Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:21])[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.O>C1COCC1.[OH-].[Na+]>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][CH:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:21])[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (2.38 g) in THF (20 ml), 0.5N aqueous sodium hydroxide solution (14.7 ml) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water (120 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid thereto and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (2.06 g).
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.CS[C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32]>C(O)C.C(OCC)C.[Pd]>[CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:17][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
Compound 4 (125 mg, 0.344 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (36.2 mg, 0.034 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows complete conversion to compound 5, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 5 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (127.5 mg, 0.447 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 48 hours, at which time the solution was diluted with diethyl ether (100 ml) resulting in the formation of a off-white precipitate that was collected on a sintered glass funnel and washed with ether. The solid was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 8-9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95) to afford beige foam 6 (75 mg, 49.3%); 1H NMR (DMSO-d6) δ 7.71 (d, 1H, J=3.7 Hz), 7.58 (d, 1H, J=5.2 Hz), 7.35-7.20 (m, 6H), 7.09 (m, 1H), 6.92 (s, 1H), 6.64 (d, 1H, J=8.5 Hz), 6.23 (brs, 2H), 6.10 (s, 1H), 4.14 (s, 2H), 3.99 (t, 2H, J=8.0 Hz), 2.90 (quintet, 1H, J=4.6 Hz), 2.10 (s, 3H), 2.05-1.97 (m, 2H), 1.91-1.80 (m, 1H), 1.69-1.56 (m, 3H), 1.49-1.35 (m, 2H); ESI-MS (m/z, %): 443 (M+1, 70%), 219 (100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6](S(C)(=O)=O)[N:7]=1.[NH2:30][C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=1>O1CCOCC1>[CH2:38]([O:37][C:35]([C:34]1[CH:40]=[CH:41][C:31]([NH:30][C:6]2[N:7]=[C:2]([CH3:1])[C:3]3[CH:15]=[CH:14][C:13](=[O:16])[N:12]([C:17]4[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:28][CH:29]=4)[C:4]=3[N:5]=2)=[CH:32][CH:33]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(Nc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)OC(C)(C)C)cc4)c3n2)cc1
Reaction time: 14 h
Yield: 63.3 %

Procedure:
A solution of compound 2 (0.5 g; 1.2 mmol) and ethyl p-aminobenzoate (1 g; 6 mmol) in 10 mL of dioxane was refluxed under stirring for 14 h. The reaction mixture was concentrated, purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=1/1 to 1/2) to yield compound 3 (0.38 g; 63%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][C:9]([O:20][CH2:21][C:22]([NH2:24])=[O:23])=[CH:8][CH:7]=2)#[N:2].N.O1CCCC1.[ClH:35]>C(OCC)(=O)C.[Ni].CO>[ClH:35].[ClH:35].[NH2:2][CH2:1][C:3]1[C:4]([CH2:25][CH:26]([CH3:28])[CH3:27])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[CH:10][C:9]([O:20][CH2:21][C:22]([NH2:24])=[O:23])=[CH:8][CH:7]=2
Reactant: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2F)c1C#N
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2F)c1CN
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To a mixture of 2-{[3-cyano-4-(2-fluorophenyl)-2-isobutylquinolin-6-yl]oxy}acetamide (0.11 g, 0.29 mmol), 25% aqueous ammonia (2 ml), tetrahydrofuran (2 ml) and methanol (10 ml) was added Raney-nickel (1 ml), and the mixture was stirred under a hydrogen (0.5 MPa) atmosphere at room temperature for 6 hrs. The reaction mixture was filtered, and the filtrate was partitioned between ethyl acetate (50 ml) and 10% aqueous potassium carbonate solution (25 ml). The organic layer was washed with saturated brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give a colorless oil. This was dissolved in ethyl acetate (2 ml) and 4N solution of hydrogen chloride in ethyl acetate (1 ml) was added. The reaction mixture was concentrated and the obtained crude crystals were recrystallized from diisopropyl ether-methanol to give the title compound (0.078 g, yield 59%) as pale-yellow crystals.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)([OH:3])=O.[CH3:25][NH:26][CH3:27].O>CN(C=O)C>[CH3:25][N:26]([CH3:27])[C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)=[O:3]
Reactant: CNC
Reactant: O=C(O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture containing 9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (150 mg) and 1,1-carbonyldiimadazole (120 mg) in DMF (5 mL) was heated to 60° C. for 15 minutes after which time the reaction was cooled and 2 mL of dimethylamine added. The reaction was allowed to stand at room temperature for 1 hour. To the mixture was then added 10 mL of H2O and the resultant product was collected and dried to yield 9-(N,N-Dimethylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 18) m.p.>325° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:40])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:29]CC4C=CC(OC)=CC=4)=[C:24]([O:26][CH2:27][CH3:28])[CH:25]=3)=[CH:16][C:15]=2[F:39])=[CH:7][C:6]=1[C:41]([F:44])([F:43])[F:42])[CH3:3].[ClH:45]>C(Cl)Cl>[ClH:45].[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:40])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23](=[O:29])[NH:22][CH:21]=3)=[CH:16][C:15]=2[F:39])=[CH:7][C:6]=1[C:41]([F:43])([F:42])[F:44])[CH3:3]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CN(C)C)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CN(C)C)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (5.8 g, 7.30 mmol) in DCM (50 mL) was added HCl (1,4-dioxane, 5 mL, 20.00 mmol) at rt. The solution was stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give the crude product. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield an off white solid of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (1.5 g, 2.78 mmol, 38.1% yield). TLC (DCM/MeOH=5:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ 8.21 (d, J=1.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.36-7.53 (m, 5H), 4.50 (s, 2H), 4.20 (q, J=7.0 Hz, 2H), 3.87 (s, 2H), 2.95 (s, 6H), 1.50 (t, J=7.0 Hz, 3H); ES-LCMS m/z 492.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](F)(F)F)=[CH:4][CH:3]=1.[Al+3].[Cl-:13].[Cl-:14].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([Cl:14])[Cl:13])=[CH:19][CH:18]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Fc1ccccc1
Reactant: [Cl-]
Agent: [Al+3]
Product: Fc1ccc(C(Cl)(Cl)c2ccc(F)cc2)cc1

Procedure:
From 4-fluorobenzotrifluoride (164 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and fluorobenzene (96 mg, 1 mmol), light yellow oil (377 mg, 138% crude).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[O-]CC.[Na+].[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=[CH2:23].Cl>C(O)C.O>[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH:6]([C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: C=CC(=O)CCCCCCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCC(=O)CCC(C(=O)OCC)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a stirred solution of 0.91 g of ethyl 2-chlorobenzoylacetate in 10 cc of ethanol was added 0.27 g of sodium ethoxide at room temperature, and the mixture was stirred at room temperature for 10 minutes. Then, 0.62 g of 3-oxo-1-decene in 10 cc of ethanol was added and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the aqueous layer was acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane =1/9) to obtain 0.90 g of compound I. Yield: 59.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:47])[C@H:26]([CH2:45]O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH2:45][C@@H:26]([C:25]([OH:47])=[O:24])[NH2:27])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[S:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2(O)c3ccccc3Sc3ccccc32)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: Cc1ccc(C2(OC[C@H](N)C(=O)O)c3ccccc3Sc3ccccc32)cc1

Procedure:
from 9-(4-methylphenyl)-9H-thioxanthen-9-ol (Example 1p) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:10]1[N:15]=[CH:14]N=[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(NC(=O)CC3C=CC(F)=CC=3)=S)=[CH:19][C:18]=2[F:37])[CH:11]=1.[C:38]([O-])([O-])=O.[K+].[K+]>[Cu]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:12]2[CH:11]=[CH:10][N:15]=[C:14]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:38]=2)=[C:18]([F:37])[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: NCc1ccccc1
Reactant: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc2F)ncn1
Agent: [Cu]
Agent: [K+]
Product: Nc1ccc(Oc2ccnc(NCc3ccccc3)c2)c(F)c1
Temperature: 160 °C
Yield: 52.1 %

Procedure:
Benzylamine (9.1 mL, 83.8 mmol, 20 eq) was added to 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (Compound B of Example 20, 1.0 g, 4.19 mmol, 1.0 eq), copper powder (0.266 g, 4.19 mmol, 1.0 eq) and K2CO3 (0.578 g, 4.19 mmol, 1.0 eq) in a sealed tube and the reaction mixture was heated to 160° C. for 12 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NaCl solution. The solution was extracted with ethyl acetate (3×100 mL), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (YMC C-18 ODS-A S10 50×500 mm, eluting 10-90% aqueous MeOH with 0.1% TFA, 30 minute gradient) and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.675 g, 52%) as a solid. 1H NMR (CD3OD) δ 7.78-7.80 (m, 1H), 7.28-7.30 (m, 5H), 6.80-6.90 (m, 1H), 6.52-6.55 (m, 2H), 6.18-6.20 (m, 1H), 5.87-5.88 (m, 1H), 4.40 (s, 2H); MS(ESI+) m/z 310 (M+H)+; HRMS(ESI+) calcd.: 310.1356, found: 310.1360.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1

Procedure:
4-Methyl-5-nitro-pyridin-2-ylamine (1.0 g) was treated with acetic anhydride according to General Procedure Y to give N-(4-Methyl-5-nitro-pyridin-2-yl)-acetamide (1.1 g). LCMS (m/z): 196. N-(4-Methyl-5-nitro-pyridin-2-yl)acetamide (0.5 g) was reduced under hydrogen atmosphere according to General Procedure Z to give N-(5-Amino-4-methyl-pyridin-2-yl)-acetamide (0.4 g), LCMS (m/z): 166. This was converted to 6-acetylamino-4-methyl-pyridine-3-sulfonyl chloride (0.35 g) according to General Procedure AA. LCMS (m/z): 249.
Reaction SMILES: [CH2:1]([O:4][P:5](Cl)([O:7][CH2:8][CH2:9][CH3:10])=[S:6])[CH2:2][CH3:3].[OH-:12].[K+:13]>C(O)CC>[K+:13].[P:5]([O-:12])([O:7][CH2:8][CH2:9][CH3:10])([O:4][CH2:1][CH2:2][CH3:3])=[S:6]
Reactant: CCCOP(=S)(Cl)OCCC
Reactant: [OH-]
Agent: [K+]
Solvent: CCCO
Product: CCCOP([O-])(=S)OCCC
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To 100 g (460 mmole) of di-n-propylchlorothiophosphate in 300 ml of 1-propanol was added 58.8 g (920 mmole) of 88% potassium hydroxide pellets. The reaction mixture was refluxed overnight and then cooled to room temperature. The precipitated potassium chloride was filtered off and the solvent was stripped in vacuo. The resulting solid was slurried in 20% diethyl ether/80% hexanes and filtered yielding 67 g of the title compound, a fluffy white solid, mp 205°-207° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[CH:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28])=O>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:22][C:24]5[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=5)[C:27]#[N:28])[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: N#Cc1cccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)c1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formylbenzonitrile was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-[[5-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]methyl]benzonitrile.
Reaction SMILES: [Na+].[CH2:2]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21]([O-:23])=O)[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5].[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:42]=1[CH2:43][NH2:44])[CH2:37][CH:38]=[CH2:39].C(OC1C=CC=CC=1CNC(C1N=C2C=C(C)C([C@H](OC(C)(C)C)C(OC)=O)=C(N3CCC(CCC=C)(C)CC3)N2C=1)=O)C=C>>[CH2:2]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21](=[O:23])[NH:44][CH2:43][C:42]4[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:41]=4[O:40][CH2:36][CH2:37][CH:38]=[CH2:39])[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCOc1ccc(F)cc1CN
Reactant: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)[O-])cn23)CC1
Agent: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)NCc4ccccc4OCC=C)cn23)CC1
Agent: [Na+]
Product: C=CCCOc1ccc(F)cc1CNC(=O)c1cn2c(N3CCC(C)(CCC=C)CC3)c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc2n1
Yield: 75 %

Procedure:
Prepared from (S)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylic acid sodium salt and 2-(but-3-en-1-yloxy)-5-fluorobenzylamine in 75% yield using the same procedure as (S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (500 MHz, CDCl3) [note: appears to be 2:1 mixture of rotamers, major rotamer transcribed] δ 8.24-8.21 (m, 1H), 7.90-7.81 (m, 1H), 7.23-7.18 (m, 1H), 7.14-7.09 (m, 1H), 6.95-6.87 (m, 1H), 6.83-6.77 (m, 1H), 6.12-6.08 (m, 1H), 6.05-5.89 (m, 2H), 5.28-5.21 (m, 1H), 5.19-5.15 (m, 1H), 5.14-4.98 (m, 2H), 4.69-4.64 (m, 2H), 4.07 (s, 2H), 3.74-3.73 (m, 1H), 3.71 (s, 3H), 3.64-3.49 (m, 1H), 3.14-2.93 (m, 1H), 2.91-2.83 (m, 1H), 2.70-2.60 (m, 2H), 2.47-2.46 (m, 3H), 2.17-2.09 (m, 2H), 1.71-1.60 (m, 6H), 1.26 (s, 9H), 1.15 (s, 3H); LCMS (ESI, M+1): 649.35.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3[O:21][C:20]([CH3:23])(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[N:2]1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.C(=O)([O-])[O-:51].[Na+].[Na+]>COCCOC.O>[C:20]([OH:51])(=[O:21])[CH3:23].[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([C@H:37]3[CH2:42][CH2:41][C@H:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)[N:28]=[C:27]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[CH:16][CH:15]=3)[C:35]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3noc4ccccc34)cc2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5noc6ccccc56)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of N-benzo[d]isoxazol-3-yl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.10 g, 0.000298 mol), trans-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.101 g, 0.000229 mol), tetrakis-(triphenylphosphine)palladium (0.016 g, 0.0000137 mol) and sodium carbonate (0.061 g, 0.000573 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)benzo[d]isoxazol-3-amine acetate (0.102 g, 0.000175 mol) as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:33]([OH:37])(=[O:36])[CH:34]=[CH2:35].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:35]=[CH:34]/[C:33]([OH:37])=[O:36])=[CH:3][C:4]=1[CH3:10])#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: C=CC(=O)O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(/C=C/C(=O)O)ccc1C#N
Temperature: 200 °C
Reaction time: 2 h

Procedure:
9.0 g 4-bromo-2-methylbenzonitrile, 2.76 g tri-o-tolylphosphine, 3.11 ml acrylic acid and 25.1 ml triethylamine are dissolved in 80 ml acetonitrile. The reaction mixture is degassed, then 2.0 g palladium (II)acetate were added and the mixture stirred two hours under microwave irradiation at 200° C. The cooled reaction mixture was diluted by addition of 50 ml ethyl acetate. Thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated as a white solid. The precipitate was filtered off and dried in vacuo to obtain 2.5 g (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid. The filtrate was washed with 1N HCl, thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated again as a white solid. The precipitate was filtered off and dried in vacuo to obtain 2.0 g (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid. The filtrate was reduced in vacuo to one third of its volume, 150 ml diethyl ether were added, thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated again as a white solid. The precipitate was filtered off and dried in vacuo to obtain 840 mg (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][N:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCCNC(=O)c1ccc(C#N)nc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 66.2 %

Procedure:
A mixture of methyl thiosalicylate (2.2 g, 13.3 mmol), 6-cyano-N-propylnicotinamide (1.2 g, 6.5 mmol), triethylamine (2.0 ml, 14.3 mmol) and toluene (4 ml) was refluxed for 5 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from diisopropylether-chloroform to give the titled compound (1.4 g, 67%) as crystals.