and stirred at room temperature followed by the addition of isopropylmagnesium bromide (0.87 mL, 2.0 mmol). Addition Grignard was added in 1 hour intervals until the starting material was consumed. Once complete, the crude reaction mixture was quenched with DI water and extracted 3× with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulphate, filtered, concentrated in vacuo, and purified via HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=O)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH2:24][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Reactant: CN1CCNCC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCN6CCN(C)CC6)ccn45)cccc32)n1

Procedure:
Prepared according to procedure for Example 72 from N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide and 1-methylpiperazine. MS (ES+APCI) m/z=523 (M+H) detected.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:14](Br)[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[NH2:40])O1.C(=O)([O-])O.[Na+]>COCCOC.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:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=3[NH2:40])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(N)c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(N)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a suspension of N-tert-butyl-2-bromo-3-cyclohexyl-1H-indole-6-sulfonamide (2.10 g, 5.08 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-methylphenylamine (1.86 g, 8.00 mmol) in 1,2-dimethoxyethane (20 ml) and water (10 ml) were added sodium hydrogen carbonate (1.60 g, 19.2 mmol) and tetrakis(triphenylphosphine)palladium (176 mg, 0.15 mmol), and the mixture was heated under reflux for 14 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and diisopropy ether was added to the residue. The precipitated solid was collected by filtration and dried in vacuo to give N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonamide (2.14 g, yield 96.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)=[O:26])([CH3:21])[CH3:20])#[N:18].O>CN(C)C=O>[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:29]=1)=[O:26])([CH3:21])[CH3:20])#[N:18]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])nc3)c2)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 66.7 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (4.56 g, 22.4 mmol) and cesium carbonate (10.9 g, 33.6 mmol) in N,N-dimethylformamide (40 mL) was added dropwise a solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (6.92 g, 24.6 mmol) in N,N-dimethylformamide (20 mL) over 30 min, and the mixture was stirred at room temperature for 28 hr. Cesium carbonate (3.63 g, 11.2 mmol) was added to the reaction mixture, and the mixture was further stirred with heating at 60° C. for 15 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane mixture (1:1, 200 mL, 3×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=90/10→50/50), and fractions containing the desired t product were concentrated under reduced pressure to give the title compound (6.01 g, 67%) as a yellow amorphous solid.