Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CC(=O)C=C2C=1C1C(=CC=CC=1)C=N2.C1(=O)NC(=O)C2=CC=CC=C2C1.[CH3:28][C:29]12[CH:40]=[CH:39][CH:38]=[CH:37][CH:30]1[CH2:31][C:32]([NH:34][C:35]2=[O:36])=[O:33].[CH:41]([C:43]([CH2:45][S:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])=[CH2:42]>>[CH3:28][C:29]12[CH:40]=[C:39]([CH2:42][CH2:41][C:43](=[O:44])[CH2:45][S:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:38]=[CH:37][CH:30]1[CH2:31][C:32]([NH:34][C:35]2=[O:36])=[O:33]
Reactant: CC12C=CC=CC1CC(=O)NC2=O
Reactant: C=CC(=O)CSc1ccccc1
Agent: O=C1C=c2ncc3ccccc3c2=CC1
Agent: O=C1Cc2ccccc2C(=O)N1
Product: CC12C=C(CCC(=O)CSc3ccccc3)C=CC1CC(=O)NC2=O

Procedure:
3(2H)-Phenanthridinone derivatives have been prepared from homophthalimide by the method of H. Iida et al., (Heterocycles 1983, 20, 227-30). 2-Methyl-homophthalimide is reacted with phenylthiomethyl vinyl ketone (prepared by the method A. G. Schultz et al.,J. Am. Chem. Soc. 1978, 100, 2140-9) in the presence of Triton B according to the described method to form 2-methyl-4-(3'-oxo-4'-phenylthiobutyl)-homophthalimide 9.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[C:10]1([CH:9]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1Cl
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Clc1ccccc1N=Cc1ccccc1
Temperature: 90 °C
Yield: 81 %

Procedure:
98% 2-chloroaniline (781 g; 6 mol) and 98% benzaldehyde (659.6 g; 6 mol) were dissolved in ethanol (832 g), and the solution was boiled under reflux for 8 h (heating apparatus adjusted to 90° C.). Subsequently, the reaction solution was concentrated on a rotary evaporator at 85° C. and 20 mbar and then fractionally distilled through a distillation apparatus. The main fraction distilled over at 142° C. and 1.3 mbar. 1048 g of the product were obtained in 99% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(=O)C.[Na+].[Br:20]Br.O>C(O)(=O)C>[Br:20][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][CH2:12][C:13]#[N:14]
Reactant: COc1ccc(CCC#N)cc1OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(CCC#N)cc1OC
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of 21 g of 3-(3,4-dimethoxyphenyl)propanenitrile, 10.3 g of sodium acetate and 400 mL of acetic acid there are added 20 g of dibromine in 50 mL of acetic acid. The resulting reaction mixture is stirred overnight and then poured into water and extracted with benzene. The organic phase is washed with aqueous sodium thiosulphate solution and then with water, dried over sodium sulphate and concentrated under reduced pressure. The crude reaction product is purified on a silica column (eluant: benzene), and the product obtained is recrystallised from ethanol to yield 19.3 g of the expected product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:16])=[O:15])=[CH:8][CH:7]=1.CO>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:15])=[O:16])=[CH:8][CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(-c2ccco2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(-c2ccco2)cc1
Yield: 12.7 %

Procedure:
2-[[(E)-2-[4-(2-Furyl)phenyl]ethenyl]sulfonylamino]benzenesulfonamide (Example 18) (140 mg, 0.35 mmol) was dissolved in ethyl acetate (1.5 mL) and methanol (1.5 mL) and the mixture was subjected to reduction using the H-cube instrument. The reaction mixture was eluted through the Pd/C (10%) cartridge using full hydrogen (1 atm) at 0.5 ml/min. The solvent was then removed and the crude material was purified on semi-preparative HPLC using an X-Terra column to give the title compound (18 mg, 13%) as a white solid. The compound of Example 17 was also obtained.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
The title acid of Step 9 (5.2 g, 30 mmol) was dissolved in dimethylformamide (25 mL) and cooled to 0° C. To this potassium carbonate (5.7 g, 41.48 mmol) was added followed by benzyl bromide (5.7 g, 29.7 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 3 times of water, brine. The solution was dried (Na2SO4) and evaporated. The residue was purified by flash chromotography on silica gel, eluting with 90:10 heptane:ethyl acetate to give the pure title compound as colorless oil (4.5 g, 60% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C17H16O2 : C, 80.93; H, 6.39. Found: C, 80.69; H, 6.47.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[O:14]C=CC=3)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)=[CH:4][C:3]=1[C:22]#[N:23].C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=[O:30].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:30])=[O:14])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)ccc1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-(2-furyl)pyrazole (4.0 g, 12.5 mmol) in acetonitrile (30 mL) was added carbon tetrachloride (30 mL), ruthenium chloride (0.4 g) and a solution of sodium periodate (11.9 g, 56.1 mmol) in water (45 mL). The reaction is stirred at room temperature overnight. The next day the reaction mixture was filtered through celite. The filtrate was concentrated and partitioned between ethyl acetate and HCl (1N). The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated to give 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxycarbonyl pyrazole (2.4 g, 64% yield) as pure compound. MS (ES−): 298 (M−H)− (40%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Li].C([Li])CCC.[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:14]([CH:13]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)[OH:18])[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cscn1
Reactant: CC(C)CC=O
Agent: [Li]
Agent: [Li]CCCC
Product: Cc1csc(C(O)CC(C)C)n1

Procedure:
d. Isobutyl (4-methyl-2-thiazolyl) carbinol was prepared by starting from 4-methyl-thiazole and substituting the hydrogen atom in the 2-position by lithium by reaction with butyllithium. The resulting metal-organic compound was reacted with isovaleraldehyde [cf. J.A.C.S. 74, 6260 (1952)]. The resulting product had a b.p. of 94° C./0.1 mm. Hg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]([OH:23])[CH:16]([CH3:22])[C:17]([O:19]CC)=O.[OH2:24].[OH-].[Na+]>O1CCCC1.CCOCC>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([OH:23])([OH:24])[CH:16]([CH3:22])[CH2:17][OH:19]
Reactant: O
Reactant: CCOC(=O)C(C)C(O)Cc1ccccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CO)C(O)(O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Under a nitrogen atmosphere, 2.84 g (74.9 mmol) of lithium aluminum hydride was added to 30 ml of tetrahydrofuran (hereinafter, referred to as THF). A solution of 18.0 g of ethyl 4-(2-fluorophenyl)-3-hydroxy-2-methylbutanoate in 180 ml of THF was added thereto. After stirring for 1.5 hr at room temperature, 5 ml of water and 5 ml of 1N-NaOH aqueous solution were added thereto successively to quench the reaction. 100 ml of Et2O was added to the quenched reaction mixture, after stirring a while, the obtained suspension was filtered. The filtrate was distilled off and the residue was purified by silica gel column chromatography to obtain 14.5 g of the title compound as a colorless oil. (Yield: 99%)
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:20][CH2:21][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])=[O:8])[CH3:5].[OH-].[Na+]>C1COCC1>[CH3:5][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:20][CH2:21][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])=[O:8])([CH3:30])[C:3]([OH:31])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCC(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CCOc1c(C(=O)NC(C)(C)C(=O)O)ccc2ccccc12)c1ccccc1

Procedure:
A solution of 105 mg 2-methyl-2-{[1-(3-phenyl-butoxy)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester in 2.5 ml THF was treated with 0.2 ml of 2 M aqueous sodium hydroxide. After 3 h at 60° C. another 0.1 ml of 2 M NaOH was added, and after 6 h at 65° C. the reaction was concentrated, the residue was taken up in 3 ml of water, treated with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate and evaporated. After purification by RP-HPLC 15 mg 2-methyl-2-{[1-(3-phenyl-butoxy)-naphthalene-2-carbonyl]-amino}-propionic acid were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([N:34]1[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]1)=[O:23])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
21.31 g of N-benzyloxycarbonyltyrosine and 11.79 of N-(tert-butoxycarbonyl)piperazine were dissolved in a mixed solvent of 200 ml of methylene chloride and 100 ml of ethyl acetate, and to the solution was added 14 g of DCC. After stirring at a room temperature for 40 hours, precipitated insoluble matter was filtered off, and the filtrate was concentrated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (1:1) to obtain 23.9 g of the title compound in a colorless amorphous form
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(NCc3ccccc3)c2n1
Product: c1ccc(CNc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 118 from 8-benzylamino-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 139°-141° C.) and piperazine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[N:4]1[C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15]1=[O:20]
Reactant: COC(=O)Oc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of 2-fluoro-4-chloro-5-methoxycarbonyloxyaniline (20.0 g, 91.1 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (14.0 g, 92.0. mmol) in acetic acid (200 ml) was reacted for 5 hours while heating under refluxing. After completion of the reaction, the mixture was cooled to room temperature, water (200 ml) was added thereto, and extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with an aqueous solution of sodium carbonate and water, dried, and the solvent was distilled off under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent: ethyl acetate/hexane=1/5) to obtain N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (26.2 g, 72.1 mmol, 79.2% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-:26].[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[NH:3][C:4](=[O:26])[C:5]2[N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:9]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)nc(Cl)c21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)[nH]c(=O)c21
Yield: 87.4 %

Procedure:
To a solution of 2,6-dichloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-purine (0.12 g, 0.31 mmol) in dioxane (5 ml) was added aqueous solution of sodium carbonate (0.012 g, 1.24 mmol, in 4 ml water). Reaction mixture was refluxed overnight. Reaction mixture was concentrated and water was added in it and it was extracted with ethyl acetate. Ethyl acetate layer was washed with brine and water, dried over sodium sulphate, filtered and concentrated. Residue obtained was washed with ether to obtained 2-chloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 87%) as white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMF (20 mL) was added methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol). After stirring for 15 min at room temperature, benzyl bromide (1.1 g, 6.58 mmol) was added. After stirring at room temperature for 3h, the solution was partitioned between ethyl acetate and water. The organic layer was washed with water (2×75 mL), saturated aqueous sodium bicarbonate, and brine, then dried (MgSO4), filtered and concentrated to yield an off-white solid (1.013 g, 4.2 mmol). 1H NMR (400 MHz, CDCl3) d 7.67 (m, 2H), 7.48-7.34 (m. 6H), 7.19 (m, 1H), 5.12 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[C:5]#[N:6].S(=O)(=O)(O)[OH:14]>>[Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[C:5]([NH2:6])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(F)c(Br)c1F
Product: NC(=O)c1cc(F)c(F)c(Br)c1F
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-2,4,5-trifluorobenzonitrile (13.9 g) in concentrated sulfuric acid (8 ml) was heated for 20 minutes on an oil bath (100° C.), poured into ice water (350 ml). The resulting precipitate was collected by filtration and washed with water. The filtrate and washings were extracted 3 times with dichloromethane. The dichloromethane layer was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the residue. The combined mixture of the precipitate obtained previously and the residue was purified by silica gel chromatography eluting with dichloromethane dichloromethane:methanol (10:1) to give 3-bromo-2,4,5-trifluorobenzamide (8.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:12][CH3:13].[C:14](=O)([O-:16])[O-:15].[Na+].[Na+]>O1CCOCC1.O.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[Cl:11][C:9]1[CH:10]=[C:2]([C:14]([OH:16])=[O:15])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[C:5]2[CH2:12][CH3:13]
Reactant: CCc1n[nH]c2c(Cl)cc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [Mo]
Agent: [Pd]
Agent: [C-]#[O+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1n[nH]c2c(Cl)cc(C(=O)O)cc12
Temperature: 165 °C
Reaction time: 0.01 h
Yield: 86.3 %

Procedure:
To a microwave tube were added 5-bromo-7-chloro-3-ethyl-1H-indazole (127.0 mg, 0.49 mmol) dissolved in dioxane (1.0 mL). The Hermann's catalyst ((trans-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II))) (23.0 mg, 0.024 mmol) and molybdenum hexacarbonyl (64.4 mg, 0.244 mmol) were added followed by a solution of sodium carbonate (156 mg, 1.47 mmol) in water (2.0 mL). Separation occurs within the vessel. The mixture was stirred for 20 seconds and then the mixture was heated to 165° C. for 15 minutes under mircrowave irradiation with the absorption setting at very high. The reaction was stopped and the vessel was vented before handling. The mixture was filtered and washed with EtOAc. The filtrate was concentrated and the residue was re-dissolved with water. The solution was then acidified to pH ˜3. The solid was collected and dried to afford 7-chloro-3-ethyl-1H-indazole-5-carboxylic acid as a solid (95.0 mg, 86.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[Cl-].C([N+]1C=CC=CC=1)CCCCC.[Br:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:10]2[C:9]([C:12]#[N:13])=[C:8]([CH2:14][CH3:15])[N:7]([CH3:16])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[n+]1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(CC)n1C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
Step DII: In a 500 mL round bottom flask, a mixture of 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (20.00 g, 60.2 mmol, preparation 38), Pd(OAc)2 (202 mg, 0.901 mmol, 0.0150 equiv)), Ph3P (479 mg, 1.83 mmol, 0.0304 equiv) and 1-hexylpyridinium chloride (C6PyCl, 10.0 mL) is degassed 3 times by alternating house vacuum (15 seconds) and nitrogen. Degassed heptane (200 mL) is added and the mixture is kept under nitrogen and heated to ˜80° C. (nearly to reflux). The resulting brown solution is allowed to cool to rt. 4-Bromophenylboronic acid (13.60 g, 67.66 mmol, 1.12 equiv) and degassed 2M Na2CO3 (60.0 mL, 120 mmol, 2.00 equiv) are added. The mixture is heated at 84.5° C. (reflux) for 5.5 h under nitrogen. Upon cooling to rt, water (200 mL) and EtOAc (50 mL) are added and stirred for 15 min. until the layers separate. The aqueous phase is extracted 3 times with EtOAc (100 mL each). The combined organic extracts are washed with water (100 mL) and brine (100 mL), dried Na2SO4), filtered and concentrated on the rotovap. This provides 21.3 g of crude title compound. 42 mL EtOH and 4 mL THF are added to this solid and the mixture is heated to 60° C. at which point everything dissolves. Eight mL water is added at 60° C. and the solution is allowed to slowly cool. At ˜40° C. solids start to form. The mixture is cooled to 28° C. then placed in an ice bath to cool to 8° C. The solids are collected by filtration and rinsed three times with cold EtOH (25 mL each). The wet material is dried in a vacuum oven at 40° C. to provide 13.78 g of title compound (63% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:20]=[C:21]4[C:30](=[CH:31][CH:32]=3)[C:29]3[N:25]([CH:26]=[C:27]([C:33]5[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][N:34]=5)[N:28]=3)[CH2:24][CH2:23][O:22]4)=[CH:17][CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH:38]([N:37]1[C:33]([C:27]2[N:28]=[C:29]3[C:30]4[CH:31]=[CH:32][C:19]([C:18]5[N:14]([CH:11]6[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]6)[N:15]=[CH:16][CH:17]=5)=[CH:20][C:21]=4[O:22][CH2:23][CH2:24][N:25]3[CH:26]=2)=[N:34][CH:35]=[N:36]1)([CH3:40])[CH3:39]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccnn3C3CCN(C)CC3)cc1OCC2
Yield: 27.3 %

Procedure:
A mixture of tert-butyl-4-(5-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.184 mmol) and LiAlH4 (35.0 mg, 0.921 mmol) in THF (5.00 mL) was refluxed for 1 h. At the end of reaction, H2O was added to quench reaction. After filtration, the filtrate was evaporated to afford the crude product, which was purified by reverse phase combiflash eluting with 0-50% gradient CH3CN in 0.5% NH4HCO3 and followed by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give 160 (23 mg, 27% yield) as white solid. LCMS (ESI): RT=4.93 min, m/z: 459.4 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 8.53 (d, J=8.5 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.39 (d, J=1.5 Hz, 1H), 5.94-5.91 (m, 1H), 4.57 (s, 4H), 4.15 (s, 1H), 2.84-2.82 (m, 2H), 2.16 (s, 3H), 2.15-2.12 (m, 2H), 1.94-1.89 (m, 2H), 1.10-1.79 (m, 2H), 1.50 (s, 6H)
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[N:9]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1cccc(Cl)c1[N+](=O)[O-]
Product: Cc1cccc2c1nc(C)n2-c1ccccc1
Yield: 33.3 %

Procedure:
Method A applied to 3-chloro-2-nitrotoluene (86 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as brown solid (37 mg, 33%). 1H NMR (DMSO) δ 2.46 (s, 3H), 2.55 (s, 3H), 6.88 (d, J=7.3Hz, 1H), 7.04-7.11 (m, 2H), 7.50-7.64 (m, 5H); 13C NMR δ 13.8, 16.3, 107.5, 122.5, 122.6, 126.8, 129.9, 135.1, 135.3, 150.3, 158.3.