Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[O:43][CH3:44])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][C:35]=2[O:43][CH3:44])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)Nc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (148 mg, 0.335 mmol), 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (100 mg, 0.369 mmol), palladium tetrakistriphenyphosphine (23 mg, 0.020 mmol) and sodium carbonate (85 mg, 0.845 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (125 mg, 69%). 1H NMR (CDCl3) δ 1.69 (m, 2H), 1.86 (m, 2H), 2.17 (m, 2H), 2.31 (s, 3H), 2.44 (m, 11H), 4.15 (s, 3H), 4.96 (m, 1H), 5.69 (bs, 2H), 7.14 (m, 1H), 7.37 (m, 2H), 7.45 (m, 2H), 7.68 (m, 2H), 8.41 (m, 2H), 9.77 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =541.2, Rt=2.58 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[CH3:23]>CN1CCCC1=O>[CH3:23][C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[C:18]([CH3:19])[C:13]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (NaH; 60% dispersion in mineral oil; 64.11 g, 1.603 mol) in 350 mL of N-methylpyrrolidone (NMP) is cooled to 0° C. and treated with a solution of 4-methoxyphenol (208.4 g, 1.679 mol) over 30 min. The mixture is warmed to room temperature (RT) and after 30 min, 4-chloro-3,5-dimethylnitrobenzene (283.2 g, 1.526 mol; prepared by the method described by Yokoyama et. al. in EP580550) is added in one portion and the reaction is heated at 120° C. for 2 h. The reaction is cooled to room temperature (RT) and quenched with water (1500 mL). The suspension is cooled to 0° C., stirred for 30 min, then filtered and the filtercake is washed with water and dried in vacuo. The crude product, ethyl acetate (EtOAc; 2100 mL) and charcoal (42.6 g) were heated to reflux and the solids were removed by filtration through celite while hot. The filtrate is concentrated under reduced pressure to ca. 800 mL and the resulting suspension is cooled to 0° C. and stirred for 30 min. The product is collected by vacuum filtration, washed with cold EtOAc and dried in vacuo to afford 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene: NMR (CDCl3) 2.22 (s, 6H), 3.78 (s, 3H), 6.68 (d, 2H, J=8.7) 6.82 (d, 2H, J=8.7), 8.02 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>O1CCCC1.C1(C)C=CC=CC=1>[F:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[C:8]([I:12])[CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(F)cc(I)cc1C(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(F)cc(I)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg (1.78 mmol) of 2-amino-3-fluoro-5-iodo-benzoic acid in 5.0 mL tetrahydrofuran was added 1.4 mL (2.67 mmol) of 20% w/v solution of phosgene in toluene. The reaction was stirred for 16 hours at room temperature. The solution was concentrated to dryness to afford 550 mg (1.79 mmol, quantitative yield) of 8-fluoro-6-iodo-1H-benzo[d][1,3]oxazine-2,4-dione as a brown powder. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.09 (dd, 1H), 7.98 (s, 1H).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.C(OC([C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH3:23])=O)C.[OH-].[K+].Cl>C1(C)C=CC=CC=1.O>[CH2:20]([N:19]1[C:18]2[CH:17]=[CH:16][NH:15][C:14]=2[C:7](=[S:8])[NH:6][C:4]1=[O:5])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCNc1cc[nH]c1C(=O)OCC
Reactant: CCOC(=O)N=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)[nH]c(=S)c2[nH]ccc21
Temperature: 90 °C
Yield: 6.5 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.13 ml, 1.1 mmol) was added to 3-(butylamino)-1H-pyrrole-2-carboxylic acid ethyl ester (0.23 g, 1.1 mmol) in toluene (5 mL) and the mixture was heated at 90° C. for 1 h. The precipitate was filtered off and washed with hexane. The intermediate product was treated with potassium hydroxide (0.55 g, 9.9 mmol) in water (9 mL), and heated to reflux for 15 h. After cooling to ambient temperature, the pH was adjusted to pH 5 with 12 M HCl. The resultant precipitate was collected by filtration and washed with water. The crude product was purified using preparative HPLC to give the title compound (16 mg, 6%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Cl-].C([Al+]CC)C.[C:21]1([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:24]2[CH:23]=[CH:22][C:21]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:26][CH:25]=2)=[CH:4][C:3]=1[S:11]([NH2:12])(=[O:14])=[O:13]
Reactant: c1ccc(N2CCCCC2)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(N3CCCCC3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.1 %

Procedure:
A solution of 300 mg of 4-chloro-3-sulfamoyl-benzoyl chloride (1.186 mmol, 1 equivalent) in 20 mL of dichloromethane is stirred at room temperature as 2.37 mL of diethyl aluminum chloride (1.0 M in hexane) is added drop-wise. The reaction is stirred at room temperature for 10 minutes, then 229 mg of 1-phenyl piperidine is added. The reaction is stirred at room temperature for 30 minutes. The reaction mixture is poured onto ice-2 N HCl and extracted with dichloromethane. The aqueous layer is then basified with 2 N sodium hydroxide and extracted with dichloromethane. The combined organic extracts are washed with water, dried over sodium sulfate, and concentrated in vacuo. After purification by flash chromatography, 180 mg of product is obtained. 1H NMR (400 MHz, CDCl3): δ 1.69 (s, 6H), 3.18 (m, 1H), 3.42 (s, 3H), 5.18 (s, 2H), 6.86 (d, 2H, J=8 Hz), 7.62 (d, 1H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 8.42 (s, 1H). MS (m/z): 379 (M+1). Analytics calculated for C18H19ClN2O3S: C, 57.06; H, 5.05; N, 7.39. Found: C, 56.88; H, 5.04; N, 7.13.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][N:12]=[C:11]3[C:14](=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH2:15][S:16](=[O:19])(=[O:18])[CH2:17][CH:10]23)[CH:6]=[CH:7][CH:8]=1.O.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C>[C:34]([N:13]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=2)[CH:10]2[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:14](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:11]2=[N:12]1)(=[O:36])[CH3:35]
Reactant: O=S1(=O)CC(=Cc2cccc(C(F)(F)F)c2)C2=NNC(c3cccc(C(F)(F)F)c3)C2C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1N=C2C(=Cc3cccc(C(F)(F)F)c3)CS(=O)(=O)CC2C1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A suspension of 2,3,3a,4,6,7-hexahydro-3-[3-(trifluoromethyl)phenyl]-7-[[3-(trifluoromethyl)phenyl]methylene]thiopyrano[4,3-c]pyrazole-5,5-dioxide in 2ml of acetic anhydride and 25ml of acetic acid is heated on a steam bath for 15 minutes with occasional swirling. About 10ml of hot water is added and the solution is allowed to cool to room temperature. The solids are collected and washed with acetic acid/water (3/2) and water, and dried in vacuo over phosphorus pentoxide at 50°C to give 1.56g of the title compound, melting point 200°-202.5°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C:19](=[O:21])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]([O:24][CH3:25])=[O:23])[NH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C:19](=[O:21])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]([O:24][CH3:25])=[O:23])[N:11]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ICc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(Cc1ccccc1)C3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Yield: 49.1 %

Procedure:
To a solution of 2-benzyl-4-oxo-5-carbomethoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (0.928 g, 2.78 mmol) in dry tetrahydrofuran (5 mL) was added 60% sodium hydride in oil (111 mg). The resulting mixture was stirred at room temperature until gas evolution ceased. A solution of benzyl iodide (0.606. g, 2.78 mmol) in dry tetrahydrofuran (5 mL) was added to the reaction mixture and the resulting solution stirred at room temperature for 60 h. The mixture was diluted with methylene chloride and washed twice with saturated sodium chloride solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate resulting in a yellow precipitate (163 mg). The filtrate was concentrated in vacuo and chromatographed (silica gel, 5% methanol/95% methylene chloride) to provide an additional 580 mg of the title compound (743 mg total, 63%) as a crystalline solid: mp 198-199° C. 1H NMR (CDCl3) d 7.43 (d, J=7 Hz, 1 H), 7.36 (d, J=8 Hz, 1 H), 7.25 (m, 9 H), 6.95 (m, 2 H), 5.24 (s, 2 H), 4.01 (s, 3 H), 3.78 (m, 4 H), 3.40 (bs, 2 H); MS EI+ m/e 425 (p+1); IR (KBr, cm−1) 1726, 1648, 1449, 1291, 1134, 1107.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4-hydroxy-7-trifluoromethylquinoline-3-carboxylate (370.5 g), anhydrous potassium carbonate (179.4 g), iodomethane (202.4 g) and anhydrous dimethylformamide (2 liters) was stirred at room temperature overnight. More dimethylformamide (500 ml) was added and stirring was continued for 24 hours. The dimethylformamide was distilled off in vacuo and water (2 litres) was added to the residue. The resulting solid was collected, washed with water, dried and recrystallised from IMS to give the novel compound ethyl 1-methyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylate, m.p. 222°-224°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1.Cl[Sn]Cl.O.[CH:21](O)=O>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:13]=[CH:21][NH:14][C:4]=2[CH:3]=1
Reactant: Nc1cc(N2CCCC2)c(Cl)cc1[N+](=O)[O-]
Reactant: O=CO
Agent: Cl[Sn]Cl
Solvent: O
Product: Clc1cc2[nH]cnc2cc1N1CCCC1
Temperature: 130 °C
Yield: 70 %

Procedure:
Formic acid (2.9 mL) was added to a mixture of 4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine (0.240 g, 1.00 mmol) and SnCl2.H2O (0.680 g, 3.00 mmol), and the mixture was heated to 130° C. in a microwave reactor for 5 min. Six reactions were performed on the same scale. The combined crude mixture was filtered and washed with EtOAc (100 mL). The organic layer was treated with water (25 mL) and neutralized with aqueous 6M NaOH. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc and the solid was collected to yield the titled compound (1.08 g, 70%) as the formate salt. MS (ESI/CI): mass calcd. for C11H12ClN3, 221.1; m/z found, 222.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.84-12.16 (br s, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H), 7.20 (s, 1H), 3.20 (t, J=6.3 Hz, 4H), 2.06-1.66 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[NH2:19])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#N.O.S(=O)(=O)(O)[OH:24].[OH-].[Na+]>C(O)(=O)C>[CH3:18][C:14]1[C:13]2[NH:19][C:6](=[O:24])[C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:21])([F:20])[F:1])[C:4]=3[S:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(Sc2c(C#N)cccc2C(F)(F)F)c1N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c1NC(=O)c1cccc(C(F)(F)F)c1S2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Trifluoromethyl-2-(3-methyl-2-aminophenylthio) benzonitrile (2.53 g, 8 mmol) was dissolved in acetic acid (25 ml), water (25 ml) and concentrated sulphuric acid (25 ml) and the mixture stirred and heated under reflux for 7.5 hours, then at ambient temperature for 15 hours before further sulphuric acid (25 ml) was added and the mixture stirred and heated under reflux for a further 8.5 hours. The mixture was allowed to stand at ambient temperature overnight then poured onto crushed ice (200 ml) and basified to pH 4 with aqueous sodium hydroxide (10N). The mixture was extracted with dichloromethane (3×200 ml) and the combined organic fractions dried (magnesium sulphate) and evaporated. The residue was dissolved in xylene (400 ml) and heated under reflux for 72 hours in a Dean-Stark apparatus, before being allowed to cool. After evaporation of the xylene, recrystallisation from toluene, followed by recrystallisation from ethanol, the title compound was obtained as an off-white solid (1.02 g, m.p. 273°-277°).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([O:1][C:2]2[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCSc1ccc(C(=O)OC)c(O)c1
Product: CCSc1ccc(C(=O)OC)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 46 %

Procedure:
Using a method similar to Example 1-D, methyl 2-hydroxy-4-(ethylthio)benzoate and 1-Boc-4-hydroxy-piperidine gave the title compound (5.0 g, 12.64 mmol 46%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1)#[N:16]
Reactant: N#Cc1ccccc1CBr
Reactant: OB(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A suspension of (4-mercaptophenyl)boronic acid (0.847 g, 5.50 mmol), 2-(bromomethyl)benzonitrile (1.62 g, 8.25 mmol) and potassium carbonate (2.28 g, 16.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (2/1) and recrystallized from hexane/ethyl acetate to give the title compound (903 mg, yield 61%) as colorless crystals.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CN([CH:27]=[O:28])C>C1COCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:27]=[O:28]
Reactant: COc1ccncc1
Reactant: CN(C)C=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccncc1C=O
Temperature: -23 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a stirred solution of 1.7 M t-butyl lithium in THF (35.0 mL, 59.6 mmol) with THF (150 mL) at −78° C. was added dropwise 2-bromomesitylene (4.6 mL, 29.8 mmol). After stirring for 1 h, 4-methoxy-pyridine (2.5 g, 22.9 mmol) was added dropwise. This solution was warmed to −23° C. and stirred for 3 h and then cooled to −78° C. again. DMF (2.7 mL, 34.4 mmol) was added and the solution was stirred at −78° C. for 1 h. The reaction was quenched at this temperature with brine (150 mL) and extracted with ether. The combined ether was dried over K2CO3 and evaporated in vacuo. The residue was chromatographed with 50%-80% EtOAc/hexanes to give 2.1 g (65%) of 4-methoxy-pyridine-3-carbaldehyde as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.[CH:33]([C:36]1[NH:37][CH2:38][CH2:39][CH:40]=1)([CH3:35])[CH3:34].CCN(C(C)C)C(C)C>C(Cl)CCl>[CH:33]([CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:17](=[O:18])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:20])([CH3:21])[CH3:1])=[N:6]1)([CH3:35])[CH3:34]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CC(C)C1=CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)N3CCCC3C(C)C)c2c1
Temperature: 45 °C

Procedure:
To a solution of 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid 1 mL DMF was added 23.0 mg HOBt, 22.5 mg 2-isopropylpyrroline hydrochloride, 38.3 mg EDC, and 64.6 mg DIEA in that order. The mixture was stirred heated at 45° C. for two hours and purified by RP-HPLC using 60-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound. LC-MS: 4.05 min. (m/Z=386.4, 408.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:23]([C:26]2[S:27][C:28](Br)=[CH:29][CH:30]=2)(=[O:25])=[O:24])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].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.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:23]([C:26]2[S:27][C:28]([C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)=[CH:29][CH:30]=2)(=[O:25])=[O:24])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(C)C1(NS(=O)(=O)c2ccc(Br)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)C1(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Temperature: 60 °C

Procedure:
A solution of the bromo intermediate D6 (0.2 g, 0.00037 moles), 4-chlorophenylboronic acid (0.070 g, 0.00045 moles), K2CO3 (2M solution, 1 ml), ethanol (1 ml) and toluene (2 ml) at room temperature was degassed by bubbling argon through the solution for 10 minutes. Pd(PPh3)4 (0.1 g, 0.000086 moles) was added and the mixture heated at 60° C. under argon for 24 hours. Upon cooling the mixture was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (×3) and the combined organic phase washed with water, brine then dried over anhydrous MgSO4. The solution was evaporated to dryness then purified by chromatography over silica eluting, with hexane up to 50% EtOAc/hexane, affording the title compound D8 as a off white foam, which was used directly in the next step. M-H 563.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]#[N:25])[CH:16]=[CH:15]4)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:16]=[CH:15]4)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCOc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)cs2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
A mixture of {[6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetonitrile (204 mg, 0.596 mmol), prepared in the previous step, sodium azide (119 mg, 1.82 mmol) and ammonium chloride (98 mg, 1.82 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 5 h. The reaction was partitioned between 10% methanol-methylene chloride and 1 N HCl. The organic layer was separated, extracted three times with water, dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (87 mg, 37%) as a white solid, mp 226-228° C. Elemental Analysis for C21H15N5OS+0.23 H2O Calc'd: C, 64.74; H, 4.00; N, 17.98. Found: C, 63.46; H, 4.08; N, 16.95