Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C>Cl.O1CCOCC1>[ClH:25].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-[1-(4-Chloro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl)-carbamic acid tert-butyl ester (475 mg, 1.2 mmol) was dissolved in 4M HCl-dioxane (5 mL) at 0° C. The mixture was stirred for 1.5 hour at 25° C., concentrated and the residue triturated with ether. Yield, 422 mg, 105%; TSPMS 283 (MH+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1F)[C:22]#[N:23]>CN(C=O)C>[F:18][C:19]1[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[CH:25][C:26]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(NCc2cccnc2)cc1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(NCc3cccnc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-hydroxyphenyl)-3-pyridylmethylamine (1.0 equiv.) in DMF (0.1-0.3M) was treated with sodium hydride (1.0-1.5 equiv.)(60% dispersion in mineral oil). The reaction mixture was allowed to stir at room temperature for 30 minutes. The solution was then treated with 3,4-difluorobenzonitrile (1.6 equiv.) and allowed to stir. When complete (about 3 hours) the reaction mixture was partitioned between ethyl acetate/0.1M K2CO3, the organic layer separated, and the aqueous layer extracted 3 times with ethyl acetate. The organic layers were combined, washed with brine, and dried over MgSO4. The organic phase was concentrated in vacuo and purified by recrystallization from ethyl acetate/hexanes to give N-(4-(2-fluoro-4-cyanophenoxy)phenyl)-3-pyridylmethyl-amine 1H NMR(400 MHz, DMSO-d6): 4.29(2H, d, J=5.9 Hz), 6.40(1H, t, J=5.5 Hz), 6.63-6.65(2H, m), 6.83(1H, t, J=8.6 Hz), 6.90-6.92(2H, m), 7.33-7.36(1H, m), 7.55-7.57(1H, m), 7.74-7.76(1H, m), 7.93-7.97(1H, m), 8.43-8.44(1H, m), 8.58(1H, s). MS Found 320.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:2]2[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:25][C:22]=1[CH:23]=[O:24]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: N#Cc1cnc(Cl)cc1OCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Oc2ccc(Br)c(C=O)c2)cc1OCCOC1CCCCO1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a mixture of 6-chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (4.8 g, 16.62 mmol) and 2-bromo-5-hydroxy-benzaldehyde (4.01 g, 19.94 mmol) in DMF (30 mL) was added potassium carbonate (3.44 g, 24.93 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure and the residue was diluted with EtOAc (200 mL). The organic layer was washed with water (20 mL) and brine (3×20 mL), dried over Na2SO4, filtered, and concentrated to give white solid. Purification was accomplished by flash chromatography on silica gel using 2-25% EtOAc/hexanes as gradient elution yielding the title compound (4.8 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1 H), 8.46 (s, 1 H), 7.88 (d, J=8.6 Hz, 1 H), 7.60 (d, J=2.7 Hz, 1 H), 7.49 (dd, J=8.6, 2.7 Hz, 1 H), 7.09 (s, 1 H), 4.75-4.67 (m, 1 H), 4.49-4.45 (m, 2 H), 4.00-3.89 (m, 1 H), 3.85-3.74 (m, 2 H), 3.49-3.41 (m, 1 H), 1.78-1.53 (m, 2 H), 1.39-1.53 (m, 4 H).
Reaction SMILES: Cl.[CH2:2]([NH:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](=O)[C:12]([CH3:14])=[O:13]>O.C(Cl)Cl>[CH2:2]([NH:9][N:10]=[CH:11][C:12](=[O:13])[CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)C=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)C=NNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of benzylhydrazine hydrochloride (11.1 g, 57.1 mmol) in water (100 mL) was added dropwise a solution of pyruvaldehyde (10.3 g, 9.3 mL, 57.1 mmol) in water (500 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (4×150 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to provide 2-oxopropanal benzylhydrazone (10.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=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>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=3)=[CH:23][C:24]=2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1cc(F)c(S(=O)(=O)Nc2nccs2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2cccc(F)c2)ncc1Oc1cc(F)c(S(=O)(=O)Nc2nccs2)cc1Cl
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
10 mg (0.02 mmol) of 5-chloro-4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.2 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2.3 mg (10 mol %) of Pd(PPh3)4, 6.3 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 4 mg (36% yield) of the title compound.
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[NH:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11]2
Reactant: O=C(O)c1ccc2c(=O)c3c([nH]c2c1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1ccc2c(Cl)c3c(nc2c1)CCCC3
Temperature: 100 °C
Yield: 88 %

Procedure:
A suspension of 9-oxo-5,6,7,8,9,10-hexahydro-acridine-3-carboxylic acid (VIa) (10 g, 4.1 mmols) in phosphorous oxychloride (50 mL) was heated to 100° C. for 1 h. Reaction completion was monitored by TLC. After completion, the reaction mixture was cooled to 25° C. and excess phosphorous oxychloride was removed under vacuum. The residue was mixed with ice (50 g) and the pH was adjusted to 4-5 with solid sodium bicarbonate. The solid obtained was filtered, washed with water (250 mL) and dried under vacuum to get 9.6 g (88%) of compound (Vila) as a white solid.
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].C(N(CC)CC)C>ClCCl>[C:2]([NH:26][C@H:25]([C:24]([O:23][CH3:22])=[O:29])[CH2:27][OH:28])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
Chlorotriphenylmethane (265 g, 950 mmol) dissolved in 750 mL of dichloromethane was added dropwise to a stirred solution of L-serine methyl ester hydrochloride (148 g, 950 mmol) and triethylamine (260 mL, 1900 mmol) in 1.5 L of CH2Cl2 at 0° C. The cloudy yellow solution was stirred for 18 hours at ambient temperature. The reaction mixture was filtered to remove solids and the filtrate was washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil. The oil was concentrated from acetonitrile and then stirred in hexanes until a precipitate formed. The resulting solid was filtered to afford 310 g of methyl N-trityl-L-serinate as an off white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([C:32]#[N:33])=[N:26][CH:27]=2.[OH-].[Na+].OO.S([O-])([O-])=[O:39].[Na+].[Na+]>CS(C)=O>[C:32]([C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[CH:27][N:26]=1)(=[O:39])[NH2:33]
Reactant: O=S([O-])[O-]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3cnc(C#N)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3cnc(C(N)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-cyano-7,9-dihydro-8H-purin-8-one (43 mg) in dimethyl sulfoxide (2 mL) were added 2 mol/L aqueous sodium hydroxide solution (0.14 mL) and 30% aqueous hydrogen peroxide solution (0.02 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred at room temperature for 10 minutes, and extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure to give the title compound (3 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.[Na+].[I-]>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCN1CCCCl
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1 g, 6.2 mmol), 1-(3-chlorophenyl)piperazine (1.22 g, 6.2 mmol) anhydrous Na2CO3 (0.33 g, 3.1 mmol) and NaI (0.093 g, 0.6 mmol) in dry DMF (5 ml) was stirred at 70° C. for 14 hrs. The reaction mixture was cooled, poured on water (20 ml) and the separated residue was extracted with CHCl3 (2×25 ml). The extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 1.50 g (75%) . IR (Neat): 3020, 2820, 1660, 1590, 1450, 1210, 730. 1H NMR (CDCl3): 1.30-2.60(m, 12H, 3', 4', 2, 1 & 2×N--CH2), 2.40-3.50(m, 8H, 5', 3 & 2×N--CH2), 6.40-7.20(m, 4H, ArH). MS: m/z 321 (M+) 323 (M+2).
Reaction SMILES: [CH2:1]([CH:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[CH2:1]([C:9]1([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1C(=O)NC(=O)NC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCC1(CC(=O)OCC)C(=O)NC(=O)NC1=O
Reaction time: 3 h

Procedure:
4.05 g of 5-octylbarbituric acid (preparation 7) are dissolved in 25 ml of dimethylformamide, 1.16 g of sodium carbonate are added. Ethyl bromoacetate (2.25 ml) is added dropwise to the reaction mixture in 5 minutes, then the mixture is kept at room temperature under stirring for about 3 hours. The reaction mixture is then partitioned between 400 ml of water, 17 ml of 1 N hydrochloric acid and 150 ml of ethyl acetate. The organic phase is separated and washed with 150 ml of water and 100 ml of brine, then it is dried over sodium sulfate. The aqueous phases are extracted with 100 ml of ethyl acetate and the organic extracts are pooled, dried over sodium sulfate and evaporated to dryness, to give 6.5 g an oily residue. This residue is purified by silica gel chromatography (eluant methylene chloride/ethyl acetate 9 1) to give 3.87 g of the product.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]2[N:19]=[C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[C:14]2[N:13]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([CH:7]=[CH:22][C:20]2[N:21]=[C:14]3[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([CH3:18])[N:15]3[N:19]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cn1nc(Br)nc1C=O
Reactant: Cc1cc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)n2nc(C=Cc3nc(Br)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (193 mg, 1.02 mmol, Eq: 1.00), ((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (466 mg, 1.02 mmol, Eq: 1.00) and DBU (387 mg, 383 μl, 2.54 mmol, Eq: 2.5) in tetrahydrofuran (12 ml) was stirred for 18 hours at 25° C. under argon atmosphere. Chromatography afforded) 2-[2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (161 mg/47.4%) as a white solid. MS: m/z=334336 (M+H+), mp: 277.4° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2].[CH:21]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc(NC(C)=O)ccc3nc21
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(NC(C)=O)ccc3nc21
Temperature: 110 °C
Yield: 78.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-acetamido-1H-pyrazolo[3,4-b]quinoline (0.2 g, 0.7 mmol), cyclohexanemethylamine (0.5 ml, 3.5 mmol) and DMSO (3 ml) was heated at 110° C. for 6 hours. The reaction mixture was poured into water (50 ml), extracted with CH2Cl2 (4×25 ml) and the organic layers were combined and evaporated. The residue was slurried in ether and a yellow solid was collected by filtration and recrystallized from ethanol/ethyl acetate to afford 200 mg of 1-ethyl-6-acetamido-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 277°-278° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2nc(N3CCOCC3)sc2c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 2-chloro-6-methoxy-benzothiazole (9.96 g, 0.05 mol), morpholine (10.86 mL, 0.12 mol) and triethylamine (13.9 mL, 0.10 mol) in ethanol (75 mL) was refluxed for twenty-one hours before it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a light yellow solid (12.23 g): MS: (+) m/z 251 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17](Cl)[N:16]=2)[CH:9]=1)=[O:6].Cl>COCCO.O1CCOCC1>[ClH:21].[Cl:21][C:20]1[CH:19]=[N:18][C:17]2[NH:1][C:2]3[CH:25]=[CH:24][CH:23]=[C:4]([CH:3]=3)[C:5](=[O:6])[NH:7][C:8]3[CH:9]=[C:10]([NH:14][C:15]=1[N:16]=2)[CH:11]=[CH:12][CH:13]=3
Reactant: Nc1cccc(C(=O)Nc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: O=C1Nc2cccc(c2)Nc2nc(ncc2Cl)Nc2cccc1c2
Temperature: 150 °C
Yield: 121 %

Procedure:
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}benzamide (20.0 mg, 0.053 mmol) in 2-methoxyethanol (0.295 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (67 μL). The resulting mixture was heated at 150° C. in a microwave for 15 min. After filtration of the reaction mixture, the crude was triturated with MeOH/EtOAc to give the desired product as an off-white powder (12 mg, 66%). LCMS for C17H12ClN5O (M+H)+: m/z=337.9. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 10.16 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 9.66 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 9.38 (s, 1H), 6.30 (br, 1H), 8.24 (m, 1H), 7.38 (ddd, J=8.0, 2.0, 1.2, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.25 (m, 2H), 7.16 (m, 1H), 6.95 (t, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH:23]([CH:28]([CH3:30])[CH3:29])[C:24]([O:26]C)=[O:25])=[O:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH:23]([CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])=[O:21])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To Methyl 2-(3-(4-(benzyloxy)phenyl)isoxazole-5-carboxamido)-3-methylbutanoate (150 mg) in THF (3 ml), 1 M aqueous solution of Lithium hydroxide monohydrate (0.735 ml) was added and reaction mixture was stirred at RT for 6 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from EtOAc to obtain the title compound as white solid. Yield: 80 mg (55%); MS (ES+): m/z 395 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 12.91 (bs, 1H), 8.94 (d, 1H), 7.87 (d, 2H), 7.69 (s, 1H), 7.32-7.49 (m, 5H), 7.19 (d, 2H), 5.19 (s, 2H), 4.28 (m, 1H), 2.22 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[S:12])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Br[CH:44]([CH3:49])[C:45](OC)=[O:46]>CCO.C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[C:45](=[O:46])[CH:44]([CH3:49])[S:12]/[C:11]/2=[N:13]/[N:14]=[CH:15]\[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:31][CH:32]=4)[N:23]=3)=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(/C=N/NC(=S)Nc4ccccc4C4CC4)cc3)n2)cc1
Reactant: COC(=O)C(C)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC1S/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N(c2ccccc2C2CC2)C1=O
Temperature: 60 °C
Yield: 29.3 %

Procedure:
To (E)-N-(2-cyclopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (100 mg, 0.191 mmol) and sodium acetate (63.0 mg, 0.765 mmol) in EtOH (4 mL) was added methyl 2-bromopropanoate (0.026 mL, 0.230 mmol). The reaction was heated to 60° C. overnight. The reaction was then heated to 85° C. for 72 hours. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound as a white solid (32.5 mg, 0.056 mmol, 30%): mp 112-115° C.; 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=8.3 Hz, 2H), 7.87-7.75 (m, 4H), 7.43-7.32 (m, 4H), 7.26-7.24 (m, 2H), 4.23 (q, J=7.3 Hz, 1H), 1.85-1.78 (m, 4H), 0.90-0.78 (m, 2H), 0.78-0.69 (m, 1H), 0.65-0.55 (m, 1H); ESIMS m/z 578 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CC#CCO
Reactant: Fc1cccc(F)c1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2c(F)cccc2F)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 43.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 226 mg of 4-chloro-6-(2,6-difluorophenyl)pyrimidine and 84 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 114 mg of 4-(2,6-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (87)).