Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:14].[K+]>CO.CC(C)=O>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: O=C[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CSc1ccc(C(=O)CO)cc1

Procedure:
119 g of 2-bromo-1-[4-methylthiophenyl]ethanone (prepared according to J. Amer. Chem. Soc., 1952, p. 5475) are dissolved in a mixture of 200 ml of methanol and 300 ml of acetone. 53 g of potassium formate are added and the mixture is heated under reflux for 4 hours. The organic solvents are evaporated, the residual oil is taken up with ethyl acetate and washed with a saturated solution of sodium chloride. The ethyl acetate is evaporated and the residual oil crystallises in isopropyl ether.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([Cl:14])[CH:7]=1.[OH-].[Na+]>ClC(Cl)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:2])=[C:8]([Cl:14])[CH:7]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Phosphorus tribromide (40.5 mL, 0.431 mol) was added dropwise to a solution of (4-bromo-2-chlorophenyl)-methanol (15, 86.1 g, 0.386 mol) in dichloroethane (430 mL) at 0° C. The reaction mixture was stirred for 10 minutes at this temperature then for 0.5 h at 10° C. The mixture was cooled to 0° C. and a sodium hydroxide solution (600 mL, 2N) was added dropwise. The two layers were separated and the aqueous layer was extracted with dichloroethane (200 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and evaporated in vacuo. The crude product (91 g) was distilled under reduced pressure (7 mmHg), to give 4-bromo-1-bromomethyl-2-chlorobenzene (62.5 g, 0.22 mol, 57%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1([CH2:7]Cl)[CH2:6][O:5][CH2:4]1.[F:9][C:10]([F:20])([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][OH:12].[H-].[Na+]>CN(C=O)C>[F:9][C:10]([F:20])([C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[CH2:11][O:12][CH2:2][C:3]1([CH2:7][O:12][CH2:11][C:10]([F:9])([F:20])[C:13]([F:18])([F:19])[C:14]([F:15])([F:17])[F:16])[CH2:6][O:5][CH2:4]1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: ClCC1(CCl)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)C(F)(F)COCC1(COCC(F)(F)C(F)(F)C(F)(F)F)COC1
Yield: 70.5 %

Procedure:
In a manner similar to that described above, 3,3-bis(chloromethyl) oxetane (155 g, 1 mole) was reacted with 2,2,3,3,4,4,4-heptafluorobutan-1ol (402 g, 2.01 moles) in DMF (2 L) in the presence of sodium hydride (100 g of 50% dispersion in mineral oil, 2.3 moles) at 85° C. for 16 h to give 340 g (70%) of 3,3-bis(2,2,3,3,4,4,4-heptafluorobutoxymethyl) oxetane, a clear, colorless liquid. Glc analysis revealed the purity of this material to be in excess of 99%: BP=70°-72° C./1.0-1.3 mm-hG; 1H NMR (CDCl3) δ 4.44 (s, 4H), 3.97 (t, J=13.2 Hz), 3.86 (s, 4H); 13cNMR δ 43.9, 68.1 (t), 73.5, and 75.6 (Signals from carbons bearing fluorine are not included due to the complex splitting patterns and overlap of signals); 19fNMR δ -81.6 (3 F), -121.0 (2 F) and -128.3 (2 F); Anal. Calcd for C13H12F14O3 : C, 32.4; H, 2.5. Found: C, 32.3; H, 2.3.
Reaction SMILES: [CH3:1][C:2]([NH2:11])([CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:3].[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1COCC1>[CH3:3][C:2]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CC(C)(N)CCN1CCCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC(C)(CCN1CCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
Crude 2-methyl-4-(pyrrolidin-1-yl)butan-2-amine (5.70 g, 31.7 mmol) was dissolved into THF (200 mL). To this solution was added CbzOSu (7.92 g, 1 equiv, 31.7 mmol) in one portion. The reaction was left to stir at room temperature for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1 M HCl (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (9.0 g). The crude oil was purified on an ISCO purification system with gradient elution from 5-90% ethyl acetate in hexanes. The desired fraction was collected and concentrated to give a pale yellow oil (5.76 g, yield: 62.5%). 1H NMR (CDCl3, 400 MHz): δ 1.34 (s, 6H), 1.76-1.84 (m, 6H), 2.58-2.66 (m, 6H), 5.04 (s, 2H), 6.36 (bs, 1H), 7.27-7.39 (m, 5H). LRMS (ESI+) for C17H26N2O2 (290.2); Found: 291 (MH+).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]1([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]4[C:26]5[C:21](=[N:22][C:23]([C:27]6[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=6[F:37])=[CH:24][CH:25]=5)[N:20](C5CCCCO5)[N:19]=4)[CH:15]=3)[C:10]2=[O:44])[CH2:8][CH2:7]1>C(Cl)Cl.CO>[Cl:4][C:32]1[C:31]([O:33][CH3:34])=[CH:30][C:29]([O:35][CH3:36])=[C:28]([F:37])[C:27]=1[C:23]1[N:22]=[C:21]2[NH:20][N:19]=[C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[C:10](=[O:44])[N:9]([CH:6]3[CH2:8][CH2:7]3)[CH2:17]4)[C:26]2=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(OC)c(F)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)n[nH]c3n2)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sulfuryl chloride (10. μL, 0.12 mmol) was added to a stirring solution of 2-cyclopropyl-5-[6-(2-fluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one (65 mg, 0.12 mmol) in methylene chloride (1 mL). The mixture was stirred at r.t. for 30 min. It was concentrated to dryness. The solid was dissolved in methanol (0.3 mL). To the solution was added a solution of HCl previously prepared from acetyl chloride (0.15 mL) and methanol (0.15 mL). The mixture was stirred at r.t. for 1 h and then diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=479.1.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[CH2:28][C:29](Cl)=[O:30])[CH3:18]>C(#N)C>[CH2:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26][CH3:27])[C:20]=1[CH2:28][C:29]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:30])[CH3:18]
Reactant: CCOC(=O)C(C)=NNC
Reactant: CCc1cc(C)cc(CC)c1CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.4 %

Procedure:
To a mixture of 2.0 g of ethyl 2-(methylhydrazono)propanoate and 35 mL of acetonitrile, 1.5 g of potassium carbonate was added. To the mixture, a solution of 2.6 g of 2,6-diethyl-4-methylphenylacetyl chloride in 10 mL of acetonitrile was added dropwise over about 20 minutes under ice cooling. This mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue, 20 mL of ice water was added, followed by extraction with ethyl acetate (20 mL×3). The organic layer was washed with an aqueous saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to basic alumina column chromatography (ethyl acetate:hexane=1:3) to obtain 1.9 g of ethyl 2-[2-(2,6-diethyl-4-methylphenylacetyl)-2-methylhydrazono]propanoate [compound (VI-2)] as a white crystal.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33](Cl)([Cl:35])=[O:34]>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:33]([Cl:35])=[O:34]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)Cl)CCC5(C)C4CCC32CN1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Compound 7B (125 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL) and cooled to 0° C. Triethylamine (150 μL, 1.1 mmol) and phosgene (20% in toluene, 0.23 mL, 0.44 mmol) were added to it. The mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with water, extracted with dichloromethane. The combined extracts were dried over Na2SO4, filtered and concentrated to give crude desired product (144.6 mg, 97.8%), which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Product: COCc1cc(Nc2cc(OC)ccc2C)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (50 mg, 0.201 mmol) and 5-methoxy-2-methylaniline (28 mg, 0.201 mmol) similar to Example 13. 1H NMR (CDCl3): 8.20–8.16 (m, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.28 (s, 1H), 7.18 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.73 (dd, J=2.7, 8.4 Hz, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.49 (s, 2H), 3.82 (s, 3H), 3.47 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.FC(F)(F)S(O[C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[Br:26])(=O)=O>>[Br:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[CH:18]=[N:17][C:16]([NH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[CH:25]2
Reactant: O=S(=O)(Oc1cc2cccc(Br)c2cn1)C(F)(F)F
Reactant: N#Cc1cnc(N)cn1
Product: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile and 8-bromoisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 1H NMR (DMSO, 400 MHz) δ 11.30 (br s, 1H), 9.40 (s, H), 8.95 (s, H), 8.80 (s, H), 8.60 (s, H), 8.05 (d, 1H, J=8.5 Hz), 7.95 (d, 1H, J=7.5 Hz), 7.75 (dd, 1H, J=8.5 Hz, 7.5 Hz). LC-MS (2) Rt=3.21 min, m/z (ESI+) 326 & 328 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.S(=O)(=O)(O)O.[BrH:17]>>[Br:17][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCCC(C)CCO
Reactant: Br
Agent: O=S(=O)(O)O
Product: CC(C)CCCC(C)CCBr
Temperature: 100 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
3,7-Dimethyloctan-1-ol (10.0 g, 63.2 mmol) was suspended in 48% aqueous hydrobromic acid solution, concentrated sulfuric acid (0.17 ml) was added dropwise and the mixture was stirred at 100° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, extracted with hexane (200 ml), and washed twice with 5% aqueous sodium hydrogen carbonate solution (100 ml) and once with 20% brine (100 ml). The organic layer was dried over sodium sulfate, and the solvent in the filtrate was evaporated to give the title compound (13.3 g, 95.1%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[N:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[N:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)nnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)F
Yield: 51 %

Procedure:
The title compound is prepared in 51% yield (170 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride (230 mg, 0.90 mmol, Amine-50) in a similar manner to Intermediate-2.
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:13])[C:4]([C@H:6]1[CH2:12][CH2:11][C@@H:10]2[C@@H:8]([O:9]2)[CH2:7]1)=[O:5]>>[NH2:1][C@H:8]1[C@H:10]([OH:9])[CH2:11][CH2:12][C@H:6]([C:4]([N:3]([CH3:13])[CH3:2])=[O:5])[CH2:7]1
Reactant: CN(C)C(=O)[C@H]1CC[C@H]2O[C@H]2C1
Reactant: N
Product: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](N)C1
Temperature: 40 °C

Procedure:
A 28% aqueous ammonia solution (5 ml) was added to (1S,3S,6R)—N,N-dimethyl-7-oxabicyclo[4.1.0]heptane-3-carboxamide (5) (1 g) at room temperature. The mixed solution was stirred at 40° C. for hours, and then, the solvent was concentrated under reduced pressure to obtain (1S,3R,4R)-3-amino-4-hydroxy-N,N-dimethylcyclohexanecarboxamide (1.18 g).
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48].[C:49](Cl)(=[O:51])[CH3:50]>C(N(CC)CC)C.ClCCl>[C:49]([NH:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])(=[O:51])[CH3:50]
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1NC(C)=O
Reaction time: 2 h

Procedure:
The solution of 0.380 g of tert-butyl 3-[4-amino-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 0.168 ml of triethylamine and 10.0 ml of dichloromethane is cooled to 0° C. and admixed slowly with the solution of 0.090 ml of acetyl chloride in 1.0 ml of dichloromethane. The reaction solution is stirred over 2 hours, poured onto ice-water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with successively with water (20 ml) and brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1)=[O:28].[N:36]1([CH2:42][CH2:43][NH2:44])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:44][CH2:43][CH2:42][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH2:31][CH2:30]1)=[O:28]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(=O)CC1
Reactant: NCCN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(NCCN2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-one (Compound number 701) (2.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of 2-morpholin-4-yl-ethylamine (0.65 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and the mixture was heated at 50° C. for 3 h then stirred at room temperature for 2 days. A solution of sodium tri-acetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added and the mixture was stirred for 20 h at room temperature. Solvents were removed in vacuo to yield the title compound. MS: (ESI)+: [M+H]+=586.6
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[SH:25]>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:17]2[N:16]([CH3:15])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Cn1c(S)nc2ccccc21
Product: Cn1c(SCC(=O)N2CCCc3ccccc32)nc2ccccc21
Yield: 77 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 1-methyl-1H-benzo[d]imidazole-2-thiol as the nucleophile to yield 17 as a pale yellow solid (77%): MS m/z: 338 (M+H)+. Anal. Calcd. For, C19H19N3OS: C, 67.63; H, 5.68; N, 12.45; S, 9.50. Found: C, 67.45; H, 5.74; N, 12.25; S, 9.41.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](O)=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.C([N:20](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([NH2:20])=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccccc2)c1CCC(N)=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.95 g), triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.86 g, yield 91%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 149–151° C.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH3:15][C:14]1[N:13]=[C:12]([C:11]2[NH:10][CH:9]=[N:8][C:7]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:18][N:17]=1
Reactant: CCCCCNc1nc[nH]c1C#N
Reactant: CC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Temperature: 165 °C
Reaction time: 14 h
Yield: 9.6 %

Procedure:
To the mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (0.40 g, 2 mmol), acetic acid, hydrazide (0.33 g, 4.5 mmol) in 1-butanol (10 mL) was added potassium carbonate (0.10 g, 0.72 mmol). The mixture was sealed and stirred at 165° C. for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative LCMS (method A) to yield the desired product (45 mg, 10% yield). LCMS calculated for C11H19N6(M+H): 235.2; found: 235.1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[C:13](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[N:23]1[N:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]2=[C:25]([C:32](O)=[O:33])[CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[OH:22][CH2:21]/[CH:20]=[CH:19]/[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:32]([C:25]2[CH:24]=[N:23][N:27]3[CH:28]=[CH:29][CH:30]=[N:31][C:26]=23)=[O:33])[CH:12]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: COc1ccc(/C=C/CO)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(/C=C/CO)cc1NC(=O)c1cnn2cccnc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of diisopropylethylamine (0.25 mL), (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol (90 mg), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (65 mg), HOBT (85 mg) and HBTU (0.20 g) in anhydrous acetonitrile (5 mL) was heated to 80° C. overnight. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (MeOH/EtOAc, 3/97) to give an oil. This residue was triturated with ethyl acetate to give, upon standing for 1 hour, 20 mg of (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol as a light brown solid which was collected by filtration. MS=325 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].C([NH+](CC)CC)C>CN1CCCC1=O.O>[O:17]=[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:20][N:19]=[N:18][N:2]=2)=[CH:8][N:7]=1)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCC(=O)Nc1ccc(C#N)cn1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CCC(=O)Nc1ccc(-c2nnn[nH]2)cn1
Yield: 25 %

Procedure:
A mixture of methyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A1 (0.200 g, 0.857 mmol), sodium azide (0.169 g, 0.09 ml, 2.57 mmol) and triethylammonium chloride (0.187 g, 0.17 ml, 1.33 mmol) was stirred 4 h at 150° C. in 1-methyl-2-pyrrolidinone (10 mL). The mixture was cooled down and diluted with water. After acidification with aqueous hydrochloric acid (1N), the filtrate was extracted twice with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate and filtered to give methyl 4-oxo-4-[[5-(1H-tetrazol-5-yl)-2-pyridyl]amino]butanoate A65 (0.06 g, 25% yield). M.p.: 246-248° C., LC-MS (Method F) RT 0.53, 277 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][OH:21]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:21][CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: OCC1CCCCN1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc(N2CCCCC2CO)c2ccccc12

Procedure:
A solution of 1-cyano-4-fluoronaphthalene (200 mg, 1.168 mmol) in pyridine (0.5 mL) was transferred to a Pyrex tube and 2-piperidinemethanol (538 mg, 4.67 mmol) was added. The tube was capped and exposed to microwave irradiation (200° C., 60 min). The reaction mixture was diluted with ethyl acetate, washed with 0.4 N HCl and saturated aqueous NaHCO3. The organic phase was dried and evaporated to give a crude product which was purified by preparative TLC (65:35 n-heptane/ethyl acetate), followed by further purification by preparative HPLC to give 173FBA70e (15 mg, 5%).