Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]12[O:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][NH:11][CH2:10]2.[Cl:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[N:21]=[C:20]([CH3:28])[N:19]=1.Cl>O1CCOCC1.C(OCC)C>[ClH:17].[CH:25]1([NH:24][C:22]2[N:21]=[C:20]([CH3:28])[N:19]=[C:18]([N:11]3[CH2:10][CH:9]4[O:16][CH:13]([CH2:14][CH2:15]4)[CH2:12]3)[N:23]=2)[CH2:27][CH2:26]1
Reactant: C1CC2CNCC1O2
Reactant: Cc1nc(Cl)nc(NC2CC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(NC2CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Yield: 63 %

Procedure:
2 equivalents of triethylamine dissolved in dioxane are added to one equivalent of 8-oxa-3-azabicyclo[3,2,1]octane hydrochloride suspended in the same solvent. 1 equivalent of 2-chloro-4-cyclopropylamino-6-methyl-1,3,5-triazine dissolved in dioxane is then added. The mixture is heated under reflux for some hours. It is cooled to room temperature and the precipitate which has formed is filtered off. The filtrate is evaporated under reduced pressure and the residue is redissolved in dichloromethane. The solution is washed with water. The organic phase is separated off and dried over sodium sulfate, and the solvent is then evaporated under reduced pressure. The residue thus obtained is purified by chromatography on silica (eluent: 98:2 (v/v) dichloromethane-ethanol). 2-cyclopropylamino-4-methyl-6-(8-oxa-3-azabicyclo[3,2,1]oct-3-yl)-1,3,5-triazine hydrochloride is prepared by addition of one equivalent of hydrochloric acid to the free base in diethyl ether. Yield: 63%. M.P.: 220°-223° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.443 mmol) was reacted with N-(2-azidoethyl)-4-butylbenzamide (0.109 g, 0.443 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H0, δ 7.67 (d, 2H), δ 7.29 (s, 1H), δ 7.11 (d, 2H), δ 6.42 (s, 1H), δ 6.25 (s, 2H), δ 4.48 (s, 2H), δ 3.83 (s, 2H), δ 2.56 (t, 4H), δ 2.21 (s, 2H), 1.47 (m, 13H), δ 1.21 (m, 4H), δ 0.83 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ168.3, 140.6, 149.5, 148.2, 147.1, 138.4, 131.5, 128.7, 127.4, 122.2, 106.4, 84.9, 49.4, 40.2, 35.7, 33.5, 29.2, 28.9, 28.3, 28.1, 27.9, 25.5, 22.4, 14.1 ppm; HRMS (ESI) calcd for C28H41N7O3(M+) 523.3271. Found 523.3261, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-butylbenzamide hydrochloride (0.191 g, 94% yield). 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), δ 7.69 (s, 2H), δ 7.22 (s, 2H), δ 6.44 (s, 1H), δ 4.73 (s, 2H), δ 3.89 (s, 2H), δ 3.34 (s, 2H), δ 2.59 (s, 4H), δ 2.41 (s, 2H), δ 1.54 (s, 4H), δ 1.29 (s, 4H), δ 0.88 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 169.2, 165.1, 160.3, 158.1, 147.4, 141.4, 131.2, 128.5, 127.7, 127.3, 126.9, 92.9, 39.6, 36.3, 33.4, 30.9, 28.0, 27.7, 24.1, 22.2, 13.2, 12.1, 10.9, 8.9, 6.2, 2.5 ppm; HRMS (ESI) calcd for C23H33N7O (M+) 423.2747. Found 423.2738.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][OH:17])=[S:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:13][C:12]([NH:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NC(CO)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc2sc(NC(CO)c3ccccc3)nc2c1

Procedure:
A mixture of 116 parts of N-(2-chloro-5-nitrophenyl)-N'-(2-hydroxy-1-phenylethyl)thiourea, 50 parts of potassium carbonate and 675 parts of N,N-dimethylacetamide is stirred and refluxed for 1 hour. The reaction mixture is poured onto 2000 parts of water. After cooling, the whole is filtered over Hyflo and the product is allowed to crystallize from the filtrate. It is filtered off and dried, yielding 23 parts of β-(5-nitro-2-benzothiazolylamino)benzeneethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]1[C:20]([Cl:33])=[CH:21][C:22]2[CH:23]3[CH2:32][CH2:31][CH2:30][CH:24]3[C:25](=O)[NH:26][C:27]=2[CH:28]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]1[C:20]([Cl:33])=[CH:21][C:22]2[CH:23]3[CH2:32][CH2:31][CH2:30][CH:24]3[C:25](=[S:43])[NH:26][C:27]=2[CH:28]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCc1cc2c(cc1Cl)C1CCCC1C(=O)N2)Cc1cccc(Cl)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)(C)OC(=O)N(CCc1cc2c(cc1Cl)C1CCCC1C(=S)N2)Cc1cccc(Cl)c1

Procedure:
A solution of 90 mg (0.18 mmol) of 7-(N-tert-butoxycarbonyl-3-chlorobenzyl-amino)ethyl-8-chloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 194 mg (0.48 mmol) of Lawesson's reagent are stirred for 1 hour at room temperature and refluxed for 1 hour. After concentration by evaporation in a vacuum, the residue is purified by column chromatography with hexane-ethyl acetate: 80 mg of product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:22](CC)CC)C.ClC(OC(CC)C)=O.N>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([NH2:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCC(C)OC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
trans-1-Benzyloxycarbonyl-4-hydroxy-L-proline (3.55 g) was dissolved in dry tetrahydrofuran (60 ml), and triethylamine (2.80 ml) was added thereto, followed by addition of sec-butyl chloroformate (2.75 g) at 0° to 5° C. under nitrogen stream. The resultant mixture was stirred at the same temperature for 30 minutes and cooled to -50° C. 28 Aqueous ammonia (3.62 ml) was added thereto, and the resulting mixture was stirred at the same temperature for 30 minutes, followed by removal of the solvent. The residue was diluted with ethyl acetate and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2S,4R)-1-benzyloxycarbonyl-2-aminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:36]=[CH:35][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21](O)=[O:22])[CH2:14][N:13]2[C:12](=[O:25])[N:11]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:10]3=[O:34])=[CH:6][CH:5]=1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)CCl>[F:37][C:2]([F:38])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([N:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)=[O:22])[CH2:14][N:13]2[C:12](=[O:25])[N:11]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:10]3=[O:34])=[CH:35][CH:36]=1
Reactant: O=C(O)CCC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)CCC(=O)N[C@@H]2CN3C(=O)N(c4cc(Cl)nc(Cl)c4)C(=O)[C@@]3(Cc3ccc(OC(F)(F)F)cc3)C2)CC1
Reaction time: 8 h

Procedure:
To a solution of the compound from Example 66 (0.12 g) in THF (5 mL) was added N-methyl piperazine (50 μL), EDC (0.90 g), HOBt (0.090 g), and DIEA (0.10 mL). After stirring overnight the reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with water and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel: 95:5 CH2Cl2: MeOH, Chromatotron) to afford the titled compound (0.10 g). MS (m/z) 657 [MH+]. mp 70° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O[Li].O.Cl>O1CCCC1.O>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)nc3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of methyl 2-(6-fluoropyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (130 mg, 0.37 mmol) in tetrahydrofuran (10 mL) was added LiOH.H2O (35 mg, 0.83 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with hydrochloric acid (1N). The solid was precipitated and filtered to afford 2-(6-fluoropyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (81.6 mg, 65%).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[C@@H:11]1([NH:21][CH2:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: N#Cc1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4-Formylbenzonitrile and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[N:14][C:13]=23)O1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.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.O>[CH3:39][O:38][C:34]1[N:33]=[C:32]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]4)=[N:14][C:13]=23)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(Br)n1
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(B4OC(C)(C)C(C)(C)O4)c3n2)CC1
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cnn3ccc(N4CCN(C(=O)OC(C)C)CC4)nc23)n1
Yield: 67.5 %

Procedure:
To 65 mg (0.157 mmol) of isopropyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate in a microwave vial was added, 29 mg (0.157 mmol) of 2-bromo-6-methoxypyridine, 43 mg (0.313 mmol) of K2CO3, 18 mg (0.016 mmol) Pd(PPh3)4, 3 mL of DME and then 1 mL water. The resulting mixture was microwaved at 125° C. for 0.33 hr. It was diluted with EtOAc, washed with brine, and the organic layer dried over MgSO4. It was concentrated and purified on the neutral PREP HPLC to obtain 42 mg of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=6.32 Hz, 6 H) 3.60-3.74 (m, 4 H) 3.81 (br. s., 4 H) 4.04 (s, 3 H) 5.00 (quin, J=6.25 Hz, 1 H) 6.39 (d, J=7.83 Hz, 1 H) 6.55 (dd, J=8.08, 0.76 Hz, 1 H) 7.62 (dd, J=8.08, 7.58 Hz, 1 H) 7.83-7.93 (m, 1 H) 8.37 (d, J=7.83 Hz, 1 H) 8.66 (s, 1 H). LRMS (ESI) m/e 397 [(M+H)+, calcd for C20H24N6O3 396 ].
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:27]1[C:35]3[C:30](=[N:31][CH:32]=[C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:34]=3)[C:29]3([CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH2:28]1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[N:7]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:27]1[C:35]3[C:30](=[N:31][CH:32]=[C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)[CH:34]=3)[C:29]3([CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[CH2:28]1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Tert-Butyl 4-(5,7-difluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-1-piperazinecarboxylate (450 mg, 0.70 mmol) was dissolved in DCM (5.0 mL) and cooled to 0° C. TFA (5.0 mL, 65.0 mmol) was then added and the reaction mixture was allowed to warm to rt and stirred for 2.5 h. The reaction was diluted with DCM and concentrated to dryness. The residue was then converted to the free amine by eluting through an SCX column with 0 to 2M ammonia in MeOH to give 1′-(5,7-difluoro-3-methyl-2-(1-piperazinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.56 (1H, d, J=2.3 Hz), 7.36 (1H, ddd, J=9.9, 2.5, 1.3 Hz), 6.73 (1H, ddd, J=11.8, 9.1, 2.5 Hz), 5.66 (1H, d, J=2.3 Hz), 4.04-4.21 (2H, m), 3.80-3.97 (2H, m), 3.70-3.79 (4H, m), 3.56 (2H, qd, J=11.6, 2.4 Hz), 3.27-3.46 (4H, m), 3.02-3.18 (4H, m), 2.90-3.02 (4H, m), 2.26-2.38 (2H, m), 2.24 (3H, s), 1.97 (1H, br. s.), 1.79 (1H, d, J=13.3 Hz), 1.70 (1H, dd, J=13.6, 1.9 Hz). Mass Spectrum (ESI) m/e=537.3 (M+1).
Reaction SMILES: Br[CH:2]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[OH-].[K+]>O1CCCC1.O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:3]([S:4]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])=[CH:2][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)C=C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a solution of 4.44 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one in 50 ml of tetrahydrofuran, a solution of 0.56 g of potassium hydroxide in 30 ml of water was added dropwise and vigorously stirred for 3 hours. The reaction mixture was combined with 100 ml of ice water, and extracted with 100 ml of chloroform. The organic solvent layer was washed twice with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 3.61 g of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-phenylsulfonyl-1-penten-3-one.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:23]([NH2:26])[CH2:24][NH2:25].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:25][CH2:24][CH2:23][NH:26][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C(O)c1cn(Cc2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: NCCNc1ccc2c(=O)c(C(=O)O)cn(Cc3ccccc3)c2c1
Temperature: 130 °C
Yield: 52.1 %

Procedure:
To a solution of 7-chloro-1-benzyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g) in 1-methyl-2-pyrrolidinone (10 mL) was added ethylenediamine (0.95 g). The mixture was heated at 130° C. for 10 h. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered to give the title compound (560 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:33]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:23](=[O:24])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][NH:20][CH:19]=2)=[O:17])=[CH:11][C:10]=1[F:32].C(=O)([O-])[O-].[K+].[K+].[P:53]([O:65]CCl)([O:60]C(C)(C)C)([O:55][C:56](C)(C)C)=[O:54].Cl>CN(C=O)C.CCOC(C)=O.CCO.O>[P:53]([OH:65])([OH:60])([O:55][CH2:56][N:20]1[CH:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:23](=[O:24])[C:18]([C:16](=[O:17])[NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH2:33])[C:2]=3[Cl:1])=[C:10]([F:32])[CH:11]=2)=[CH:19]1)=[O:54]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Nc1nccc(Oc2ccc(NC(=O)c3cn(COP(=O)(O)O)cc(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a solution of N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (5.0 g, 7.90 mmol) in DMF (50 mL) at room temperature were added potassium carbonate (7.64 g, 55.3 mmol) and di-tert-butyl chloromethyl phosphate (9.19 g, 35.5 mmol, see: PCT WO 2005/090367). The reaction mixture was stirred at room temperature for 2 days. The mixture was then diluted with EtOAc (250 mL), washed with water (200 mL), aq 10% LiCl (3×250 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue, which was dissolved in EtOH (160 mL). To this stirred solution, was added water (60 mL), followed by the slow addition of conc. HCl (40 mL). The resulting mixture was stirred at rt for 15 min, and then allowed to stand overnight. HPLC analysis indicated that the reaction was complete. The solid was collected by filtration, rinsed with 50% EtOH/H2O (5×), water, EtOH, and EtOAc. The solid was dried under vacuum to give the title compound (4.3 g, 93%) as a white solid. 1H NMR (TFA-d) δ 9.60 (s, 1H), 8.79 (s, 1 H), 7.80-7.90 (m, 2H), 7.65-7.75 (m, 2H), 7.57 (d, 1H, J=7.04 Hz), 7.45 (t, 1H, J=6.80 Hz), 7.25-7.33 (m, 2H), 6.50 (d, 1H, J=5.92 Hz), 6.39 (d, 2H, J=9.88 Hz); MS (ESI+) m/z 579 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH2:23])([CH3:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:10]([C:8]1[N:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][CH:7]=1)[CH3:11])([CH3:15])[CH3:14]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1

Procedure:
1-(6-Acetyl-pyridin-2-yl)-ethanone 2 (35.54 g, 0.22 mol), 25.0 g (0.168 mol) of 2-Isopropyl-6-methyl-phenylamine 14, 350 ml of n-propanol, and a few crystals of p-toluenesulfonic acid were stirred at room temperature for 36 h in a 500 ml flask under a flow of the nitrogen. The resultant yellow precipitate was filtered and washed by 20 ml of methanol. It was then dried at 1-mm vacuum overnight. The yield of 1-{6-[1-(2-Isopropyl-6-methyl-phenylimino)-ethyl]pyridin-2-yl}-ethanone 15 was 13.35 g (27%) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(S)nc1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (2.2 g), 2-mercapto-5-trifluoromethylpyridine (1.9 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 90° C. for 4.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (3.2 g, yield: 100%). mp: 165°-170° C. (dec.) IR (Nujol): 3175, 1695, 1640, 1600, 1565, 1330 cm-1
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:39][CH2:38][CH2:37][C@H:31]1[C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCOCC1.ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.[NH:66]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C@@H:67]([C:72](O)=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70]>CN(C=O)C.C1COCC1>[NH:66]([C:75]([O:77][C:78]([CH3:80])([CH3:79])[CH3:81])=[O:76])[C@@H:67]([C:72]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:39][CH2:38][CH2:37][C@H:31]1[C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=1)(=[O:18])=[O:19])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
H-Leu-Arg(Tos)-Pro-NHEt was dissolved in 80 mL of DMF and 200 mL of THF. With cooling the solution was neutralized with N-methylmorpholine. To the solution, a solution in which 8.86 g of Boc-D-Leu-OH and 23.02 g of HOSu were dissolved in 200 mL of THF, and 36.4 mL of WSC were added. Next the mixture was stirred at 0° C. for 5 minutes and at room temperature overnight. After confirmation with ninhidrin, the reaction mixture was concentrated under reduced pressure. To the residue, 500 mL of water was added, then the mixture was extracted 5 times with 200 mL of n-butanol and washed five times with water. The n-butanol layer was concentrated under reduced pressure, then the residue was solidified by treatment with ether. Thus 21.5 g of Boc-D-Leu-Leu-Arg(Tos)-Pro-NHEt (92.1% yield) was obtained.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([OH:12])(=[O:11])=[O:10].O(C1C=C[C:23]([S:26](O)(=O)=O)=CC=1)C1C=CC=CC=1>>[CH3:23][S:26][C:7]1[CH:6]=[CH:5][C:4]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][CH:8]=1
Reactant: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccccc1S(=O)(=O)O
Product: CSc1ccc(S(=O)(=O)O)cc1

Procedure:
2-methoxybenzene sulphonic acid: 4-phenoxybenzenesulphonic acid;