Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH:24]=[O:25])([O-:14])=[O:13].[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[N:19]=[C:18]2[CH:24]=[O:25])([O-:14])=[O:13]
Reactant: C1=COCCC1
Reactant: O=Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
p-Toluenesulfonic acid (30 mg, 0.158 mmol) was added to a solution of 5-nitro-indazole-3-carbaldehyde (300 mg, 1.569 mmol) and 3,4-dihydro-2H-pyran (265 mg, 3.150 mmol) in a mixture of THF/CH2Cl2 (1:1, 8 mL). The reaction mixture was stirred for 12 h at room temperature and then the solvent was removed in vacuo. The residue was taken in CH2Cl2 (50 mL) and poured in water (20 mL). The organic layer was separated, the aqueous layer was extracted with CH2Cl2 (50 mL), the combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and concentrated. Purification by flash chromatography (CH2Cl2) afforded title compound 215 mg (50% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 9.23 (d, 1H, J=2.0 Hz), 8.35 (dd, 1H, J=2.0 and 9.2 Hz), 7.80 (d, 1H, J=9.2 Hz), 5.89 (dd, 1H, J=2.8 and 8.8 Hz), 3.98 (m, 1H), 3.80 (m, 1H), 2.53 (m, 1H), 2.19 (m, 2H), 1.76 (m, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([Br:17])[CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].Cl[CH2:19][C:20]#[N:21]>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:19][C:20]#[N:21])[C:10]2[C:15]([CH:16]=1)=[C:14]([Br:17])[CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2c(Br)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Br)cccc2n1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Sodiumhydride (4.0 g, 92 mmol) was suspended in dimethylformamide (20 mL) and a solution of 4-bromo-1H-Indole-2-carboxylic acid ethyl ester (16.4 g, 61 mmol) in dimethylformamide (70 mL) was added. The mixture was stirred for 1 h at room temperature and after cooling to 0° C. chloroacetonitrile (7.7 mL, 122 mmol) was added. After 1 h at room temperature the mixture was added to an ice/water mixture (800 mL) and extracted with ethylacetate. The organic phases were pooled washed with brine, dried with MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel (ethyl acetate/n-hexane 4:1) yielded 4-bromo-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (13.4 g, 71%) as a colorless solid, MS: m/e=306.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[F:12].Cl.[O:14]=[CH:15][CH2:16][C:17](S)=[NH:18]>>[C:10]([O:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([F:12])[C:2]([NH:1][C:17](=[NH:18])[CH2:16][C:15]([C:6]2[CH:5]=[CH:4][C:3]([F:12])=[CH:2][C:7]=2[F:8])=[O:14])=[C:7]([F:8])[CH:6]=1)(=[O:11])[CH3:9]
Reactant: N=C(S)CC=O
Reactant: Nc1c(F)cc(CCO)cc1F
Agent: Cl
Product: CC(=O)OCCc1cc(F)c(NC(=N)CC(=O)c2ccc(F)cc2F)c(F)c1

Procedure:
In stage 1, the 2-(4-Amino-3,5-difluorophenyl)ethanol and 4-Chlorophenyl difluorophenyl)-3-oxopropanimidothioate hydro-chloride are reacted together to form 2-(4-{[3-(2,4-Difluorophenyl)-3-oxopropanimidoyl]amino}-3,5-difluorophenyl)ethyl acetate. In stage 2, propiolic acid is added to form 2-{4-[6-Amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl acetate. In stage 3, the acetate group is hydrolysed to leave an alcohol and in stage 4 the resulting alcohol group is oxidised to an aldehyde. The compound of the invention is then formed in stage 5, by the addition of tert-butyl L-alaninate hydrochloride. Tert-butyl L-alaninate hydrochloride is commercially available.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[Br:9][C:10]1[N:14]2[N:15]=[C:16](F)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1>>[Br:9][C:10]1[N:14]2[N:15]=[C:16]([NH:1][CH2:2][C@H:3]3[NH:7][C:6](=[O:8])[CH2:5][CH2:4]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: NC[C@@H]1CCC(=O)N1
Reactant: Fc1ccc2ncc(Br)n2n1
Product: O=C1CC[C@@H](CNc2ccc3ncc(Br)n3n2)N1
Yield: 62 %

Procedure:
The (S)-5-(aminomethyl)pyrrolidin-2-one was reacted with 3-bromo-6-fluoroimidazo[1,2-b]pyridazine under the amine displacement conditions described in example 5.6.42, Part A, to obtain the titled in 62% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.90-2.04 (m, 1H) 2.24-2.50 (m, 3H) 3.46-3.56 (m, 2H) 4.09 (quin, J=5.84 Hz, 1H) 6.74 (d, J=9.70 Hz, 1H) 7.43 (s, 1H) 7.60 (d, J=9.70 Hz, 1H); LRMS (ESI) m/310.0 doublet [(M+H)+, calcd for C11H12BrN5O 309.0].
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C(O)CCC>[N:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: Brc1nccs1
Reactant: C1CNCCN1
Solvent: CCCCO
Product: c1csc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Bromothiazole (15 g, 91.45 mmol) and piperazine (27.6 g, 320 mmol) were dissolved in 1-butanol (290 ml) and the solution was refluxed for 5 h and stirred at room temperature for 15 h. The precipitate was filtered off, the mother liquor was concentrated and saturated sodium carbonate solution (100 ml) was added to the residue. The mixture was extracted with methylene chloride (2×80 ml) and the organic phases were combined, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol (1:1). Yield: 14.2 g (91%)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.Cl.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CSc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2)cc1

Procedure:
A solution of 4,4,4-trifluoro-(4-methylsulfanylphenyl)-butane-1,3-dione (3.0 g) and phenyl hydrazine hydrochloride (1.18 g) in ethanol (20 mL) was refluxed for 7 h. The solvent was evaporated and the residue was chromatographed over silicagel using 20% ethyl acetate in petroleum ether as eluent yielding 2.25 g (% yield=83, Mol. Weight=334) of product as a gum.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(F)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(F)ccc1O
Yield: 58.7 %

Procedure:
Using 5-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Li]CCCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>>[B:14]([OH:19])([OH:15])[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccc(F)nc1
Yield: 74 %

Procedure:
5-Bromo-2-fluoropyridine was treated with n-BuLi (1.6 M in hexanes, 19.5 mL, 31.3 mmol), triisopropyl borate (7.9 mL, 34.1 mmol) and HCl(aq) (2.7 N, 28.4 mL) as for 1 to give the title compound 2 (3.0 g, 74% yield) as a brown semi-solid: 1H NMR (CD3OD) δ 8.45 (br s, 1H), 8.21 (br s, 1H), 7.01 (m, 1H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[Br:12]Br>CC(O)=O>[Br:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[CH:3][C:2](=[O:11])[NH:1]2)=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: O=c1cnc2ccccc2[nH]1
Solvent: CC(=O)O
Product: O=c1cnc2ccc(Br)cc2[nH]1

Procedure:
Quinoxalin-2-one (2-hydroxyquinoxaline) (14.62 g, 100 mmol) was added to glacial AcOH (700 ml) and treated with bromine (5.4 ml, 105 mmol in 1 ml AcOH) added dropwise over 15 minutes, yielding 7-bromoquinoxalin-2-one. The reaction mixture was diluted with 750 ml of H2O and 50 ml of 1 N Na2S2O3 and the precipitate was collected by filtration to give 13.7 g of a tan solid. This compound (1.00 g, 4.46 mmol) was added to 30 ml of POCl3 and warmed to reflux for 1 hour. The mixture darkened and became homogeneous. Upon cooling, the mixture was poured slowly onto 300 ml of H2O, and the resultant solid collected by filtration. This 2-chloro product (0.90 g, 3.7 mmol) was added to abs EL OH (30 ml) and treated with anhydrous hydrazine (0.30 ml, 9.4 mmol). The mixture was heated at reflux under N2 for 3 hours. Upon cooling, a precipitate formed. The solution was cooled further in an ice bath before collecting the resultant brown crystals. The hydrazino compound (0.67 g, 2.80 mmol) was added to 20 ml of triethylorthoformate and the suspension heated at 100° C. under N2 for 5 hours. The remaining precipitate was collected by filtration, washed with Et2O and air-dried, yielding 8-bromo-1,2,4-triazolo[4,3-a]quinoxaline (15).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O1CCOCC1>[Cl:9][C:4]1[N:3]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1cc(Cl)nc(Cl)n1
Solvent: C1COCCO1
Product: Nc1cc(Cl)nc(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 2,6-dichloro-pyrimidin-4-yl-amine (0.492 g, 3.0 mmol) and 4-chloro-aniline (1.54 g, 12.0 mmol) in dioxane (25 ml) was heated under reflux for 3 hours. After cooled to room temperature, the mixture was filtered. Concentration of the filtrate under reduced pressure provided the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide 6-chloro-N*2*-(4-chloro-phenyl)-pyrimidine-2,4-diamine (0.32 g, 42% yield) as a white powder.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[OH-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
1.42 g (0.0048 mol) of L-alanyl-L-proline ethylamide hydrobromide were dissolved in 20 ml of methylene chloride, 21.8 ml (0.01 mol) of 0.5-N sodium hydroxide solution were added followed by 0.54 ml (0.0053 mol) of benzoyl chloride. The mixture was stirred vigorously at room temperature for 1 hour with care being taken that the solution remained basic, this being achieved by the addition of a few drops of 0.5-N sodium hydroxide solution. The layers were then allowed to separate and the methylene chloride layer was separated, dried over magnesium sulphate and evaporated to an oil which crystallised on treatment with ethyl acetate. The crystals were filtered off, washed and dried to yield 1.05 g of N-benzoyl-L-alanyl-L-proline ethylamide of melting point 200°-202° C.; [α]D20 =-82.7° (c=0.99 in methanol).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][CH2:13][C:12]2[NH:11][C:10]3[CH:9]=[CH:8][C:7]([C:15]#[N:16])=[CH:6][C:5]=3[C:4]=2[CH2:3]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>CS(C)=O>[CH3:28][O:27][C:25](=[O:26])[NH:1][C@H:2]1[CH2:3][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:15]#[N:16])[CH:6]=3)[NH:11][C:12]=2[CH2:13][CH2:14]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N)CC3
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)N[C@@H]1CCc2[nH]c3ccc(C#N)cc3c2C1

Procedure:
Combine 6-amino-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile (2.4 mmol, 0.5 g) and triethylamine (4.7 mmol, 0.66 mL) in DMSO (10 mL) with 15 stirring. Add methyl chloroformate (3.6 mmol, 275 μL) and stir the resulting mixture at room temperature for 5-10 min. Quench with water (35 mL) and dilute the reaction mixture with ethyl acetate (200 mL). Separate the layers and wash the organic layer with with brine (100 mL). Back wash the brine layer with ethyl acetate (2×100 mL) and dry the combined organic layers with magnesium sulfate. Filter and concentrate in vacuo to provide crude product that is used without further purification. LCMS of the reaction mixture prior to workup gave masses 270.0 (APCI-pos) and 268.0 (APCI-neg) for the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[CH2:13]([N:15](CC)[CH2:16]C)C.CNC>C(#N)C>[CH3:13][N:15]([CH3:16])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Agent: CNC
Solvent: CC#N
Product: CN(C)CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a 250 mL round bottom flask was charged 1-(2-bromoethyl)-3-nitrobenzene (10 g, 43.5 mmol) and acetonitrile (36 mL). The suspension was treated with triethylamine (18.1 mL, 130 mmol) and dimethylamine (2 M in tetrahydrofuran, 65.2 mL, 130 mmol). The resulting solution was stirred at ambient temperature for 48 hours. The reaction was concentrated. The residual solid was partitioned between ethyl acetate (130 mL) and 60 ml saturated aqueous sodium bicarbonate. The aqueous layer was washed with ethyl acetate (75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography on an 80 g silica gel column using an AnaLogix IntelliFlash 280 system eluting with a gradient of from 0% to 7% methanol in CH2Cl2 to provide the title compound. MS (DCI+) m/e 195.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[F:23].C(N(CC)CC)C>O1CCCC1.[Ni]>[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]
Reactant: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccccc1F
Yield: 31.8 %

Procedure:
A solution of N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4iodo-phenylamino)-benzamide (0.260 g, 0.539 mmol) and triethylamine (2.0 mL, 14.3 mmol) in tetrahydrofuran (14 mL) was hydrogenated over Raney Nickel (0.2 g wet) at 50 psig at room temperature for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organics were washed twice with saturated sodium bicarbonate solution, twice with water, collected, dried over sodium sulfate, filtered and concentrated in vacuo. HPLC purification was performed using a YMC 30×100 mm 5u (C18) column in 0-100% acetonitrile (3.0% n-propanol)/100-0% water (3.0% n-propanol) at 30 mL/min. The desired fractions were collected and concentrated. The afforded residue was extracted with ethyl acetate/water. Organic layers were washed with saturated NaCl solution, collected and dried in vacuo to afford N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamide as a white solid (0.061 g, 31%): m.p.=113-115° C.; 1NMR(400MHz; DMSO-d6) δ 11.90(s, 1H), 8.73 (s, 1H), 7.37 (m, 1H), 7.10-7.19 (m, 2H), 7.02 (t, 1H, J=7.4 Hz), 6.84-6.93 (m, 2H), 4.82 (m, 1H), 4.57-4.58 (m, 1H), 3.86-3.88 (m, 1H), 3.67-3.73 (m, 2H), 3.3 (2H, under HDO); MS(APCI+)=357.1; Anal.calcd/found for C16H15F3N2O4: C, 53.94/53.97; H, 4.24/4.37; N, 7.86/7.83.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)=[O:5])C.C(O)C>[OH-].[Na+]>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCc1cccc2cncn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCc1cccc2cncn12
Reaction time: 0.75 h

Procedure:
A suspension of 26 g of 5-(5-ethoxycarbonylpentyl)imidazo[1,5-a]pyridine in 100 ml of 1N aqueous sodium hydroxide solution is heated on a steam bath for two hours; 10 ml of ethanol is added and heating is continued for 45 minutes. The reaction mixture is cooled, washed with 300 ml of ether and the solution is adjusted to pH 5.5 with concentrated hydrochloric acid. The crystallized product is collected to yield 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at 144°-147°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH:21]1[CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][CH:21]1[CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCC1
Reactant: COC(=O)c1cc(Cl)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(C)c1OC1CCC1
Temperature: 37 °C
Reaction time: 288 h
Yield: 67.6 %

Procedure:
A 100 mL round bottom flask is charged with 5-chloro-2-hydroxy-3-methyl-benzoic acid methyl ester (0.92 g, 4.59 mmol). Dry N,N-dimethylformamide (DMF, 15 mL) and a stirring bar are added. Stirring is initiated. After dissolution, K2SO4 (1.90 g, 13.76 mmol) and bromocyclobutane (0.65 mL, 6.88 mmol) are added. After 12 days, tlc analysis (silica, 25% EtOAc/heptanes) indicated a slight consumption of starting material and the appearance of a UV positive spot with a slightly higher Rf value. The reaction is fitted with a heating mantle and warmed to 37° C. After 3 more days, tlc analysis (silica, 25% EtOAc/heptanes) indicates a slight consumption of starting material and complete conversion to a UV positive spot with a slightly higher Rf value. The reaction mixture is filtered through a pad of Celite. The filtrate is diluted with EtOAc and (100 mL) and transferred to a separatory funnel. The EtOAc solution is washed with saturated NaHCO3 (2×25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated by pumping to constant weight to give 0.79 g of semi-solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([N:16](C)C)=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2=[N:20][NH:21][CH:22]=[C:9]12.[NH2:23]N>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([NH:16][NH2:23])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]2=[N:20][NH:21][CH:22]=[C:9]12
Reactant: NN
Reactant: CC1=C(C(=O)N(C)C)C(c2ccccc2Cl)c2c[nH]nc2N1
Solvent: CC#N
Product: CC1=C(C(=O)NN)C(c2ccccc2Cl)c2c[nH]nc2N1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a solution of 4-(2-chlorophenyl)-4,7-dihydro-5-dimethylaminocarbonyl-6-methyl-2H-pyrazolo[3,4-b]pyridine (200 mg) in acetonitrile (200 mL) was added hydrazine (200 mg) and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound as colorless crystals (150 mg).
Reaction SMILES: Br[CH2:2][CH2:3]Br.C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[C:13]([F:22])=[C:14]([OH:21])[C:15]([OH:20])=[C:16]([O:18][CH3:19])[CH:17]=1.Cl>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[O:20][CH2:2][CH2:3][O:21][C:14]=2[C:13]=1[F:22]
Reactant: BrCCBr
Reactant: COc1cc(Br)c(F)c(O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(F)c2c1OCCO2
Temperature: 80 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
After adding 830 mg of 1,2-dibromoethane and 1.4 g of potassium carbonate to a solution of 880 mg of 4-bromo-3-fluoro-6-methoxybenzene-1,2-diol in 10 ml of DMF, the mixture was stirred at 80° C. for 6 hours. Next, 1N hydrochloric acid was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (549 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc3nc(Nc4ccc(OCCO)cc4)nn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3nc(Nc4ccc(OCCOS(C)(=O)=O)cc4)nn23)cc1
Temperature: 0 °C

Procedure:
2-{4-[5-(4-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-ethanol (XX-011) (0.48 g, 1.26 mmol) was dissolved in dichloromethane (20 mL). Triethyl amine (0.805 mL, 5.8 mmol) was added and the mixture cooled to 0° C., then methanesulfonyl chloride (0.39 mL, 5.05 mmol) was added dropwise and the reaction was allowed to warm to room temperature. The reaction mixture was washed with 5% sodium hydrogencarbonate, dried over magnesium sulfate and concentrated in vacuo and used without further purification. LCMS method: 1, RT: 5.11 min, MI: 455 [M+1].
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>O1CCCC1.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To 1.3 L (liters) of dry tetrahydrofuran (THF) was added 162 g of 60% sodium hydride (NaH) and 342 g of diethyl carbonate. To this mixture was added a solution of 200 g p-fluoroacetophenone in 440 ml dry THF dropwise over about 1 hour while refluxing, followed by 6 hours of refluxing. This reaction mixture was cooled, poured into iced water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate (MgSO4), and concentrated. The residue was distilled under reduced pressure to provide 291 g of ethyl 3-(4-fluorophenyl)-3-oxopropionate as pale yellow oil.