Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH:4]([NH:7]C(C1C=CC=CC=1)C1C=CC=CC=1)C#N.[C:25](=[O:28])([O-])[O-:26].[K+].[K+].[OH-].[K+]>Cl>[CH:22]1[CH:21]=[C:3]([C@H:4]([NH2:7])[C:25]([OH:26])=[O:28])[C:2]([Cl:1])=[CH:24][CH:23]=1
Reactant: N#CC(NC(c1ccccc1)c1ccccc1)c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: N[C@H](C(=O)O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
The above product was dissolved in aqueous hydrochloric acid (6N, 10 ml) and heated at 70° C. for six hours (until exhaustion of the nitrile). The reaction mixture was cooled to room temperature, made basic (pH >10) by addition of solid potassium carbonate, then with aqueous potassium hydroxide (2M, ca. 5 ml). Washing with ether (3×30 mL), followed by titration to pH 6.5 and concentration of the aqueous phase afforded, upon cooling, a white solid, which was recrystallized to afford a near quantitative yield of L-2-chlorophenylglycine. Analysis by HPLC indicated optical purity of >99%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)=[O:11])[N:9]=1)[C:2]#[CH:3].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[C:2]#[CH:3]
Reactant: C#CCOc1nc(C(=O)OCC)cs1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCOc1nc(CO)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
In a nitrogen atmosphere, 0.30 g of ethyl 2-(2-propynyloxy)-1,3-thiazole-4-carboxylate was dissolved in 10 ml of tetrahydrofuran, and 3.3 ml of a solution (1 mol/L) of diisobutylaluminum hydride in toluene was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was added to aqueous saturated sodium chloride and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 0.22 g of [2-(2-propynyloxy)-thiazol-4-yl]methanol.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2 g, 8.99 mmol), methyl 4-(piperidin-4-yl)benzoate (CAS 281235-04-9, 2.168 g, 9.89 mmol) and DIPEA (3.91 mL, 22.47 mmol) were dissolved in DMA (10 mL) and sealed into a microwave tube. The mixture was heated to 110° C. for 5 minutes in the microwave reactor and cooled to room temperature. The reaction mixture was added dropwise to stirred water (30 mL), stirred for 10 minutes then the precipitate was collected by filtration, washed with ether (2×2 mL) and dried to give methyl 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoate (3.32 g, 91%) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([NH2:34])=[O:33])[N:27]=1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][C:32]([C:28]3[N:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC(=O)c1cccnn1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)c3cccnn3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and pyridazine-3-carboxamide. MS obsd. (ESI+) [(M+H)+] 460, 1H NMR (400 MHz, CD3OD) δ ppm 9.52-9.48 (d, J=8 Hz, 1 H), 8.68 (s, 1 H), 8.62-8.58 (d, J=7.6 Hz, 1 H), 8.10-8.02 (m, 3 H), 7.94 (s, 1 H), 7.88-7.82 (d, J=8 Hz, 1 H), 7.75-7.68 (t, J=7.6 Hz, 2 H), 7.60-7.52 (t, J=7.2 Hz, 1 H), 5.36 (s, 2 H), 4.80-4.55 (m, 2 H), 3.83-3.78 (t, J=2.8 Hz, 2 H), 2.56 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[CH:16]=O.[CH2:18]([O:20][C:21]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22])[CH3:19]>>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1/[CH:16]=[CH:23]/[C:21]([O:20][CH2:18][CH3:19])=[O:22]
Reactant: O=CC1=C(Cl)C[C@@H]2[C@H](CCc3ccccc3)[C@H]12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/C1=C(Cl)C[C@@H]2[C@H](CCc3ccccc3)[C@H]12

Procedure:
±(1S,5R,6S)-3-chloro-6-phenethylbicyclo[3.1.0]hex-2-ene-2-carbaldehyde (11 mmol crude weight) was olefinated with ethoxycarbonylmethylene triphenylphosphorane (4.6 g, 13.2 mmol) according to General Procedure 1.1.B to afford the title compound. The material was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 10% EtOAc. 2.2 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08-1.19 (m, 1H), 1.23-1.31 (m, 1H), 1.30-1.37 (m, 3H), 1.39-1.51 (m, 1H), 1.59-1.68 (m, 1H), 2.14 (td, J=7.25, 3.03 Hz, 1H), 2.38 (dd, J=19.57, 2.68 Hz, 1H), 2.53-2.66 (m, 2H), 2.92 (dd, J=19.55, 7.88 Hz, 1H), 4.20-4.31 (m, 2H), 6.04 (d, J=15.72 Hz, 1H), 7.10-7.22 (m, 3H), 7.23-7.31 (m, 2H), 7.61 (d, J=15.72 Hz, 1H).
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:10](OCC)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CO>[CH3:13][CH:12]1[CH:3]([C:2]([O:8][CH3:9])=[O:7])[C:4](=[O:5])[CH2:6][C:10](=[O:14])[CH2:11]1
Reactant: C/C=C/C(=O)OCC
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CO
Product: COC(=O)C1C(=O)CC(=O)CC1C
Reaction time: 0.25 h

Procedure:
To a freshly prepared solution of sodium (17.78 g, 0.77 gram-atom) in methanol (220 mL) is added methyl acetoacetate 89.66 g (0.77 mole) and the mixture is stirred on an ice bath 15 min after the addition. Ethyl crotonate (100 mL of a 96% product≈88.13 g (100%; 0.77 mole) is added dropwise and the mixture is stirred at room temperature for an additional 30 min. After refluxing (2 h), methyl 6-methyl-2,4-dioxo-cyclohexane carboxylate enolate, which separates, is filtered, and the solid residue is dissolved in a minimum amount of cold water. The aqueous solution acidifed with sulfuric acid (500 mL of a 2 M solution), the precipitate extracted with dichloromethane (4×300 mL) and the organic phase dried over sodium sulfate. The residue is evaporated and the residue recrystallized from toluene to give the title compound: yield, 37 g, 40%, mp 122-123° C. The mother liquor from the reaction is evaporated to dryness, dissolved in cold water and extracted with dichloromethane (after acidification with the same 2 M sulfuric acid used previously). After evaporation and recrystallization from toulene, the mp is identical to the original crop. Total yield: 47 g; 51%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][O:8][C:9]2=O)([O-:3])=[O:2].[CH3:15][NH2:16].CO>>[CH3:15][N:16]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:8]
Reactant: CN
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: Cn1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (1.2 g, 0.0063 mol) and 40% aqueous methylamine (10 mL, 0.09 mol) were refluxed in methanol (40 mL, 1 mol) for 1 hour. The solvents were removed and the residue was diluted with CH2Cl2/MeOH (95:5 v/v, 100 mL), washed with brine (20 mL×2). The CH2Cl2 layer was dried over Na2SO4, purified via flash chromatography (40 g of silica gel, 0-50% EtOAc/Hexanes) to give a yellow solid. MS m/z (M+H) 204.8.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([OH:27])=[O:26])=[C:22]([CH3:28])[C:21]=3[CH:29]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]([OH:27])=[O:26])=[C:22]([CH3:28])[C:21]=2[CH:29]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:31])[C:2]([CH3:32])([CH3:33])[CH3:1])=[C:7]([CH3:30])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)c(C)c2c1
Yield: 70.1 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-benzofuran-2-carboxylic acid (170 mg g, 0.378 mmol) is reduced with NaBH4 (29 mg, 0.756 mmol) analogous to Example 3 to give the title product (120 mg, 71%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([Cl:17])=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.0 g (59.7 mmol) trans-4-tert-Butylcyclohexanecarboxylic acid are dissolved in 400 ml dichloromethane plus a few drops of DMF, 9.09 g (71.6 mmol) ethanedioyl dichloride are added and the solution is stirred at room temperature for one hour. The mixture is then stirred at reflux for two hours and, after cooling down to room temperature, evaporated to dryness in vacuo. The residue is then dissolved in toluene two times and again evaporated to dryness in vacuo. The residue is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=O)/[C:7](=[CH:12]/N(C)C)/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:25]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:24][CH:23]=[C:22]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CCO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:29]=[C:27]([NH:26][C:25]4[C:20]([CH3:19])=[N:21][C:22]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:23][CH:24]=4)[N:28]=[CH:12][C:7]=3[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1nc(NC2CCN(C)CC2)ccc1NC(=N)N
Reactant: CN(C)/C=C1\CC(=O)Nc2cc(Cl)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Temperature: 70 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To (4E)-8-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-1-benzazepine-2,5-dione (3.25 g. 12.3 mmol) in EtOH (50 mL) were added N-{2-methyl-6-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}guanidine *xHCl (6.5 g, 14 mmol) and potassium carbonate (13.6 g, 98.3 mmol). The reaction mixture was allowed to stir for 2 days at 70° C. and then allowed to cool to room temperature. The solids were filtered and the filtrate was concentrated to give a thick red oil. Water was added to the residue and the aqueous solution was extracted with EtOAc. The organic solutions were combined, dried, filtered and concentrated to give 9-chloro-2-({2-methyl-6-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (5,3 g, 93%).
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:8][C:9]1([CH3:11])[O:6][C@@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1
Reactant: OCC[C@H](O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To (S)-(−)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) were added and the mixture was stirred at room temperature overnight. To the reaction mixture, triethylamine (4 ml) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel 350 g, elution solvent: ethyl acetate/heptane=18/82→6/4) to obtain the title compound (30.2 g, yield: 73%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]3[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]3[CH:20]=2)[N:5]([CH3:7])[CH:6]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC.CN(C=O)C.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:19][C:14]1[N:13]2[CH:20]=[C:10](/[CH:9]=[CH:8]/[C:4]3[N:5]([CH3:7])[CH:6]=[C:2]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[N:3]=3)[N:11]=[C:12]2[N:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cc1cc(C)n2cc(C=Cc3nc(Br)cn3C)nc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C)n2cc(/C=C/c3nc(-c4cccs4)cn3C)nc2n1
Temperature: 160 °C
Yield: 39.8 %

Procedure:
A glass vial was charged with 2-[2-(4-Bromo-1-methyl-1H-imidazol-2-yl)-vinyl]-5,7-dimethyl-imidazo[1,2-a]pyrimidine (150 mg, 0.45 mmol), tributyl-(2-thienyl)-stannane (226 μL, 0.67 mmol), DMF (4 mL) and the slurry was deoxygenated by bubbling argon through then tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.05 mmol) was added and the vessel sealed and heated in a microwave reactor at 160° C. for 30 minutes. THF (15 mL) was added followed by saturated sodium bicarbonate solution (25 mL). The organic layer was separated and the aqueous extracted with THF (15 mL). The combined extracts were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (EtOAc:Et3N, 95:5) to yield the title compound (60 mg, 40%) as a light brown solid. 1H NMR (500 MHz, CDCl3): δ 8.10 (s, 1H), 7.58 (s, 1H), 7.49-7.41 (m, 1H), 7.39-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.18-7.12 (m, 1H), 6.83 (s, 1H), 3.79 (s, 3H), 2.60 (s, 3H), 2.49 (s, 3H). LCMS (MH+): m/z=336.4, tR (minutes, method A)=0.51
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(OCC)C>CO.CCCCCC.[Cu](Br)Br>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8]
Reactant: CC1(C)C(=O)CCC1=O
Agent: Br[Cu]Br
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: CC1(C)C(=O)C=CC1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
Copper (II) bromide (63.4 g, 0.28 mol) was added to a stirred solution of the dione 2 (17.9 g, 0.14 mol) in methanol (280 ml) at room temperature, under an atmosphere of nitrogen. The reaction was heated under reflux for 90 minutes and then cooled to room temperature. The mixture was then filtered through celite, washing with dichloromethane (3×250 ml) and evaporated in vacuo. Flash chromatography (SiO2, 50% diethyl ether in hexane) gave the enedione 3 (11.3 g, 91.0 mmol, 64%) as a yellow oil; δH (300 MHz, CDCl3) 7.22 (2H, s, CH═CH), 1.17 (3H, s, CH3), 1.15 (3H, s, CH3); δC (75.5 MHz, CDCl3) 207.7 (s), 147.1 (d), 46.4 (s), 19.5 (q).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([NH:10][CH:11]([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][S:21][C:17]=2[CH:16]=1.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([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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].O>[S:21]1[C:17]2[CH:16]=[C:15]([NH:14][C:2]3[CH:9]=[C:8]([NH:10][CH:11]([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=3)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20]1
Reactant: CC(C)Nc1cc(Cl)ncc1C#N
Reactant: Nc1ccc2ncsc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C#N
Temperature: 115 °C

Procedure:
To a solution of 6-chloro-4-(isopropylamino)nicotinonitrile (18) (1 g, 5.1 mmol) in dioxane (40 mL): H2O (4 mL), 6-amino benzothiazole (5.1 mmol, 1 equiv.), xanthphos (2.0 mmol, 0.4 equiv.) and Na2CO3 (20.5 mmol, 4 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (2.0 mmol, 0.4 equiv.) was added and degassed again for 10 min. It was then heated at 115° C. for overnight. The reaction mixture was cooled and filtered through small pad of celite. The filtrate obtained was concentrated and the crude material was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinonitrile.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.N1(C(OC(C)(C)C)=O)CCC[C@H]1C(N[C@H](C(OCC1C=CC=CC=1)=O)CC1C=CC=CC=1)=O.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CN(C=O)C>[NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: COc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN1

Procedure:
Boc-L-Pro-OH and L-Phe-OBn.Hcl were treated with BOP and NMM in DMF to give, after aqueous workup and flash chromatography, Boc-L-Pro-L-Phe-OBn. This product was then treated with TFA and anisole, and the mixture was evaporated. The residue was dissolved in Et2O and washed with saturated aqueuos NaHCO3 and saturated aqueous NaCl. The Et2O layer was dried over anhydrous MgSO4, filtered, and the solvent evaporated to give L-Pro-L-Phe-OBn. The residue was treated with CH3SO2Cl and Et3N in CH2Cl2 to give, after aqueous workup and flash chromatography, N-(CH3SO2)-L-Pro-L-Phe-OBn. This product was then treated with 10% Pd on C in THF, and the mixture was shaken under 50 psi H2. The mixture was filtered through Celite, and evaporated to give the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[C:11]([C:15](Cl)=[N:16][OH:17])=[N:12][O:13][N:14]=1.C(N(CC)CC)C>C(O)C>[NH2:9][C:10]1[C:11]([C:15](=[N:16][OH:17])[NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)=[N:12][O:13][N:14]=1
Reactant: Nc1cccc(F)c1
Reactant: Nc1nonc1C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nonc1C(=NO)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A solution of 3-fluoroaniline (36 μL, 0.37 mmol) in ethanol (0.5 mL) was treated with a solution of 4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (50 mg, 0.31 mmol) in ethanol (1.5 mL) followed by triethylamine (51 μL, 0.37 mmol) dropwise. The reaction mixture was stirred at 25° C. for 1 h and purified by preparative LCMS to give the desired product (21 mg, 29%). LCMS for C9H9FN5O2 (M+H)+: m/z=238.0.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:30]1[C:31]([CH3:39])=[CH:32][C:33]2[N:34]([N:36]=[CH:37][N:38]=2)[N:35]=1>O1CCCC1>[C:23]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:30]3[C:31]([CH3:39])=[CH:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[N:35]=3)[CH2:13][CH2:12]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: OCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 64.4 %

Procedure:
190 mg of 60% sodium hydride in oil was suspended in 15 ml of tetrahydrofuran; 1.47 g of 2-[2-[4-(diphenylmethoxy)piperidino]ethoxy]ethanol was added, followed by heating and refluxing for 1 hour. After cooling, 660 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol a (10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 1.23 g of the title compound.