Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13]>>[C:1]1([CH:7]([O:13][CH2:12][C:11]([F:15])([F:14])[F:10])[CH2:9][OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: OCC(F)(F)F
Product: OCC(OCC(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
Into a 25-mL round-bottom flask was placed (2S)-2-phenyloxirane (1 g, 8.32 mmol, 1.00 equiv), 2,2,2-trifluoroethan-1-ol (5 mL) and bis[(trifluoromethane)sulfonyloxy]alumanyl trifluoromethanesulfonate (197 mg, 0.42 mmol, 0.05 equiv). The resulting solution was stirred for 2 h at room temperature. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). Purification afforded 410 mg (22%) of 2-phenyl-2-(2,2,2-trifluoroethoxy)ethan-1-ol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:13]([NH2:15])=[O:14].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C:13]([NH2:15])=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NC(=O)[C@H](N)Cc1cccs1
Reactant: N#Cc1ccc(F)cc1Br
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(N[C@H](Cc2cccs2)C(N)=O)cc1Br
Yield: 18.3 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (120 mg, 0.600 mmol), (R)-2-amino-3-(thiophen-2-yl)propanamide (93 mg, 0.547 mmol) and DIEA (0.200 mL, 1.15 mmol) in DMSO (3 mL) was stirred at 120 C for 4 d. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, which was eluted with 0-80% EtOAc in hexane to give (R)-2-(3-bromo-4-cyanophenylamino)-3-(thiophen-2-yl)propanamide (35 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][C:16]=1[CH3:17])[CH3:2].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:24][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:15][C:16]=2[CH3:17])=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH3:31]
Reactant: CCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(CC)c1
Yield: 68 %

Procedure:
A mixture of 3-ethyl-4-[2-(5-methyl-2-phenyloxazole-4-yl)ethoxy]phenol (0.29 g. 0.90 mmol), ethyl bromoacetate. (0.25 mL, 2.25 mmol) and cesium carbonate (0.45 g, (1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% EtOAc/MeCl2 to give a white solid (0.25 g, 68%): 1H NMR (400 MHz, CDCl3) δ 7.97 dd, J=8.3, 2.4 Hz, 2H), 7.45-7.39 (m, 3H), 6.75 (dd, J=8.3, 2.0 Hz, 2H), 2H), 6.64 (dd, J=8.8, 3.4 Hz, 1H), 4.55 (s, 2H), 4.24 (q, J=6.5 Hz, 2H), 4.10 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.57 (t, J=7.3 Hz, 2H), 2.37 (s, 3H), 1.29 (t, J=7.3 Hz, 3H), 1.12 (t, J=6.5 Hz, 3H); MS (ES) m/e 410 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].C(N(CC)CC)C.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:42])=[C:37]([CH:41]=1)[C:38](Cl)=[O:39]>ClCCl>[N:16]1[C:8]2[CH2:9][C:10]3[CH:15]=[CH:14][S:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:20]=[CH:21][C:22]([NH:24][C:38](=[O:39])[C:37]4[CH:41]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=4[CH3:42])=[CH:23][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3sccc3Cc3ncccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ncccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 mmol of 5-(2-chloro-4-aminobenzoyl)-6,10-dihydro-5H-pyrido[3,2-b]thieno[3,2-e]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1 mmol of 5-fluoro-2-methylbenzoyl chloride. After stirring at room temperature for 16 hours, the solution is washed with H2O, 1M NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH2:17])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C.O.C(OCC)(=O)C>[Cl:18][C:9]1[C:10]([NH2:17])=[C:11]2[CH2:16][CH2:15][CH2:14][C:12]2=[N:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(-c2cccc(Cl)c2)nc2c1CCC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(Cl)c(-c2cccc(Cl)c2)nc2c1CCC2
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A 25-mL round bottom flask was charged with 2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (0.250 g, 1.02 mmol) in DMF (6 mL). N-Chlorosuccinimide (0.136 g, 1.02 mmol) was added at rt and the resultant solution was stirred for 3 h. Further N-chlorosuccinimide (0.036 g, 0.27 mmol) was added and the reaction was stirred for 2 h. The reaction was diluted with water (100 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×25 mL). The combined extract acetate extract was washed with saturated sodium chloride (2×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexanes/ethyl acetate (10:0 to 9:1) as the eluent to afford the title compound (0.110 g, 38%) as a white solid. MW=279.16. 1H NMR (CD3, 500 MHz) δ 7.62-7.59 (m, 1H), 7.52-7.48 (m, 1H), 7.37-7.32 (m, 2H), 4.54 (s, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.21 (quin, J=7.5 Hz, 2H); ESI MS m/z 279 [M+H]+.
Reaction SMILES: [C:1]([C:3]12[CH2:11][CH:8]3[CH2:9][CH:10]1[CH:6]([CH:7]3[OH:12])[O:5][C:4]2=[O:13])#[N:2].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].O>O1CCCC1.C1(C=CC(O)=CC=1)O>[C:1]([C:3]12[CH2:11][CH:8]3[CH2:9][CH:10]1[CH:6]([CH:7]3[O:12][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[O:5][C:4]2=[O:13])#[N:2]
Reactant: N#CC12CC3CC1C(OC2=O)C3O
Reactant: C=C(C)C(=O)Cl
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3(C#N)C2
Temperature: 5 °C

Procedure:
In 252 g of tetrahydrofuran (THF) was dissolved 23 g (in terms of 0.127 mol) of the above-prepared compound represented by Formula (2a) (crude product). The solution was combined with 16.9 g of triethylamine and 0.2 g of hydroquinone and was further combined with 18.3 g of methacryloyl chloride (3a) added dropwise while cooling the mixture to 5° C. The reaction mixture was combined with 300 ml of water and was extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous sodium hydrogen carbonate solution and water, was concentrated, the concentrate was crystallized from diisopropyl ether and thereby yielded 14 g of 1-cyano-5-methacryloyloxy-3-oxatricyclo[4.2.1.04,8]nonan-2-one represented by Formula (1a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:13][O:14][CH3:15])[CH2:11][F:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]([N:13]([O:14][CH3:15])[C:30]([C:29]2[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=2)=[O:31])[CH2:11][F:12])=[CH:6][CH:7]=1
Reactant: CONC(CF)CCc1ccc(Cl)cc1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(CF)CCc1ccc(Cl)cc1
Temperature: 24 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To a stirred solution of N-[3-(4-chlorophenyl)-1-fluoromethyl-propyl]-O-methyl-hydroxylamine (60 mg; 0.26 mmol), prepared as described in example P8c and triethylamine (0.05 ml; 0.31 mmol) in dichloromethane (1 ml) under nitrogen was added drop wise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (51 mg; 0.26 mmol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen. The mixture was washed with 1M sodium hydroxide (20 ml), 1M hydrochloric acid (20 ml) and brine (20 ml). Organics were dried over sodium sulfate and evaporated under reduced pressure. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 70:30) to afford 67 mg (66% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [3-(4-chloro-phenyl)-1-fluoromethyl-propyl]-methoxy-amide as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[O:8][CH:17]([CH3:19])[CH3:18]
Reactant: Nc1ncnc(Cl)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)Oc1c(N)ncnc1Cl
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
A reaction mixture of 4-Amino-6-chloro-pyrimidin-5-ol (500.00 mg; 3.44 mmol; 1.00 eq.), Cs2CO3 (2238.59 mg; 6.87 mmol; 2.00 eq.), and 2-Iodo-propane (1167.95 mg; 6.87 mmol; 2.00 eq.) in acetone 10 ml was stirred at 65° C. for 3 hr, desired as major, also found dialkylation by product, removed off solvent, treated with ethyl acetate, solid came out, filtered, washed with ether, collected product 6-chloro-5-isopropoxypyrimidin-4-amine 160 mg, yield 24.8%
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14](O)=[O:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1COCC1>[CH:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[NH:7][C:6]3[C:14](=[O:15])[NH:1][C:2]4[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=4[O:4][C:5]=3[C:13]=12
Reactant: Nc1ccccc1Oc1c(C(=O)O)[nH]c2ccccc12
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2Oc2c1[nH]c1ccccc21
Reaction time: 18 h

Procedure:
A solution of 1.5g of 3-[o-aminophenoxy]-indole-2-carboxylic acid in 50ml of THF was treated with 1.48g of EEDQ and the clear solution left 18 hours at ambient temperature. The THF was removed by distillation, and the residue was rubbed with 2N HCl to give a yellow solid. Recrystallization from ethanol gave analytical material, mp. 233°-4°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1.[CH2:43](N(CC)CC)C.CS(Cl)(=O)=O.C[O-].[Na+]>C1COCC1.O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][CH3:43])=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (210 mg) and triethylamine (150 μl) were dissolved in THF (4 ml), and methanesulfonyl chloride (45 μl) was added under ice-cooling. The mixture was stirred at 0° C. for 4 hr, sodium methoxide (28% methanol solution, 350 mg) and methanol (4 ml) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (195 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[S:13][C:12]=2[CH:21]=1)C>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[S:13][C:12]3[CH:21]=[C:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=[CH:10][C:11]=3[C:15]=2[CH:16]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1ccc(Cl)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)sc1ccc(Cl)cc12

Procedure:
To a 500 ml. flask, fitted with a condenser and containing a solution of 1.84 g. of sodium hydroxide in 150 ml. of ethanol was added 14 g. of 8-chloro-dibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and the aqueous solution acidified with dilute hydrochloric acid. The 8-chloro-dibenzothiophene-3-acetic acid was removed by filtration, washed with water and dried at 60° C. in a vacuum oven overnight. The yield of 8-chloro-dibenzothiophene-3-acetic acid, after crystallization from i-propanol, was 8 g., mp 220°-221°.
Reaction SMILES: [BrH:1].[Br-].[Br:3][CH2:4][CH2:5][CH2:6][P+:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:26][NH:27][CH3:28]>C(O)C>[BrH:3].[Br-:1].[CH3:26][N:27]([CH3:28])[CH2:4][CH2:5][CH2:6][P+:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Solvent: CCO
Product: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Then, 100.0 g of (3-bromopropyl)-triphenylphosphonium bromide hydrobromide is suspended in 500 ml of ethanol and 300 ml of 50% aqueous dimethylamine solution is added thereto. After heating the mixture at reflux for 10 minutes, the mixture is allowed to stand for cooling. The solvent is distilled away under reduced pressure and the resultant crude product is recrystallized from ethanol to obtain 64.0 g of the desired product having the physicochemical properties as identified in Table 8.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12]2.CI>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:1])[C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12]2
Reactant: COC(=O)c1cc2cc(OC)ccc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OC)ccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 ml of a 1 N solution of potassium tert-butoxide in tetrahydrofuran is added dropwise to a solution, cooled to -20° C., of 0,1 mol of methyl 5-methoxy-1H-indolecarboxylate in tetrahydrofuran. The medium is stirred for 30 minutes at this temperature, followed by dropwise addition of a solution of 0.1 mol of methyl iodide in tetrahydrofuran. Once the addition is complete, the medium is warmed slowly to room temperature, stirred for 1 h at this temperature and filtered. The expected product is obtained after concentration of the solvent.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[CH:15][C:14]=12.C(N(CC)CC)C>CN1CCCC1=O>[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([CH:28]4[CH2:33][CH2:32][N:31]([C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[CH:15][C:14]=12
Reactant: O=C(Cl)N1CCCCC1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(C(=O)N3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of piperidine-1-carbonyl chloride (0.033 g, 0.224 mmol) in N-methyl-2-pyrrolidinone (1 mL) was treated with N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)-benzamide (0.05 g, 0.150 mmol) and triethylamine (0.042 ml, 0.299 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was purified by reverse-phase HPLC to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (t, J=5.9 Hz, 1H), 8.84 (d, J=7.0 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.91-7.84 (m, 2H), 7.76 (s, 1H), 7.50-7.44 (m, 1H), 7.42-7.36 (m, 2H), 4.67 (d, J=5.8 Hz, 2H), 3.71-3.62 (m, 2H), 3.16-3.10 (m, 4H), 2.89-2.68 (m, 3H), 1.81-1.72 (m, 2H), 1.68-1.44 (m, 8H); MS (ESI(+)) m/e 446 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:30][N:29]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: Nc1ncc(B(O)O)cn1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnc(N)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), (2-aminopyrimidin-5-yl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (45% yield). LCMS: 433.20 (M+1)+; HPLC: 98.75% (@ 254 nm) (Rt;5.252); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.09 (s, 2H), 8.84 (t, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.15 (s, 2H), 5.89 (s, 1H), 5.32-5.28 (m, 1H), 4.40 (d, 2H, J=4.0 Hz), 2.22 (s, 3H), 2.12 (s, 3H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1>CC(O)=O.O>[Br:1][C:11]1[S:10][C:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C:6]=2[CH:12]=1
Reactant: CN1CCc2sccc2C1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2sc(Br)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Bromine (0.3 mL) in HOAc (10 mL) was slowly added over 5 min to a mixture of 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.0 g, 6.5 mmol) in acetic acid (10 mL) and water (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. Work-up: the reaction mixture was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (300 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was recrystallized from 1:4 EtOAc/petroleum ether (150 mL) to afford the title compound as white solid (660 mg, 43%). 1H NMR (DMSO-d6, 400 MHz): δ 6.91 (s, 1H), 3.33 (s, 2H), 2.73-2.71 (m, 2H), 2.52-2.51 (m, 2H), 2.33 (s, 3H). LCMS: 233 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[N:7]1)[CH3:2].Cl.[Cl:18][C:19]1[C:20]([F:27])=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH:10]=[C:9]([S:11][C:12]2[C:22]3[C:21](=[C:20]([F:27])[C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:13]=2[CH3:14])[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc(SCC(C)=O)cn1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)Cn1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)cn1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [4-(2-oxo-propylsulfanyl)-pyrazol-1-yl]-acetic acid ethyl ester and 3-chloro-2-fluorophenylhydrazine hydrochloride.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([NH:9][C:10]([C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21](OC)=[O:22])[O:14][N:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.C(OC)(C)(C)C>[C:5]([NH:9][C:10]([C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:22])[O:14][N:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: NC1CC1
Reactant: COC(=O)c1onc(C(=O)NC(C)(C)C)c1C(=O)OC
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)c1c(C(=O)NC(C)(C)C)noc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.75 g (I3.1 mmol) of cyclopropylamine was added dropwise at 20° C., with cooling, to a solution of 2.5 g (8.8 mmol) of dimethyl 3-tert-butylaminocarbonylisoxazole-4,5-dicarboxylate in 50 ml of dry methanol, and the mixture was stirred at room temperature for 20 hours. The solvents were stripped off under reduced pressure, and the residue was taken up in methyl tert-butyl ether and extracted with dilute HCl and once with water. The organic phase was then dried over magnesium sulfate, and the solution was evaporated. The resulting methyl3-tert-butylaminocarbonyl-5-cyclopropylaminocarbonylisoxazole-4-carboxylate was purified by column chromatography (SiO2 ; cyclohexane/ethyl acetate 4:1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:28]2[N:29]=[CH:30][CH:31]=[N:27]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-n2nccn2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 14.9 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1H-1,2,3-triazole (197 mg, 2.84 mmol) and potassium carbonate (47 mg, 0.34 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20, 34 mg, 15%) which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:5]=2[CH:4]=1.[CH2:16](I)[CH3:17]>>[CH3:13][O:12][C:10]([C:8]1([CH2:16][CH3:17])[CH2:7][C:6]2[CH:14]=[CH:15][C:3]([OH:2])=[CH:4][C:5]=2[O:9]1)=[O:11]
Reactant: COC(=O)c1cc2ccc(OC)cc2o1
Reactant: CCI
Product: CCC1(C(=O)OC)Cc2ccc(O)cc2O1

Procedure:
The title compound was prepared following the procedure described in Example 1, Step 1 employing methyl 6-methoxy-benzofuran-2-carboxylate instead of methyl 5-methoxy-benzofuran-2-carboxylate and ethyl iodide instead of methyl iodide.