Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][OH:23])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][OH:23])[CH:5]=1
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CO
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2C(=O)c3ccc(Cl)cc3C2=O)c(CO)c1

Procedure:
The mixture of 3.0 g of N-(4-nitro-2-hydroxymethylphenyl)-4-chlorophthalimide, 1.5 g of Raney nickel and 250 ml of ethyl acetate is hydrogenated at room temperature and atmospheric pressure until the hydrogen uptake ceases. It is filtered, the filtrate evaporated and the residue recrystallized from ethyl acetate-diethyl ether, to yield the N-(4-amino-2-hydroxymethylphenyl)-4-chlorophthalimide melting at 228°-230°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.N1CCCC1>>[NH2:20][C:8]([N:4]1[CH2:1][CH2:2][CH2:6][CH2:5]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CS(=O)(=O)O
Solvent: C1CCNC1
Product: NC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CCCC1

Procedure:
The compound of Example 25 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 287.77; found mol. wt. (M+H) 288.3; 574.8 (Dimer)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](=[S:10])[NH:6][C:5]=1[C:11]#[N:12])([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:17]C(Br)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:17][S:10][C:7]1[N:6]=[C:5]([C:11]#[N:12])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: Fc1cc(F)cc(CC(Br)c2ccccc2)c1
Reactant: N#Cc1[nH]c(=S)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 97.9 %

Procedure:
A mixture of 3-nitro-6-thioxo-1,6-dihydropyridin-2-carbonitrile (4.42 mmol, 1.34 g), 3,5-diflurobenzylbenzylbromide (8.83 mmol, 1.828 g), and K2CO3 (11.04 mmol, 1.525 g) in 5 ml of acetone is heated at 70° C. for 10 hours and then evaporated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield 1.33 g (98%) of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][N:11](C([C@@]34C(C)(C)[C@@](C)(CC3)C(=O)O4)=O)[CH2:10][C@@H:9]2[O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:4][CH:3]=1.CNC(NCCC[C@H](N)C(O)=O)=NC.C(O)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)N1CC[C@H](c3ccc(Br)cc3)[C@@H](OCc3ccc4ccccc4c3)C1)OC2=O
Agent: CN=C(NC)NCCC[C@H](N)C(=O)O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3ccccc3c2)cc1
Temperature: -40 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 736 mg (1.28 mmol) of (3R,4R)-4-(4-bromophenyl)-3-(naphthalen-2-ylmethoxy)-1-[(1 S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl]-piperidine in 32 ml of absolute tetrahydrofuran was cooled to -70° C. Thereto there was added dropwise a solution of 1.86 ml (6.5 mmol) of sodium dihydrido-bis-(2-methoxyethoxy)-aluminate (70% in toluene, about 3.5M) in 32 ml of tetrahydrofuran. The mixture was warmed to -40° C., stirred at -40° C. for 8 hours, thereafter cooled to -78° C. and treated dropwise with a solution of 0.5 ml of glacial acetic acid in 10 ml of tetrahydrofuran. For the working-up, the reaction mixture was partitioned between 200 mg of ethyl acetate and 200 ml of aqueous 5% sodium hydrogen carbonate solution. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product (800 mg) was purified by chromatography on silica gel with a 9:1 mixture of methylene chloride and methanol as the eluent. There were obtained 344 mg (68% of theory) of (3R,4R)-4-(4-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless solid; MS: 396, 398 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5]>CCOC(C)=O.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ccc1O
Reaction time: 1.5 h

Procedure:
4.50 g (27.00 mmol) of 2-hydroxy-5-nitro-benzonitrile was added to a suspension of 0.45 g Pd/C (10%) in 45 mL EtOAc and the mixture was hydrogenated for 1.5 hours under 3 bar H2atmosphere. The catalyst was filtered off and the residue dried i. vac.
Reaction SMILES: [C:1]1([NH:7][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][CH:28]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33]([N:7]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9](=[O:10])[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:34])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: O=C(C(Nc1ccccc1)c1ccccc1)N1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)N2CCCC2)c2ccccc2)c1
Yield: 20.5 %

Procedure:
A suspension of 1.6 g of (RS)-1-(α-phenylaminophenylacetyl)pyrrolidine and 1.2 g of 2-[3-(3-methylphenyl)ureido]acetic acid in 50 cm3 of anhydrous 1,2-dichlorethane is heated to reflux. 0.68 g of thionyl chloride is added, maintaining reflux until the evolution of gas has ceased. The reaction mixture is then poured into 30 cm3 of a saturated aqueous sodium bicarbonate solution and 50 cm3 of methylene chloride are then added. The organic phase is washed with 50 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The product obtained is purified by chromatography on 50 g of silica (0.065-0.200 mm) contained in a column 2.2 cm in diameter [eluent: ethyl acetate/methylene chloride (50-50 by volume)], collecting 25 cm3 fractions. Fractions 9 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from a mixture of ethyl acetate and acetonitrile (90-10 by volume), 0.55 g of (RS)-2-[3-(3-methylphenyl)ureido]-N-[2-oxo-1-phenyl-2-(1-pyrrolidinyl)ethyl]-N-phenylacetamide melting at 138° C. is obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C>[Br:12][C:10]1[CH:11]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: BrBr
Reactant: CC(C)Oc1ccc(N)cc1
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Isopropoxyaniline (24.2 g) was dissolved in acetic acid (300 mL), and a mixture of bromine (8.25 mL) and acetic acid (80 mL) was added dropwise. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Water was added to residue, and the mixture was extracted with diethylether. The extract was washed successively with aqueous sodium thiosulfate solution and brine, is and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-bromo-4-isopropoxyaniline (10.2 g) as a black brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:29])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[C:20]=2[CH:28]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:30][O:31][C:32]([C:34]1[C:35]([Cl:41])=[N:36][C:37](Cl)=[CH:38][CH:39]=1)=[O:33].C1N2CCN(CC2)C1>>[CH3:30][O:31][C:32](=[O:33])[C:34]1[CH:39]=[CH:38][C:37]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:29])[C:10]([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[C:20]=4[CH:28]=3)([OH:15])[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:36][C:35]=1[Cl:41]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)cc21
Agent: C1CN2CCN1CC2
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(Oc4ccc(C(=O)OC)c(Cl)n4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 62 step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-ethyl-4H-benzo[1,4]oxazin-3-one (Example 64, step 5) was reacted with methyl-2,6-dichloro-pyridine-3-carboxylate and DABCO (21 h, r.t.) to give the title compound as a white solid. MS (m/e)=599.3 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.CO.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([Cl:30])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cl)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXXII) (12.0 g, 45.6 mmol) was taken in neat oxalyl chloride (30 ml), 0.2 mL of DMF was added and the mixture was stirred at room temperature for 1 hour. Completion of the reaction was monitored by TLC which showed the formation of a non-polar spot after treatment of a small amount with methanol. Then the reaction mixture was concentrated under reduced pressure to provide (S)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXXIII) (12.66 g) which was directly used in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:12]O[C:10]=1[C:21]([O:23]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[NH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:12][N:31]2[CH2:32][CH2:33][NH:34][C:21](=[O:23])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1occ(-c2nccs2)c(=O)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1NCCn2cc(-c3nccs3)c(=O)c(OCc3ccccc3)c21
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
Methyl 3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate (1.47 g) was suspended in ethanol (15 ml)-dioxane (15 ml), and tert-butyl (2-aminoethyl)carbamate (0.816 ml) was added. After stirring at 70° C. for 1.5 hr, the solvent was evaporated and 4N hydrochloric acid/dioxane solution (70 ml) and chloroform (10 ml) were added to the residue. After stirring at room temperature for 2 hr, the reaction mixture was concentration under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution (20 ml) and methanol (50 ml) were added to the residue and the mixture was stirred for 2 hr. The solvent was evaporated and the obtained solid was collected by filtration and washed thoroughly with water to give 9-benzyloxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (1.07 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C[Si](C)(C)[O-:21].[K+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([C:8]([NH2:9])=[O:21])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(F)cc1Nc1ccc(I)cc1F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: NC(=O)c1ncc(F)cc1Nc1ccc(I)cc1F
Temperature: 100 °C

Procedure:
To 5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-pyridine-2-carbonitrile (50 mg, 0.14 mmol) in THF (0.7 mL) was added potassium trimethylsilanolate (40 mg, 0.28 mmol). The mixture was heated in sealed tube at 100° C. overnight. The mixture was then concentrated and purified by HPLC to afford the pure product. LC/MS [6.90 min; 376 (M+1)].
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=[O:10])([O-:5])=[O:4].[F:25][C:26]([F:35])([F:34])[C:27](I)([F:32])[C:28]([F:31])([F:30])[F:29]>CN(C)C=O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[N+:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:27]([F:32])([C:28]([F:31])([F:30])[F:29])[C:26]([F:35])([F:34])[F:25])=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])=[O:10])([O-:5])=[O:4]
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Reactant: O=C(Nc1ccccc1C(F)(F)F)c1cccc([N+](=O)[O-])c1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
1.1 g (27 mmol) of powdery sodium hydroxide and 1.2 g (4.5 mmol) of iron(II) sulfate heptahydrate were stirred in an ice bath, until the color of the mixture changed to black. Immediately after the discoloration, 5 g of N,N-dimethylformamide were added thereto, and then, a solution obtained by dissolving 1.0 g (3.2 mmol) of 3-nitro-N-(2-(trifluoromethyl)phenyl)benzamide and 1.3 g (4.5 mmol) of heptafluoroisopropyl iodide in 5 g of N,N-dimethylformamide was added thereto, followed by stirring at room temperature for 3 hours. The obtained reaction liquid was filtered through cerite and the residue was washed with 50 mL of ethyl acetate. Then, 40 g of water were added to the resulting reaction liquid, and after performing extraction, the organic layer was dried over magnesium sulfate. Then, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. Thereafter, the condensed residue was purified by silica gel chromatography, to obtain 0.44 g (yield 28%) of the title compound as a red solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4](=[O:27])[CH2:3]1>Cl.O1CCOCC1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:4](=[O:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
tert-butyl (2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)acetate (9.5 g, 25.9 mM) was dissolved in 200 ml of 4N HCl in dioxane and stirred overnight. Solvent was evaporated under reduced pressure providing 7.8 g of product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:9][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:10])[CH3:23]
Reactant: CCO
Reactant: O=C(O)C1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1CCC(O)CC1
Yield: 100 %

Procedure:
4-Hydroxycyclohexane carboxylic acid (5 g, 34.5 mmol) was heated to reflux for 16 hours in the presence of 50 mL of ethyl alcohol and 2 mL of sulfuric acid. Reaction volume was reduce by half at reduced pressure and mixture was poured into sat. Na2CO3. Mixture was extracted 3×50 mL of ethyl acetate and combined organics were washed with brine and dried over MgSO4. Title compound was obtained as a colorless crude oil. (5.9 g; 100% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18]C)=[N:16][N:17]=[C:10]1[C:9]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[N:8]2)=[O:4]>C(O)(=O)C.Br>[O:18]=[C:15]1[N:11]2[C:12]3[C:7]([N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:10]2=[N:17][NH:16]1)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=3
Reactant: COC(=O)c1ccc2c(c1)nc(NCCc1ccncc1)c1nnc(OC)n12
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)nc(NCCc1ccncc1)c1n[nH]c(=O)n12
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A suspension of 1-methoxy-4-(2-pyridin-4-ylethylamino)-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester (47 mg) in acetic acid (3 mL) and hydrobromic acid (1 mL) was stirred at 23° C. for 60 min., and was then heated to 100° C. for 90 min. After cooling to 23° C., the solution was concentrated and the resulting residue was triturated with MeOH/methylene chloride. Filtration afforded the title compound as a white solid. MS (M+H)+=351.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O-:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[OH:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C([O-])c1cnc2cc(O)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2cc(O)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (414 mg, 2.01 mmol) in a 2:1:1 THF/ethanol/water mixture (36 mL) was treated at ambient temperature with lithium hydroxide monohydrate (2.1 equivalents). The reaction mixture was stirred at ambient temperature overnight. To the reaction were then added another 2.1 equivalents of lithium hydroxide monohydrate and stirring continued for 72 hours. After removal of the volatiles the mixture was diluted with water, cooled in an ice bath, and the pH adjusted to 4 with aqueous 6N hydrochloric acid. The resulting white precipitate was isolated and dried to afford the desired product (358 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([Sn](CCCC)(CCCC)CCCC)=[CH2:5])[CH3:2].[NH2:19][C:20]1[N:41]=[C:40](Cl)[CH:39]=[CH:38][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23].C1(C)C(C)=CC=CC=1.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(OCC)(=O)C>[NH2:19][C:20]1[N:41]=[C:40]([C:4]([O:3][CH2:1][CH3:2])=[CH2:5])[CH:39]=[CH:38][C:21]=1[C:22]([NH:24][CH2:25][C:26]1[S:27][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 130 °C
Reaction time: 2.5 h
Yield: 82.6 %

Procedure:
1-Ethoxyvinyl(tri-n-butyl)tin (0.47 mL, 1.4 mmol) was added to a mixture of 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (170 mg, 0.46 mmol) described in Preparation Example A+-11, tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.046 mmol) and xylene (5 mL), and the solution was stirred for 2.5 hours at 130° C. After cooling, water and ethyl acetate were added to the reaction solution for extraction, and the solution was washed with brine. The solvent was evaporated in vacuo, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (150 mg, 0.38 mmol, 82%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:10][C:2]=1[CH3:1])=[O:18]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc2ccncc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1[nH]c2cnccc2c1C(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 2-methyl-1H-pyrrolo[2,3-c]pyridine (2.5 g, 18.9 mmol) and aluminum chloride (5 g, 37.8 mmol) in DCM (100 mL), trichloroacetylchloride (4.1 g, 22.7 mmol) was added dropwise into the reaction over 0.5 hours at room temperature. After stirring 2 hours, the reaction was cooled to 0° C. and was quenched with water (100 mL). The resulting precipitate was isolated by filtration to afford 2,2,2-trichloro-1-(2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone which was used for next step without further purification. Assumed 100% yield. (5.24 g).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[Si:10]([O:17][C:18]1[C:23]([CH2:24][CH3:25])=[CH:22][C:21]([CH:26]([C:28]2[N:29]([CH3:39])[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)O)=[C:20]([F:40])[CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CCN(CC)CC.[C:48]([O:52][C:53]([N:55]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:56]1[C:65]2[C:60](=[CH:61][C:62]([NH2:66])=[CH:63][CH:64]=2)[CH:59]=[CH:58][N:57]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl.O>[Si:10]([O:17][C:18]1[C:23]([CH2:24][CH3:25])=[CH:22][C:21]([CH:26]([C:28]2[N:29]([CH3:39])[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[NH:66][C:62]2[CH:61]=[C:60]3[C:65](=[CH:64][CH:63]=2)[C:56]([N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[C:67]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:68])=[N:57][CH:58]=[CH:59]3)=[C:20]([F:40])[CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3)nn2C)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
Methanesulfonic anhydride (184 mg, 1.3 mmol) was added to a solution of Intermediate 386.4 (292 mg, 0.66 mmol) and Et3N (0.30 mL, 2.2 mmol) in CH2Cl2 (5 mL) at 0° C. The mixture was stirred 1 h at 0° C., 1-(di-(tert-butyloxycarbonyl)amino)-6-aminoisoquinoline (475 mg, 1.3 mmol) was added and it was stirred 16 h at ambient temperature. Water (10 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes, EtOAc) yielded 280 mg of Intermediate 386.5 as a yellow solid. LCMS 783.53 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:14].CCCCCC>C(Cl)Cl.CO>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:12])=[C:10]([F:11])[C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)c(F)c1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(C)c(F)c1F
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,3-difluoro-4-methyl-benzoic acid (5.0 g, 29 mmol) in CH2Cl2 (20 mL) and MeOH (20 mL) is added 2.0 M TMSCHN2 in hexane (17.5 mL, 34.9 mmol) at 0° C. The reaction mixture is stirred for 1.0 h. The reaction mixture is concentrated to a residue and the residue is purified by flash chromatography to afford the title compound as an oil (5.7 g, 100%). LC-ES/MS m/e 208.3 (M+23).