Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C.O>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccccc2N1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of oxindole (5.0 g, 37.5 mmol) in acetic anhydride (7.1 mL, 75.1 mmol) and acetic acid (25 mL) was refluxed for 20 h. After cooling to room temperature, the reaction mixture was diluted with water (200 mL). The resulting solids were filtered, washed with water and dried to give N-acetyl oxindole as a white solid (5.2 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:29])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 50.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.47 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (1.5 g), 2-amino-6-(trifluoromethoxy)benzothiazole (1.62 g), 1,1′-thiocarbonyl-diimidazole (1.48 g), and EDC (1.99 g). LC/MS: m/z 423.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.20 (s, 1H), 7.92 (s, 1H), 7.85 (bs, 1H), 7.78-7.63 (m, 1H), 7.51 (d, 1H), 7.35 (d, 2H), 3.86 (s, 3H), 3.63 (bs, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[CH3:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NN(Cc2ccccc2)C(=O)OC(C)(C)C)c1C
Temperature: 50 °C
Yield: 39.6 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 790 mg, 3.55 mmol), 2,3-dimethylphenylboronic acid (Aldrich; 522 mg, 3.48 mmol), copper(II) acetate (646 mg, 3.55 mmol) and triethylamine (500 μL, 3.55 mmol) in 1,2-dichloroethane (5.5 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (450 mg, 39%) as a yellow oil.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][C:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH2:20][N+:21]([O-:23])=[O:22])[C:12]=2[S:13][CH:14]=1>O.COCCOC>[CH3:9][C:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:20][N+:21]([O-:23])=[O:22])=[O:2])[C:12]=2[S:13][CH:14]=1
Reactant: Cc1csc2c(SC[N+](=O)[O-])cccc12
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1csc2c(S(=O)C[N+](=O)[O-])cccc12
Temperature: 5 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of potassium peroxymonosulphate (`oxane` trade mark; 1.0 g, 1.63 mmol) in water (20 ml) was added in one portion to a stirred solution of 3-methyl-7-(nitromethylthio)benzo[b]thiophene (0.7 g, 2.93 mmol) in 1,2-dimethoxyethane (40 ml) cooled to 5° C. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). These extracts were washed with water, dried (MgSO4), and evaporated to leave an oil, which was purified by flash chromatography using 4:1 v/v dichloromethane/hexane as eluant, to give 3-methyl-7-(nitromethylsulphinyl)benzo[b]thiophene as a pale yellow solid (0.35 g); NMR:2.5(s, 3H), 5.55(s, 2H), 7.25(s, 1H), 7.6-8.0(m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[C:31]([Cu])#[N:32].O.Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:31]#[N:32])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (200 mg, 0.43 mmol) and CuCN (77 mg, 0.86 mmol) in 5 mL of DMF was refluxed for 40 min, then cooled to r.t., and poured into a mixture of water and CH2Cl2. 4M HCl was added with vigorous stirring until no more solid was present. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 140 mg of the title compound. MS: (+) m/z 412.12 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.CS(Cl)(=O)=O.[C:42](O)([C:44](F)(F)F)=[O:43]>CN(C=O)C>[C:42]([N:24]1[CH2:23][CH2:22][C:21]2([C:16]3[C:17](=[CH:18][C:13]([C:11]4[N:10]=[C:9]([O:28][C@@H:29]([C@@H:31]5[CH2:35][C:34](=[O:36])[NH:33][CH2:32]5)[CH3:30])[C:8]5[N:4]([CH:1]6[CH2:2][CH2:3]6)[CH:5]=[N:6][C:7]=5[CH:12]=4)=[CH:14][CH:15]=3)[NH:19][C:20]2=[O:27])[CH2:26][CH2:25]1)(=[O:43])[CH3:44]
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCNCC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: O=C(O)C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC2(CC1)C(=O)Nc1cc(-c3cc4ncn(C5CC5)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To solution of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one: (0.094 g, 0.193 mmol) in DMF was added TEA (0.119 g, 1 mmol), then followed by the addition of methanesulfonyl chloride (0.022 g, 0.193 mmol). Reaction was stirred at 0° C. for 10 minutes; LC-MS showed reaction was complete. TFA was added, and the crude material was purified by HPLC.
Reaction SMILES: C[C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[C:6]2[C:7]([CH3:14])=[C:8]([OH:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30](C)[CH:29]=1>>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:2]2[C:6]3[C:7]([CH3:14])=[C:8]([O:13][CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=4)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:16])[CH3:15])=[CH:18][CH:19]=1)([CH3:25])[CH3:24]
Reactant: COC(=O)c1ccc(CBr)cc1C
Reactant: Cc1c(C)c2c(c(C)c1O)C(C)(c1ccc(C(C)C)cc1)C(C)(C)O2
Product: COC(=O)c1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 82 %

Procedure:
Using methyl 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and methyl 4-(bromomethyl)methylbenzoate, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH2:8](OCC)C.[CH3:13][C@H:14]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(OCC)(=O)C>C1COCC1>[OH:19][C@@:18]1([CH3:8])[CH2:17][CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:14]1[CH3:13]
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A suspension of cerium chloride (47 g) in THF (300 mL) was cooled to −78° C., methylmagnesium bromide-diethyl ether solution (56 mL, 3 mol/L) was added dropwise while adjusting the solution temperature to −70° C. or below. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min, a solution of benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (18 g) in THF (60 mL) was added dropwise while adjusting the solution temperature to −70° C. or below. The reaction mixture was warmed to 0° C. over 2 hr, ethyl acetate (1 L) was added, and insoluble materials were filtered off. The filtrate was partitioned with water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1→1/1) to give the title compound as a colorless oil (yield: 16.2 g, 84%).
Reaction SMILES: ClC1C(Cl)=CC2OC3C=C(Cl)C(Cl)=CC=3OC=2C=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[OH:28].Cl[CH2:30][C:31]([OH:33])=[O:32]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1[O:28][CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C(O)CCl
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: Clc1cc2c(cc1Cl)Oc1cc(Cl)c(Cl)cc1O2
Product: O=C(O)COc1cc(Cl)c(Cl)cc1Cl

Procedure:
The above objects have been achieved by the synthesis of 2,4,5-trichlorophenoxyacetic acid and its intermediate, 2,4,5-trichlorophenol, which are free from contamination with 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD). The synthesis involves the nitration of 1,2,4-trichlorobenzene to form 1,2,4-trichloro-5-nitrobenzene, which is reduced (usually with hydrogen) to produce 2,4,5-trichloroaniline. The 2,4,5-trichloroaniline is reacted with sulfuric acid and a nitrite to form 2,4,5-trichlorobenzenediazonium sulfate, which is reacted with water and distilled to produce 2,4,5-trichlorophenol which is analytically free of TCDD. The 2,4,5-trichlorophenol is reacted with monochloroacetic acid in the presence of aqueous base, followed by acidification, to produce 2,4,5-trichlorophenoxyacetic acid which also is analytically free of TCDD.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].Cl.C(N(CC)CC)C.[N-:25]=[N+:26]=[N-:27].[Na+]>C1(C)C=CC=CC=1>[NH:25]1[C:1]([CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[N:2][N:27]=[N:26]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnn[nH]2)CC1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
To a stirred suspension of 1.50 g (6.66 mmol) of the title compound from Step A above in 25 mL of anhydrous toluene was added 1.38 g (10.0 mol) of triethylamine hydrochloride followed by 0.65 g (10 mmol) of sodium azide. The resulting mixture was heated to 80° C. for 12 h then cooled to ambient temperature. All volatiles were removed in vacuo, and the residue suspended in 5 mL of brine and 1.0 N aqueous hydrogen chloride solution was added until pH of ˜4 was achieved. The aqueous phase was extracted with chloroform and the combined organics were dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% acetone in hexanes gradient to afford the title compound (i-18) as white solid (1.1 g, 63%). 1H-NMR (500 MHz, DMSO-d) δ 3.82 (s, 2H), 3.29 (br s, 4H), 2.38-2.34 (m, 4H), 1.36 (s, 9H). LC-MS: m/z (ES) 269.0 (MH)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[CH3:25][NH:26][C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30]>C1COCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:28]([C:27]([NH:26][CH3:25])=[O:32])=[C:29]([CH3:30])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[C:10](=[S:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: CNC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CNC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde (238.2 mg, 1.82 mmol) and N-methyl-3-oxobutanamide (299 mg, 1.82 mmol) are dissolved in 5 ml THF. Ethyl polyphosphate (0.30 g) is added and the reaction mixture is stirred at reflux temperature overnight. After cooling to room temperature, the reaction is quenched with 10 ml of water and extracted with 10 ml ethyl acetate (2×). The combined organic layers are dried with sodium sulfate and the solvent is removed in vacuo. The product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:44][C:45](=[N:48]C(OCC1C=CC=CC=1)=O)SC)(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C>>[ClH:1].[C:28]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15][NH:16][C:45](=[NH:44])[NH2:48])=[O:10])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 116.1 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(S)-N-(1-phenylethyl)ornithine amide hydrochloride (0.50 g; 1.0 mmol; from step (c) above), N,N'-bis(Cbz)-S-methyliso-thiourea (0.40 g; 1.1 mmol) of and DiPEA (0.3 mL; 1.6 mmol), yielding 0.59 g (74%) of sub-title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][C:37]=1[CH3:38])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=1)=[O:17]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:36]2[CH:35]=[C:15]([CH:14]=[CH:13][C:37]=2[CH3:38])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([C:31]([F:32])([F:33])[F:34])[CH:20]=2)=[O:17])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)cc2C(F)(F)F)cn1
Reactant: C#Cc1cnc2cccnn12
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(C#Cc4cnc5cccnn45)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 3-iodo-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The title compound was obtained as a light yellow solid. Mp: 124-126° C.; 1H NMR (300 MHz, CDCl3) δ: 9.00 (1 H, s), 8.48 (1 H, d, J=4.8 Hz), 8.17 (1 H, s), 8.09 (3 H, m), 7.93-7.95 (1 H, d, J=8.7 Hz), 7.86-7.89 (1 H, d, J=8.1 Hz), 7.55 (1 H, s), 7.39-7.42 (1 H, d, J=8.1 Hz), 7.34-7.36 (1 H, d, J=8.4 Hz), 7.11-7.16 (1 H, dd, J=4.2 and 8.4 Hz), 6.82 (1 H, s), 2.64 (3 H, s), 2.29 (3 H, s). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C27H20F3N6O: 501.1645. found: 501.1626.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]#[N:20])=[C:12]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1.[CH:30]([N:33](CC)[CH:34](C)[CH3:35])(C)[CH3:31].C(NCC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([NH:8][C:5](=[O:6])[CH:4]=[CH:3][CH2:2][N:33]([CH2:34][CH3:35])[CH2:30][CH3:31])[CH:10]=3)[N:15]=[CH:14][C:13]=2[C:19]#[N:20])[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: O=C(Cl)C=CCBr
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)CC=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Added 500 μl (4.80 mmol) 4-bromo-but-2-enoyl chloride to a solution of 1.50 g (4.80 mmol)) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile and 836 μl (4.80 mmol) N,N-diisopropylethylamine in 50 ml THF at 0° C. under N2. At 1 hour added the mixture dropwise to 1.26 ml (24 mmol) diethylamine in 11 ml THF chilled to −78° C. Removed dry ice bath after complete addition, and at 2 hours, 45 minutes poured onto a mixture of ice and saturated sodium bicarbonate. Extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent. Loaded compound onto a column of silica gel, eluted with 35% methanol/ethyl acetate, stripped solvent from desired fractions, and dried in vacuo, giving 292 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=452.4, 454.4.
Reaction SMILES: [C:1]([NH:18][CH2:19][C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[CH3:53][O:54][C:55]1[CH:81]=[CH:80][C:58]([C:59]([O:74][CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:60]2[CH:65]=[CH:64][C:63](OC)=[CH:62][CH:61]=2)=[CH:57][CH:56]=1.CN(C)[CH:84]=[O:85]>>[CH3:84][O:85][CH:75]([O:74][C:59]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([C:58]1[CH:80]=[CH:81][C:55]([O:54][CH3:53])=[CH:56][CH:57]=1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[CH2:76][CH2:77][CH2:78][NH:79][C:24](=[O:25])[CH2:23][NH:22][C:20](=[O:21])[CH2:19][NH:18][C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: O=C(O)CNC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN(C)C=O
Reactant: COc1ccc(C(OCCCCN)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Product: COc1ccc(C(OC(CCCNC(=O)CNC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)OC)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution (70 ml) of Fmoc-glycylglycine (Fmoc-GlyGly-OH, purchased from China Langchem) (2.50 g, 7.05 mmol), dicyclohexylcarbodiimide (1.75 g, 8.46 mmol) and 1-hydroxybenzotriazole monohydrate (2.59 g, 16.92 mmol) in anhydrous N,N-dimethylformamide was added a solution (50 ml) of compound 12 (3.31 g, 8.46 mmol) in anhydrous N,N-dimethylformamide under ice-cooling under an argon atmosphere. After removing the ice bath, the mixture was stirred at room temperature overnight under an argon atmosphere. The resulting precipitate was filtered off, and the filtrate was concentrated at 35° C. under reduced pressure. To the obtained residue was added dichloromethane (200 ml), and the mixture was washed twice with saturated brine. The organic layer was fractionated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol (95:5)+0.05% pyridine, and then dichloromethane-methanol (9:1)+0.05% pyridine) to give Fmoc-glycylglycine-4,4′-dimethoxytrityloxybutylamide (13) (3.49 g, 68%) as a colorless syrup.
Reaction SMILES: Br[C:2]1[N:3]([CH3:24])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([S:22][CH3:23])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC.O.C1(P([Pd-4](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)C=CC=CC=1>[CH3:24][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([S:22][CH3:23])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(-c4ccccc4)n3C)nc12
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)-[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 37) (50 mg), tetrakis(triphenylphosphino)palladium(0) (28 mg), sodium carbonate (33 mg) and phenylboronic acid (14 mg) in DME (2 mL) and water (1 mL) was heated at 90° C. for 2 hours. After cooling to ambient temperature and extraction into DCM (3×5 mL), the combined organics were dried, filtered and the solvent evaporated in vacuo to give a brown oil. Purification by flash chromatography on silica eluting with EtOAC:hexane (1:9) gave the title compound as a yellow solid (25 mg, 50%);
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.CC(O)=O.O>CCO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:27])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCc4ccc(F)cc4)ncc3c2=O)c(OC)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (15 mg, 0.041 mmol) and 4-fluorobenzylamine (0.020 mL, 0.14 mmol) in EtOH (2 mL) was refluxed for 16 h. After cooling the mixture to r.t., AcOH (0.1 mL) and water (2 mL) were added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and purified by silica gel chromatography (0-2% MeOH/CH2Cl2) to give 15 mg of the title compound. MS: (+) m/z 464.35 (M+1).