Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](Cl)=[O:22])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[N:24]([CH2:27][C@@H:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:24]([CH2:27][C@@H:28]([NH:36][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C@:2]([OH:1])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH2:16]1)=[O:22])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:25]=[N-:26]
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN=[N+]=[N-])Cc2ccccc2)C1
Reaction time: 12 h
Yield: 109.8 %

Procedure:
A solution of (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride (135 mg, 0.4 mmol) in CH2Cl2 (10 mL) was added to a solution of (S)-1-azido-3-phenylpropan-2-amine (156.3 mg, 0.73 mmol), triethylamine (0.6 mL, 4.3 mmol), and DMAP (16.6 mg, 0.13 mmol) in CH2Cl2. After stirring for 12 h, the reaction was taken up in CH2Cl2 (50 mL), washed with satd aq NaHCO3 (3×10 mL), and brine (3×10 mL), dried (Na2SO4), decanted, and stripped to afford (3R)-N-((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (210.7 mg) as a brown residue (theoretical yield: 192.0 mg). MS ESI +ve m/z 502 (M+Na).
Reaction SMILES: C1(SC)C=CC=CC=1.[OH:9][C:10]1[CH:11]=[C:12]([NH:17][S:18]([NH:21][C:22]([N:24]2[CH2:27][C@H:26]([NH:28]C(=O)OCC3C=CC=CC=3)[C:25]2=[O:39])=[O:23])(=[O:20])=[O:19])[CH:13]=[CH:14][C:15]=1[OH:16].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:28][C@H:26]1[CH2:27][N:24]([C:22]([NH:21][S:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([OH:9])[CH:11]=2)(=[O:20])=[O:19])=[O:23])[C:25]1=[O:39]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccc(O)c(O)c2)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 10 ml of thioanisole and 40 ml of trifluoroacetic acid was cooled to 0° C., and 8.36 g (20 mmol) of (S)-[1-[[[[(3,4-dihydroxyphenyl)amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added. The reaction mixture was stirred overnight at room temperature and the trifluoroacetic acid evaporated in vacuo. The oily residue was triturated with ether and the precipitate filtered off by suction. The crude product was washed with ether, dichloromethane and isopropanol and dried in vacuo; yield: 6.86 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>O.C(#N)C>[OH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([NH:20][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
Potassium carbonate (304 mg, 2.2 mmol) was dissolved in a minimum amount of water. Next, 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) were added. The resulting mixture was then heated at 80° C. for 3 days. After cooling at room temperature, the mixture was concentrated under vacuum, taken up in ethyl acetate (15 mL), washed with saturated aqueous ammonium chloride (2×10 mL), and washed with water (10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a colorless solid (456 mg, 80% yield).
Reaction SMILES: O[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[Cl:29][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)c2cc(C(O)c3cccc(F)c3)ccc2[nH]1
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)c2cc(C(Cl)c3cccc(F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A mixture of (±)-6-[hydroxy(3-fluorophenyl)methyl]-4-phenyl-2(1H)-quinolinone (11 g) of thionyl chloride (11 ml) and DCM (120 ml) was stirred at room temperature for 12 hours. The solvent was evaporated till dryness and used without further purification, yielding 11.6 g (±)-6-[chloro(3-fluorophenyl)methyl]-4-phenyl-2(1H)-quinolinone (100%) (interm. 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:5]([NH:7][C:8]1[C:16]2[NH:15][C:14](=O)[NH:13][C:12]=2[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)=[O:6].O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:14]1[NH:15][C:16]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([F:1])[C:24]([F:25])=[C:23]([F:26])[CH:22]=3)=[CH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[N:13]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12)c1cc(F)c(F)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(Nc1cc(C(F)(F)F)cc2nc(Cl)[nH]c12)c1cc(F)c(F)c(F)c1

Procedure:
3,4,5-Trifluoro-N-(2-oxo-6-trifluoromethyl-2,3-dihydro-1H-benzoimidazol-4-yl)-benzamide from step (c) above (1.12 g, 3.0 mmol) reacted with POCl3 (5 mL, Aldrich) under the conditions of Example 1c to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 393.7 (M+1), (ESI, neg. ion) m/z: 392 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (4.3 g) in methylene chloride (50 ml) was added a solution of (R)-(+)-1,1,1-trifluoro-2-octanol (2.9 g) ([α]D22.5 =+20.1, optical purity 96.3 % ee), dimethylaminopyridine (0.6 g) and triethylamine (1.7 g) in methylene chloride (50 ml) under ice-cooling. The mixture was left to stand at the room temperature for 24 hours before being poured in ice water. The methylene chloride layer separated was washed with diluted hydrochloric acid, water, 1N aqueous sodium carbonate solution and water in this order before being dried over magnesium sulfate. After distillation was over purification by toluene/silica gel chromatography and recrystallization from ethanol gave the titled compound (3.8 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.[C:16]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][CH3:16])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Solvent: CO
Product: COC1CCN(C)C(=O)N1c1nnc(C)s1

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[O:4][Si](C(C)(C)C)(C)C.N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-]>>[NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[OH:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 2, using Intermediate 3 as a substrate. ES/MS calcd. for C11H13N2O3+ 221.1. found m/z=221.1 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[Cl:12][CH2:13][CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Para-toluenesulphonyl chloride (20.5 g) was added to a mixture of 2-chloroethanol (8.6 g) and pyridine (50 ml). After stirring for one hour at 0° C., the mixture was added to ice and the organic phase was extracted with ether. The extract was washed with dilute hydrochloric acid, dried with magnesium sulphate, and evaporated, to yield 2-chloroethyl-p-toluenesulphonate.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[Li])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH3:30])[C:24]=1[C:31]([N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[O:32])(=[O:22])[CH3:21].C1(S(N2C3C(=CC(OC)=CC=3)C=C2[Li])(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH3:30])[C:24]=2[C:31]([N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[O:32])([OH:22])[CH3:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1
Reactant: COc1nccc(C(C)=O)c1C(=O)N(C(C)C)C(C)C
Agent: [Li]c1cc2cc(OC)ccc2n1S(=O)(=O)c1ccccc1
Product: COc1nccc(C(C)(O)c2cc3cnccc3n2S(=O)(=O)c2ccccc2)c1C(=O)N(C(C)C)C(C)C

Procedure:
Starting from 1-benzenesulfonyl 2-lithio 5-aza indole and 4-acetyl 3-diisopropylaminocarbonyl 2-methoxy pyridine as reagent with electrophilic character, prepared according to paragraph (a) (stabilization reagent: tetramethylethylenediamine).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[N:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>O1CCCC1>[I:15][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]([CH:18]([CH3:20])[CH3:19])=[C:9]([CH:14]=1)[O:8][C:7]1[C:2]([NH:1][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[N:3][C:4]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[N:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2N)cc1I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2NC(=O)C(C)C)cc1I
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-isobutyramide (386 mg, 0.82 mmol), dissolved in anhydrous tetrahydrofuran, was added triethylamine (0.13 mL, 0.90 mmol) and isobutyryl chloride (0.09 mL, 0.90 mmol). After stirring one hour, the reaction was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (50 mL), and the dichloromethane layer was washed with water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by preparatory TLC plates (98/2/0.5 dichloromethane/methanol/ammonium hydroxide) yielded 96 mg (22%) of N-[5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-4-isobutyrylamino-pyrimidin-2-yl]-isobutyramide as white solid, MS (M+H)=541.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)([O-:3])=[O:2].[NH2:9]N1C=NN=C1.[Cl-].[NH4+]>CS(C)=O>[N+:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH2:9])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccs1
Reactant: Nn1cnnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Nc1ccsc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
12.8 g of 85% 2-nitro-thiophene and 33.6 g of 4-amino-4H-1,2,4-triazole (1-1, 3-4) were dissolved at ambient temperature in 100 ml of anhydrous dimethyl-sulfoxide and the solution was cooled down to 5° C. A solution of 22.4 g of potassium terbutylate in 100 ml of anhydrous dimethyl-sulfoxide was added over about 15 minutes and the suspension was stirred for a further 15 minutes at ambient temperature, then poured into 0.6 liter of a saturated solution of ammonium chloride. Extraction was carried out 3 times with 500 ml of ethyl acetate and the extracts were washed 3 times with 400 ml of water, dried, filtered and evaporated to dryness. The product was dissolved in 800 ml of methylene chloride, followed by filtration and evaporation to dryness. The product was crystallized from 20 ml of isopropyl ether and the crystals were separated out, washed with isopropyl ether and then dried at 80° C. under reduced pressure to obtain 5.1 g of the expected product melting at 159° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][N:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)=[O:4].[CH3:32][NH:33][CH3:34]>C(Cl)Cl.C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:11]([CH2:10][C:9]2[CH:30]=[CH:31][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]([CH3:34])[CH3:32])=[CH:7][CH:8]=2)[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CN(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (2R)-2-[[4-(2-bromo-acetylamino)-benzyl]-(4-chlorobenzenesulfonyl)-amino]-4-methyl-pentanoic acid amide (41 mg, 0.77 mmol) in CH2Cl2 (2 mL) was added excess 2.0 M dimethylamine in THF. The reaction mixture was stirred overnight. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (24 mg) in 63% yield. MS (ESI), (M+H)+ 495.14, 1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.02 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.29 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.39 (br s, 1H), 4.62 (m, 4H), 3.25 (t, 1H, J=6.0), 2.95 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][N:14]=2)=[CH:9][CH:8]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[N:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(CCl)OCc1ccccc1
Reactant: CN(C)CCCOc1ccc(-c2n[nH]c3ncccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc(-c2nn(CC(=O)OCc3ccccc3)c3ncccc23)cc1
Reaction time: 4 h

Procedure:
To a suspension of 9 g of 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine, 30 ml of dimethylformamide and 6.2 g of potassium carbonate was added dropwise 6.6 g of benzyl chloroacetate at 50° C. over the period of 2 hours. The mixture was kept at the same temperature for 4 hours. After the completion of the reaction, the reaction mixture was cooled. Water was added thereto, and the mixture was extracted with toluene. The extract was washed with water. After toluene was distilled off, diisopropyl ether was added to the residue for crystallization. The resulting crystals were recrystallized from diisopropyl ether - ethyl acetate to give benzyl 3-[4-(3-dimethylaminopropoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate, m.p. 90°-92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:25])[CH2:23][CH3:24])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added propionyl chloride (0.07 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.07 g (63%) of product as an off-white solid: mp 222-224° C.; 1H NMR (DMSO-d6) 11.03 (s, 1H), 9.63 (s, 1H), 8.51 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 2.76-2.45 (m, 5H), 2.10-2.03 (m, 1H), 1.90 (s, 3H), 1.12 (t, J=7.5 Hz, 3H); 13C NMR (DMSO-d6) 172.70, 172.14, 172.03, 168.80, 167.37, 136.48, 135.94, 131.20, 125.59, 117.67, 116.21, 58.81, 29.71, 29.07, 28.53, 20.97, 14.74, 9.18; Anal. Calcd. For C17H17N3O5: C, 59.47; H, 4.99; N, 12.24 Found: C, 59.24; H, 5.06; N, 11.97.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CC(N(C)C)=O.O>[CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution (10 mL) of 4-(cyclohexyl{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methoxy)benzoic acid (0.43 g) synthesized above in dimethylacetamide were added ethyl 3-(methylamino)propanoate (0.14 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.23 g) at room temperature, and the mixture was stirred at 60° C. for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was purified by silica gel chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a methyl ester form of the title compound (0.44 g). This was dissolved in ethanol (2 mL), 1N sodium hydroxide (1.5 mL) was added and the mixture was stirred at room temperature for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue to give the title compound (0.40 g, 78%) as an amorphous form.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[CH3:12])[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: Cc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)nn2ccnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.6 %

Procedure:
A microwave vial was charged with a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.1 g, 4.73 mmol), 4-methylpyridin-3-ylboronic acid (0.648 g, 4.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.547 g, 0.473 mmol), dioxane (14 mL), and K3PO4 (7.10 mL, 14.20 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (20-80% EtOAc/CH2Cl2, 1.5 L, then 20%-65% B/CH2Cl2, 0.9 L; B: 10% MeOH/CH2Cl2) to give 400 mg (34%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.00 (1H, s), 8.80 (1H, d, J=5.79 Hz), 8.38 (1H, d, J=1.51 Hz), 8.04 (1H, d, J=6.04 Hz), 7.96 (1H, d, J=1.51 Hz), 7.86 (1H, s), 2.73 (3H, s); LC/MS: Rt=0.98 min. LC/MS (Condition A): 245.11/247.08.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]O>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(F)c2)c1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.24 (2H, s), 5.73 (1H, d, J=2.0 Hz), 7.03-7.05 (1H, m), 7.07-7.21 (2H, m), 7.36-7.38 (1H, m), 7.40-7.42 (1H, m), 7.57 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=4.2 Hz). [M+H] Calc'd for C16H11FN4O, 295; Found, 295.