Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7].[CH:48](=O)[CH2:49][CH:50]([CH3:52])[CH3:51].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7]
Reactant: CC(C)CC=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(CCC(C)C)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
A solution of Example 283A (50 mg, 0.075 mmol) in dichloroethane (1 mL) was treated with isovaleraldehyde (10 mg, 1.5 equivalents), acetic acid (5 μL, 2 equivalents), and sodium triacetoxy borohydride (32 mg, 2 equivalents), stirred at 25° C. for 16 hrs. The mixture was quenched with 10% NaHCO3 (2 mL) and CHCl3. The organic layer was separated, dried over sodium sulfate, and the solvents were evaporated. The residue was purified using 5% methanol/CHCl3 to give 49 mg (89%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:23][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:21])[F:22])=[N:4]2)=[CH:20][CH:19]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CN(Cc1ccccc1)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-methylbenzylamine using a similar procedure to that described for Example 2.
Reaction SMILES: [Br:1]Br.[C:3]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:7])#[N:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:3]([CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][C:13]=1[Br:1])[CH3:7])#[N:4]
Reactant: COc1ccc(C(C)CC#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(C)CC#N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (17.9 ml) is added dropwise over a period of 1.5 hours to a solution of 1-cyano-2-(p-methoxyphenyl)-n-propane (61.2 g) and sodium acetate (34.4 g) in glacial acetic acid (350 ml), and the solution is stirred for 30 min. at RT. The reaction mixture is poured into H2O, extracted with diethyl ether, and the etheral extract is washed with H2O, sat'd NaHCO3, 10% NaOH, sat'd NaCl, dried, filtered, and the filtrate evaporated in vacuo. The residue is distilled affording the product as a cloudy oil, B.P.=162° C. (2 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH2:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+].I[C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:12]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:33]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:34]=3)[CH:11]=2)[C:6]([CH3:15])([CH3:16])[CH2:7][CH2:8]1)([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1ccccc1I
Reactant: CC(C)N1CCC(C)(C)c2ccc(N)cc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)N(C(C)C)CCC3(C)C)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 41.4 %

Procedure:
7-Amino-1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (Compound 33, 130 mg, 0.5954 mmol) was placed into the round bottom flask charged with argon and Pd2 (dab)3 (1.363 mg, 0.25 mol %), and BINAP (2.78 mg, 0.75 mol %) were added, followed by addition of NaOtBu (80.11 mg, 0.8335 mmol), ethyl iodobenzoate (230 mg, 0.8335 mmol) and toluene (3 mL). The resulting mixture was stirred at 80° C. for 3 days, cooled to room temperature, and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.30) to give the title compound (90.3 mg, 41%) as a solid: PNMR (300 MHz, CDCl3): δ1.20 (d, 6 H, J=6.6 Hz), 1.28 (s, 6 H), 1.38 (t, 3 H, J=7.1 Hz), 1.71 (t, 2 H, J=6.0 Hz), 3.19 (t, 2 H, J=6.0 Hz), 4.02 (sp, 1 H, J=6.6 Hz), 4.34 (q, 2 H, J=7.1 Hz), 5.92 (s, 1 H), 6.43 (dd, 1 H, J=8.1, 2.1 Hz), 6.50 (d, 1 H, J=2.1 Hz), 6.97 (d, 2 H, J=8.7 Hz), 7.14 (d, 1 H, J=8.1 Hz), 7.90 (d, 2 H, J=8.7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:8]=1)[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CNc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(Cl)nc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 10.0 g. (0.04 mole) of N-(2,6-dichloro-4-pyrimidinyl)glycine ethyl ester, prepared in Example 8, 5.6 g. (0.04 mole) of p-chlorobenzylamine and 4.24 g. (0.04 mole) of sodium carbonate in 100 ml. of ethanol was heated under reflux for 6 hours. The reaction mixture was filtered and the filtrate was cooled in ice. The precipitate thus formed was collected and recrystallized from benzene with petroleum ether being added to initiate precipitation to give 4.1 g. of product, m.p. 168°-170°C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:16]([Br:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[CH2:18]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]([Br:17])=[CH:15]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2Cc2ccccc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Br)cn(Cc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-1-benzyl-3-bromo-7-cyano-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 429 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(N(CC)CC)C>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1

Procedure:
Commercially available (tetrahydro-2H-pyran-4-yl)methanol (Maybridge), tosyl chloride and triethylamine were processed using the method described in Example 184B to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.05-1.25 (m, 2H), 1.40-1.53 (m, 2H), 1.73-1.94 (m, 1H), 2.43 (s, 3H), 3.14-3.28 (m, 2H), 3.71-3.84 (m, 2H), 3.88 (d, J=6.4 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)[NH:4][CH2:5][C:6]1=[O:12])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1CNc2c(Cl)cccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)CN1C(=O)CNc2c(Cl)cccc21

Procedure:
Following the same procedure as described for Example 1C, 5-chloro-3,4-dihydro-1H-quinoxalin-2-one from Example 12D (350 mg, 1.9 mmol) was reacted with sodium hydride (60%, 84 mg, 2.1 mmol) and tert-butyl bromoacetate (340 μl, 2.1 mmol). The product was purified by flash chromatography on silica (eluant pet. ether:EtOAc 100:0 to 50:50) to give a brown solid; yield 450 mg, 79%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2.[OH:24]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24]
Reactant: O=C1CCc2cc(OCCCCSc3ncccn3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3ncccn3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-pyrimidyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[CH:11]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:21][C:16]1([C:12]2[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][N:13]=2)[O:17][CH2:18][CH2:19][O:20]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(C2(C)OCCO2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cc(CO)ccn2)OCCO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-(2-methyl-[1,3]dioxolan-2-yl)-pyridine (840 mg, 2.71 mmol) in dry THF (15 mL) was treated at 0° C. with TBAF (4.70 mL of a 1M solution in THF, 4.70 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1.5 h. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1 to 1:3 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.10. LC-MS-conditions 02: tR=0.33 min; [M+H]+=196.54.
Reaction SMILES: [H-].[Na+].[NH:3]=[C:4]1[NH:8][CH:7]([C:9]2[O:10][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5]1.N#N.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>CN(C)C=O>[NH:3]=[C:4]1[N:8]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=2)[CH:7]([C:9]2[O:10][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5]1
Reactant: N=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Reactant: COc1cccc(CCl)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CN2C(=N)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
60% Sodium hydride (289 mg) was added to a stirred solution of 2-(5-imino-2-pyrrolidinyl)-4,5-diphenyloxazole (2.0 g) in N,N-dimethylformamide (20.0 ml) in the presence of an atmospheric N2 gas under ice cooling and the resulting mixture was stirred at the same temperature for 20 minutes and at room temperature for 1 hour 20 minutes. 3-Methoxybenzyl chloride (1.72 g) was added to the mixture under ice cooling and stirring was continued at room temperature overnight. The reaction mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and aqueous sodium bicarbonate, dried over MgSO4, and evaporated in vacuo. The oily residue was chromatographed to afford 2-[5-imino-1-(3-methoxybenzyl)-2-pyrrolidinyl]-4,5-diphenyloxazole (1.80 g) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH2:26]O)[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.Cl>O1CCCC1>[CH2:16]([O:15][C:14]1[C:13](=[O:23])[C:12]([Br:24])=[CH:11][N:10]2[CH2:25][CH2:26][N:6]([CH2:5][C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:8])[C:9]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NCc1cccc(Cl)c1)c1c(OCc2ccccc2)c(=O)c(Br)cn1CCO
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
3-Benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.75 g) was suspended in tetrahydrofuran (50 ml), and N,N-diisopropylethylamine (3.72 ml) and methanesulfonyl chloride (1.38 ml) were added. After stirring at room temperature for 1 hr, 0.5N aqueous hydrochloric acid (40 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml each). The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate, dried and concentrated. The obtained residue was dissolved in dimethylformamide (50 ml) and 60% sodium hydride was added by small portions with stirring at room temperature. After confirming the completion of the reaction by thin layer chromatography (TLC), the reaction mixture was ice-cooled, 0.33N aqueous hydrochloric acid (300 ml) was added, and the mixture was extracted twice with ethyl acetate (250 ml each). The ethyl acetate layer was washed with water, dried, concentrated, and crystallized from ethyl acetate-hexane to give 9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (1.58 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.B(O)(O)[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[N:11][CH:10]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:15][C:12]1[N:11]=[CH:10][C:9]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: Cn1ccc(N)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc(Nc2ccc(Br)nc2)n1
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-ylamine (0.23 g, 2.3 mmol, 1.0 equiv) and 2-bromopyridyl-5-boronic acid (0.70 g, 3.5 mmol, 1.5 equiv) in 10 Ml dichloromethane was added pyridine (0.43 Ml, 5.4 mmol, 2.4 equiv), copper (II) acetate (0.63 g, 3.5 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir vigorously open to air overnight. The reaction was then filtered through Celite, concentrated in vacuo, and purified by silica gel chromatography to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3H) 5.84 (s, 1H) 7.45 (d, J=8.59 Hz, 1H) 7.60 (d, J=2.02 Hz, 1H) 7.86 (dd, J=8.59, 3.03 Hz, 1H) 8.41 (d, J=2.78 Hz, 1H) 8.92 (s, 1H); (M+H)+255.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1.CC1C=CC=C(C)N=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[C:32]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=2)[CH2:14]1)(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3ccc(F)cc3c(N[C@H]3CCNC3)n2)[nH]1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a mixture of (S)-3-(7-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 0.35 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (122 mg, 1.15 mmol). The resulting mixture was cooled to −40° C. Acryloyl chloride (45 mg, 0.49 mmol) was added dropwise and the reaction mixture was stirred at −40° C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (79 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 (s, 1H), 11.70 (s, 1H), 8.25-8.22 (d, J=10.8 Hz, 1H), 7.97-7.96 (m, 1H), 7.63-7.60 (m, 2H), 7.55-7.54 (m, 1H), 6.59-6.57 (m, 1H), 6.21-6.15 (m, 1H), 5.68-5.65 (dd, J1=10.4 Hz, J2=2.4 Hz, 1H), 5.20-5.18 (m, 1H), 4.19-4.15 (m, 0.5H), 3.70-3.67 (m, 2H), 3.69-3.45 (m, 1.5H), 3.25 (m, 0.5H), 2.26-2.24 (m, 1H), 2.08-2.03 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].Cl>O>[CH3:33][S:34]([O:19][CH2:18][CH2:17][CH:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:36])=[O:35]
Reactant: OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
500 ml MDC was added in the residue of 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropan-1-ol of formula (C) followed by the addition of 50.1 g triethyl amine at 25° C. to 35° C. Reaction mass was cooled to 20° C. to 25° C. followed by the addition of 48.96 g methane sulphonyl chloride. Temperature was raised to 25° C. to 30° C. and maintained for 30 minutes. Further, 300 ml water was added and reaction mass was cooled to 0° C. to 5° C. and pH adjusted to 2 to 3 using 20% hydrochloric acid solution. The reaction temperature was raised to 25° C. to 35° C. and stirred for 30 minutes. The layers were separated and to the MDC layer added 5 g of activated charcoal and stirred for 30 minutes. MDC was distilled out under vacuum below 50° C. and co-distil by 2×50 ml methanol. The residue was treated with 300 ml methanol and heated up to 60° C. to 65° C. and maintained for 1 hour. Further, reaction mass was cooled to 25° C. to 35° C. and further cooled to 0° C. to 5° C. Finally the product was washed with 2×50 ml chilled methanol and dried in hot air oven at 55° C. to 60° C. to afford the title compound 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropyl methanesulfonate of formula (D).
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=C1)[CH2:7]3.C([OH:14])C=C>>[CH:8]12[CH2:7][CH:6]([CH:10]=[CH:9]1)[CH2:5][CH:4]2[CH2:3][OH:14]
Reactant: C=CCO
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Product: OCC1CC2C=CC1C2
Temperature: 210 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
After DCPD (dicyclopentadiene, Aldrich, 397 g, 3 mol) and allyl alcohol (Aldrich, 331 g, and 5.7 mol) were put into a 2 L high pressure reactor, temperature was increased to 210° C. After a reaction was conducted for 1 hour while agitating at 300 rpm, reactants were cooled and moved to a distillator. Distillation was repeatedly conducted under reduced pressure of 1 torr using a vacuum pump twice to obtain a product at 56° C. (yield: 52%)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]2[C:9]([C:13]3[S:17][C:16](Br)=[N:15][C:14]=3[CH3:19])=[C:10]([CH3:12])[N:11]=[C:4]2[C:3]=1[CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][N:5]2[C:9]([C:13]3[S:17][C:16]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:15][C:14]=3[CH3:19])=[C:10]([CH3:12])[N:11]=[C:4]2[C:3]=1[CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22]
Reactant: CCC(CC)c1c(Br)c(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1c(Br)c(C)nn2c(-c3sc(N4CCOCC4)nc3C)c(C)nc12
Temperature: 100 °C
Yield: 41.8 %

Procedure:
72 mg of 7-bromo-3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.15 mmol) and 66 mg of morpholine (0.76 mmol) and 97 mg of cesium carbonate (0.3 mmol) are put in 4 ml vial with 3 ml of dry THF. The vial is capped with a Teflon® lined cap and heated at 100° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 30 mg of the title compound. Yield 42%: mass spectrum (m/e): 479 (M+1); 1H-NMR (CDCl3): 3.87 (t, 4H, J=5.0 Hz), 3.55 (t, 4H, J=5.0 Hz), 3.45 (m, 1H), 2.70 (s, 3H), 2.44 (s, 3H), 2.40 (m, 2H), 2.18 (s, 3H), 2.01 (m, 2H), 0.88 (t, 6H, J=7.3 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:22])[CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CC(C)(N)C(=O)O
Reactant: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(NC(C)(C)C(=O)O)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-(3-bromo-phenyl)-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (354.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (113.4 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 378.2.