Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([CH2:4][NH2:5])[OH:3].[Na].[CH2:7]([Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(C)C>C1(C)C=CC=CC=1>[ClH:14].[C:8]1([CH2:7][O:3][CH2:2][CH2:4][NH2:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCO
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanolamine hydrochloride (20 g, 0.21 mol) in toluene (100 mL) was treated with sodium metal (pellets washed with hexane) (10.14 g, 0.44 mL). The reaction was refluxed until the sodium metal was no longer present. The mixture was cooled and benzyl chloride (24.17 mL, 0.21 mol) was added, the reaction was stirred at room temperature overnight. The reaction mixture was filtered and the solid washed with toluene. The filtrate was cooled to 0° C. and HCl gas was bubbled in for 10 minutes. A white precipitate was obtained and filtered. The solid was recrystallized using 70 mL of isopropyl alcohol (10.4 g, 0.056 mol); MS-CI 188 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](=[O:18])[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[NH:19][C:20]1[N:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][C:24]3=[C:32]([C:35]([NH:37][C@@H:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:39][NH:40]C(=O)OC(C)(C)C)=[O:36])[O:33][N:34]=[C:23]3[C:22]=2[N:21]=1>CO.Cl.O1CCOCC1>[NH2:40][CH2:39][C@@H:38]([NH:37][C:35]([C:32]1[O:33][N:34]=[C:23]2[C:22]3[N:21]=[C:20]([NH:19][C:4]4[CH:5]=[CH:6][C:7]([C:9](=[O:18])[NH:10][CH:11]5[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]5)=[CH:8][C:3]=4[O:2][CH3:1])[N:29]=[CH:28][C:27]=3[C:26]([CH3:31])([CH3:30])[CH2:25][C:24]=12)=[O:36])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1noc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)c3ccccc3)c1CC2(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1noc(C(=O)N[C@H](CN)c3ccccc3)c1CC2(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.8 %

Procedure:
To a mixture of tert-butyl [(2S)-2-({[8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,3-h]quinazolin-3-yl]carbonyl}amino)-2-phenylethyl]carbamate 110 mg (0.151 mmol) in MeOH (1 mL), 0.378 mL of 4 N HCl in dioxane was added. The reaction was stirred at room temperature for 12 h, the solvent was evaporated to dryness and the solid treated with Et2O (20 mL) and the precipitated collected by filtration to give the title compound as a pale yellow solid (96 mg; 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22]O)[C:8]2=[O:24])=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>CC#N.O>[Br:28][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:8](=[O:24])[N:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10]1
Reactant: BrP(Br)Br
Reactant: COc1nn(-c2ccccc2CO)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Solvent: CC#N
Solvent: O
Product: COc1nn(-c2ccccc2CBr)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 60 °C
Yield: 84.4 %

Procedure:
According to Scheme 9 Step 1: To a stirred solution of 4-(4-chlorobenzyl)-2-(2-(hydroxymethyl)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (70 mg, 0.19 mmol) in CH3CN (10 mL) was added phosphorus tribromide (76 mg, 0.28 mmol) and the mixture was heated at 60° C. during two hours. The reaction mixture was diluted with 100 mL of water and the aqueous layer was extracted with DCM (×2). The combined organic layers were successively washed with water, with brine, dried over MgSO4, filtered and concentrated to afford 70 mg (Yield=86%) of 2-(2-(bromomethyl)phenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione. The product was pure enough to be used in the next step without any purification
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([C:20]4[N:21]=[N:22][NH:23][N:24]=4)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[N:29](COCC[Si](C)(C)C)[CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])=[CH:4][CH2:3]1>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:43])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([C:20]4[N:24]=[N:23][NH:22][N:21]=4)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C3(c4nn[nH]n4)CCOCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(C3(c4nn[nH]n4)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 43 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (g) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[4-(2H-tetrazol-5-yl)-tetrahydro-pyran-4-yl]-phenyl}-amide (as prepared in the previous step, 51.2 mg, 0.0850 mmol). Silica gel chromatography (1-4% MeOH/DCM) afforded the title compound (17 mg, 43%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.26 (d, 1H, J=8.6 Hz), 7.90 (s, 1H), 7.22 (dd, 1H, J=8.6, 2.3 Hz), 7.12 (d, 1H, J=2.3 Hz), 5.73 (m, 1H), 3.95 (m, 2H), 3.54 (m, 2H), 2.70 (m, 2H), 2.42 (m, 2H), 2.26 (m, 2H), 2.08 (m, 2H), 1.58 (t, 2H, J=6.3 Hz), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H28N8O2, 473.2 (M+H). found 473.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.[NH3:18].CO>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:18])[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolved in 7N ammonia-methanol solution, and heated in a sealed flask at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, followed by standing overnight and filtration to give the titled compound. Yield: 40 g (80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](CO)Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2.38 g (6.98 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 3.8 mL (27.2 mmoles) of triethylamine at 10° C. was added a solution of 4.33 g (27.2 mmoles) of sulfur trioxide pyridine complex in 17 mL of dimethyl sulfoxide. The mixture was warmed to room temperature and stirred for one hour. Water (16 mL) was added and the mixture was extracted with 20 mL of ethyl acetate. The organic layer was washed with 20 mL of 5% citric acid, 20 mL of water, 20 mL of brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2.37 g (100% yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[N:9]([CH3:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11]/1)=[O:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[Br-].[CH2:59]([O:61][C:62](=[O:66])[CH2:63][CH2:64][Zn+])[CH3:60].CO>O1CCCC1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:17]([N:8]1[N:9]([CH3:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11]/[C:7]/1=[N:6]\[C:4]([C:3]1[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:2]=1[CH2:64][CH2:63][C:62]([O:61][CH2:59][CH3:60])=[O:66])=[O:5])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CC[Zn+]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2Br)cc(C(C)(C)C)n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2CCC(=O)OCC)cc(C(C)(C)C)n1C
Temperature: 65 °C
Yield: 97.9 %

Procedure:
To a mixture of Example 11A (400 mg, 0.869 mmol), palladium acetate (19.5 mg, 0.087 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (71.3 mg, 0.174 mmol) was added a solution of (3-ethoxy-3-oxopropyl)zinc(II) bromide (4.17 mL, 2.085 mmol) in tetrahydrofuran. This mixture was heated at 65° C. for 12 hours then cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, eluted with a gradient of 15-100% hexanes in solvent B, solvent B: 10:1:0.5 ethyl acetate:methanol:triethylamine) to afford the title compound (410 mg, 0.851 mmol, 98% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.96 (t, J=7.29 Hz, 3H) 1.19-1.23 (m, 3H) 1.37-1.41 (m, 2H) 1.44 (s, 9H) 1.64-1.74 (m, 2H) 2.73-2.78 (m, 2H) 3.40 (t, J=7.46 Hz, 2H) 3.80 (s, 3H) 4.10 (q, J=7.12 Hz, 2 H) 4.25-4.39 (m, 2H) 6.91-7.01 (m, 1H) 7.31-7.33 (m, 1H) 7.48 (dd, J=8.14, 1.36 Hz, 1 H) 8.17 (s, 1H); MS (DCI/NH3) m/z 482 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([B-](F)(F)F)=[CH2:19].[K+].C(N(CC)CC)C>C(O)CC>[C:1]([N:5]1[C:9]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([CH:18]=[CH2:19])[N:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nccc1Nc1cncc(Cl)n1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=Cc1cncc(Nc2ccnn2C(C)(C)C)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 65.04 g of N-(1-tert-butyl-1H-pyrazol-5-yl)-6-chloropyrazin-2-amine, 41.6 g of potassium vinyltrifluoroborate, 4.22 g of (1,1′-bis (diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane complex, 72 ml of triethylamine and 685 ml of 1-propanol was stirred at 110° C. overnight, followed by cooling down to room temperature and concentrated in vacuo. The obtained residue was diluted with ethyl acetate, and an insoluble matter was filtered off using Celite. The resulting ethyl acetate solution was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was suspended in 100 ml of ethyl acetate, and 400 ml of diisopropylether was added to the mixture. The obtained precipitate was collected to give the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH:13]=O)[CH:9]=2)[C:4](=[O:15])[O:3]1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[CH:9]=2)[C:4](=[O:15])[O:3]1
Reactant: CC1Cc2cc(CC=O)ccc2C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Reaction time: 8 h

Procedure:
Freshly prepared (3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)acetaldehyde was dissolved in DCM. To the solution was added Boc-piperazine (671 mg, 3.6 mmol) followed by sodium triacetoxyborohydride (1.91 g, 9.0 mmol), the reaction mixture was allowed to stir overnight before being quenched with 10 mL of MeOH. The excess solvent was removed and the residue was re-redissolved in DCM; washed with water and brine, dried with magnesium sulfate, filtered, concentrated and purified via MPLC (50-100% EtOAc/Hex) to afford tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([Cl:10])=[C:4](Cl)[C:3]=1[Cl:12].[NH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[Cl:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Cl:1])=[C:3]([Cl:12])[C:4]=1[NH:13][NH2:14]
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: NN
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1nc(Cl)c(Cl)c(NN)c1Cl
Temperature: 45 °C

Procedure:
To a reaction flask was added 400 milliliters of 95 percent ethanol and 24.2 grams (0.10 mole) of tetrachloropicolinonitrile. The mixture was heated to 45°C. with stirring and 3.7 grams (0.11 mole) of 95 percent hydrazine and 10.1 grams (0.10 mole) of triethylamine was added thereto. The mixture was heated under reflux for 1 hour and the reaction mixture thereafter cooled to 40°C. To this mixture was added 400 grams of an ice-water mixture and the solid 3,5,6-trichloro-4-hydrazinopicolinonitrile product which precipitated was recovered by filtration, water washed and dried. The product was recovered in a yield of 20.6 grams (87 percent of theoretical) melting at 178°-181°C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[N:13]([O-:15])=[O:14].[Na+].C(OCC)C>F[B-](F)(F)F.[H+].O.[Cu]>[N+:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[C:7](=[O:12])[CH2:6][CH2:5]2)([O-:15])=[O:14]
Reactant: O=N[O-]
Reactant: Nc1cc2c(cc1Br)C(=O)CC2
Agent: [Cu]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])c(Br)cc21
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a suspension of 5-amino-6-bromo-1-indanone (30.0 g, 0.13 mol) in 20% aqueous fluoroboric acid (120 mL) at 0° C. was added dropwise 4M aqueous NaNO2 (50 mL, 0.20 mol) over a period of 30 min. The mixture was stirred for 30 min after completion of addition. The resulting foamy suspension was added portionwise to a vigorously stirred mixture of copper powder (40 g, 0.62 mol) and sodium nitrite (120 g, 1.74 mol) in water (240 mL) at room temperature over a period of 15 min. During the addition, excessive foaming was broken up by the addition of small amounts of diethyl ether. After further stirring for 30 min, the mixture was filtered through celite, washed with ethyl acetate (5'300 mL). The ethyl acetate layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with CH2Cl2, yielded 17.5 g (51%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][F:23].Cl>CS(C)=O.O>[F:23][CH2:22][O:13][N:12]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[C:3]([O:2][CH3:1])=[O:14]
Reactant: FCBr
Reactant: COC(=O)C(=NO)c1ccccc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(=NOCF)c1ccccc1C
Reaction time: 20 h

Procedure:
A mixture of 57 g of 2-tolylglyoxylic acid methyl ester oxime and 80 g of powdered potassium carbonate is mixed into 550 ml of dimethyl sulfoxide for 30 minutes at room temperature and then a solution of 40 g of bromofluoromethane in 30 ml of dimethyl sulfoxide is added dropwise at room temperature. The reaction mixture is stirred for a further 20 hours and then poured into 1200 ml of water, neutralised with 230 ml of hydrochloric acid and extracted four times with 250 ml of ethyl acetate each time. The combined organic phases are washed with 200 ml of saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:9) yields 2-tolylglyoxylic acid methyl ester O-fluoromethyloxime in the form of a viscous oil.
Reaction SMILES: [N:1]([C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5])=[N+]=[N-]>CO.C(Cl)Cl.[Pd]>[NH2:1][C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(N)[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reaction time: 48 h

Procedure:
A mixture of N-(trans-4-(2-azidopropan-2-yl)cyclohexyl)-3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-amine (90 mg, 0.22 mmol) and Pd/C (30 mg) in MeOH (5 mL) and CH2Cl2 (5 mL) was hydrogenated under 50 psi of H2 at room temperature for 48 h. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-79 (4 mg, 5%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:25])=[C:7]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH3:26][N:27](CCN(C)C)C.CCOC(C)=O.CCCCCC>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:26]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:25])=[C:7]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1)#[N:27]
Reactant: CN(C)CCN(C)C
Reactant: Cc1c(C(=O)NCc2cccc(F)c2)c(=O)n(C)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(=O)n(C)c2cc(C#N)ccc12
Temperature: 160 °C
Yield: 118.2 %

Procedure:
To a solution of 247 mg (0.61 mmol) 7-bromo-N-[(3-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H-quinoline-3-carboxylic acid amide (example 16) in DMF (3 mL) were added 20 μL (0.22 mmol) TMEDA, 43 mg (0.37 mmol) Zinccyanide, 1 mg (0.003 mmol) Pd2 dba3 and 7 mg (0.019 mmol) Xantphos. The reaction solution was degasses and flushed with nitrogen three times and then heated in MW to 160° C. for 4 min. After cooling to RT the mixture was filtered through celite and was washed with dichloromethane. The combined filtrates were concentrated in vacuo. After CC (EtOAc/hexane 1:2) of the residue, 91 mg (0.26 mmol, 43%) 7-cyano-N-[(3-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H-quinoline-3-carboxylic acid amide (example 20) were obtained. MS: m/z 350.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1.O>O1CCCC1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][CH2:35][CH2:34][CH:7]([N:8]=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Clc1ccc(OCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
While under a nitrogen atmosphere, a solution of (benzhydrylidene-amino)-acetic acid tert-butyl ester (400 mg, 1.35 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (1.49 mL, 1.0 M in tetrahydrofuran, 1.49 mmol) in a dropwise manner. After the addition was complete, stirring was continued for 30 minutes and 1-(2-bromoethoxy)-4-chlorobenzene (398 mg, 1.69 mmol) was slowly added to the reaction mixture. Stirring was continued for 2 more hours, then slowly warmed to room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-20% ethyl acetate in heptane) gave tert-butyl 4-(4-chlorophenoxy)-2-(diphenylmethyleneamino)butanoate as a colorless oil (450 mg. 74%); MS (+CI): m/z for C27H28ClNO3: expected 449.2. found 450.2 (M+H)+, 394.2 (M+H−isobutene)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3]>CO.[OH-].[K+].O>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Yield: 88.2 %

Procedure:
A solution of methyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (315 mg, 0.95 mmol) in methanol (3 mL) and potassium hydroxide (3 mL of a 1.0 M solution in water, 3 mmol) was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, the residue was dissolved in water, and extracted with ethyl acetate. The aqueous layer was acidified to pH 3 with 1 M hydrochloric acid, extracted with chloroform (3×100 mL), and the combined organic layers were concentrated under reduced pressure to afford 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid (265 mg): 1H NMR (300 MHz, CD3OD) δ 8.71 (s, 1H), 8.08 (s, 2H), 8.05 (s, 1H), 7.34 (s, 1H), 3.52 (t, J=8 Hz, 2H), 3.26 (t, J=8 Hz, 2H), 1.75 (q, J=8 Hz, 2H), 1.59 (q, J=8 Hz, 2H), 1.02 (t, J=8 Hz, 3H), 0.74 (t, J=8 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].Cl>O>[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:21][C:22]2[CH:23]=[C:24]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
Pyridine (5 mL) was added to a mixture of 4-trifluoromethylbenzenesulfonyl chloride (0.73 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) and stirred at room temperature. After 20 hours, the mixture was added to water (50 mL), acidified with 2N HCl, and stirred for an hour. The precipitate was filtered off, rinsed with water, and dried to afford the product (1.2 g); m.p. 197-198° C.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C@H:4]1[C@H:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reaction time: 40 h

Procedure:
To 8.0 g (35 mmol) of tert-butyl trans-3-azido-4-hydroxypyrrolidine-1-carboxylate (the compound from Step A of Intermediate 11) in 117 mL of ethanol was added 500 mg of 10% palladium on carbon. The reaction mixture was purged with hydrogen gas and held under 1 atmosphere of hydrogen for 40 h. The mixture was filtered through a pad of Celite and the filter cake was successively washed with three portions of 100 mL of methanol. The combined filtrate and washings were concentrated and used without further purification. LC/MS 103 (M+1-100).