Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:25][C:24]1[CH:19]=[CH:20][C:21]([CH3:26])=[CH:22][CH:23]=1
Reactant: Cc1ccc(O)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(COc3ccc(C)cc3)c(C)o2)cc1
Yield: 93.7 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (3.1 g, 11.70 mmol, 1.00 equiv), p-cresol (2.0 g, 18.52 mmol, 1.58 equiv), Cs2CO3 (4.5 g, 13.80 mmol, 1.18 equiv) in N,N-dimethylformamide (60 mL) was stirred under nitrogen overnight at 50° C. The resulting solution was diluted with 100 mL of water and extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.7 g (94%) of methyl 4-(5-methyl-4-(p-tolyloxymethyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 379 [M+CH3CN+H]+, 338 [M+H]+, 271, 230, 203, 146, 91.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[C:16]1([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](Cl)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:12][C:24]([C:23]2[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)c2ccccc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.4 %

Procedure:
Pyridine (3.6 mL, 45 mmol) and 3-methoxyaniline (1.54 g, 12.5 mmol) were added to a solution of 2-phenylbenzoyl chloride (3.25 g, 15 mmol) in dichloromethane (30 mL) The reaction mixture was stirred at room temperature for 2.5 hours. 1M HCl solution (45 mL) was added, and the organic layer was washed with 1M NaOH solution (10 mL), aqueous sodium bicarbonate (30 mL), and brine (30 mL). The organic phase was concentrated to dryness to give the title compound as a tan solid (3.92 g). MH+304: 1H (D6-DMSO) δ 3.67 (3H, s), 6.60 (1H, dd, J=8, 2), 7.04 (1H, d, J=8), 7.14 (1H, t, J=8), 7.18 (1H, m), 7.23-7.57 (9H, m), 10.0 (1H, s, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21](=O)[CH2:22][C:23]([F:26])([F:25])[F:24].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[CH3:17][O:18][C:19]([C:20]1[C:21]([CH2:22][C:23]([F:24])([F:26])[F:25])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:28]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CC(=O)CC(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COC(=O)c1c(CC(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
To a solution of (2-amino-5-chloro-phenyl)-phenyl-methanone (120 mg, 0.52 mmol) and 5,5,5-trifluoro-3-oxo-pentanoic acid methyl ester (124 mg, 0.67 mmol) in 5 ml ethanol at room temperature was added ytterbium triflate (32 mg, 0.05 mmol). The reaction mixture was stirred for 16 h at room temperature, upon which a white precipitate was formed. The precipitated solid was filtered and washed with ethanol to afford 6-chloro-4-phenyl-2-(2,2,2-trifluoro-ethyl)-quinoline-3-carboxylic acid methyl ester (70 mg, 36%) as an off white solid. LC-MS: 380 (M+H)+.
Reaction SMILES: [H-].[Na+].N1C=CN=C1.C([NH:27][C@@H:28]([C:31]([OH:33])=[O:32])[CH2:29][OH:30])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34](I)[CH2:35][CH2:36][CH3:37]>O1CCCC1>[CH2:34]([O:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[NH2:27])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCI
Reactant: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCCCOC[C@@H](N)C(=O)O
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 52.6 %

Procedure:
To a mixed solution of 60% sodium hydride (28.8 g), imidazole (1.08 g, 15.9 mmol), and dry tetrahydrofurane (270 ml), a mixed solution of N-trityl-D-serine (25.0 g, 72.0 mmol) and dry tetrahydrofurane (150 ml) was dripped in 15 minutes at -15° C., and the mixture was stirred for 45 minutes at -15° C. Further, butyl iodide (65.5 ml, 576 mmol) was added, and the mixture was stirred for 2 hours at -15° C. Moreover, at -15° C., adding 60% sodium hydride (12.0 g) and butyl iodide (129 ml, 1.13 mol), the mixture was stirred for 1 day at -20° C. Adding water (1 liter) to the reaction solution, it was extracted with ether (300 ml×2), and the organic layer was washed with 5% aqueous solution of citric acid (200 ml) and saturated brine (100 ml), and dried over magnesium sulfate. The solvent was evaporated in vacuo, and 50% acetic acid-ethanol solution (100 ml) was added to the obtained oily matter, and the mixture was stirred for 15 hours at room temperature. The sediment was filtered, and washed with ethanol and ether, and O-butyl-D-serine (6.11 g, 53%) was obtained.
Reaction SMILES: [CH3:1]CN=C=NCCCN(C)C.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][C:35](O)=[O:36])[C:29]2=[O:38])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C1COCC1.ClCCl>[CH3:1][C:35]([CH2:34][N:30]1[CH2:31][CH2:32][CH2:33][N:28]([CH:25]2[CH2:24][CH2:23][N:22]([C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[CH2:27][CH2:26]2)[C:29]1=[O:38])=[O:36]
Reactant: O=C(O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
WSC (0.39 g) was added to a solution of [3-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-2-oxotetrahydropyrimidin-1(2H)-yl]acetic acid (0.70 g) obtained in Example 36a), a solution of methylamine in THF (1.85 mL) and HOBt (0.31 g) in THF/dichloromethane (1/1, 30 mL) and the mixture was stirred at room temperature overnight. The solvent were distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain the title compound (0.70 g, 97%) as a white powder.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[CH:24]=[C:25]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:26]=[CH:27][C:28]=1[CH3:29]>>[CH3:22][C:23]1[CH:24]=[C:25]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21](O)=[O:22]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])[CH2:4]2
Reactant: O=C(O)/C=C/c1ccccc1Cl
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccccc1Cl)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-chlorophenyl)propenoic acid; MS (ES+) 291 and 293 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][CH2:9][CH:10]([N:12](CC2C=CC=CC=2)[CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[CH3:11])=[CH:6][C:5]=1[OH:38])(=[O:3])[NH2:2]>CO.[Pd]>[C:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][CH2:9][CH:10]([NH:12][CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:19][CH:18]=2)[CH3:11])=[CH:6][C:5]=1[OH:38])(=[O:3])[NH2:2]
Reactant: CC(COc1ccc(C(N)=O)c(O)c1)N(Cc1ccccc1)CC(O)COc1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(COc1ccc(C(N)=O)c(O)c1)NCC(O)COc1ccc(NS(C)(=O)=O)cc1

Procedure:
A solution of 20.0 g of crude 1-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-benzylamino]-3-(4-methanesulfonylamino-phenoxy)-2-propanol in 250 ml of methanol is hydrogenated, after the addition of 2.5 g of Pd/C catalyst (5%), under normal conditions until debenzylation is completed (DC control), for which an addition of a further 1.0 g of catalyst is required. The catalyst is filtered off; the filtrate is concentrated by evaporation, and the oil remaining behind is dissolved in a small amount of hot isopropanol. On cooling is obtained crystalline 1-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethylamino]-3-(4-methanesulfonylamino-phenoxy)-2-propanol, m.p. 147°-150° (diastereoisomeric mixture).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:20]([N:22]1[CH2:61][CH2:60][CH2:59][C@H:23]1[C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([C:49]([O:51]CC1C=CC=CC=1)=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OCC1C=CC=CC=1Cl)=O)=[O:30])[CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8]S(C1C=CC(C)=CC=1)(=O)=O.C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:20]([N:22]1[CH2:61][CH2:60][CH2:59][C@H:23]1[C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([C:49]([OH:51])=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:30])[CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:19]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
The solution of 280 mg (0.285 mmol) of Boc-Arg(Tos)-Pro-Ala-Lys(ClZ)OBzl (SEQ ID NO: 12), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 110 mg (84%) of the title compound. Mp. 158–160° C., FAB-MS (m/e) 472[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:4][NH:5][C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:4][N:5]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[C:6]=1[S:7][CH3:8]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CSc1[nH]nc(-c2ccc(F)cc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CSc1c(Cl)c(-c2ccc(F)cc2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.46-7.5 (m, 2H), 7.12-7.18 (m, 2H), 6.96-7.1 (m, 2H), 6.88-6.92 (m, 2H), 4.86 (s, 2H), 3.72-3.78 (m, 2H), 3.56-3.62 (m, 2H), 3.06-3.18 (m, 4H), 2.54 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=[O:22])=[O:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].[I-].[K+]>C(COC)OC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])(=[O:21])=[O:22])[N:11]([CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)C(F)F
Reactant: CC(C)(C)C(=O)OCCl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)C(=O)OCn1c(S(=O)(=O)C(F)(F)C(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 63.9 %

Procedure:
To a solution of 5.0 g (0.012 mole) of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole in 50 ml glyme was added 1.7 g (0.015 mole) of potassium t-butoxide, followed by a solution of 4.6 g (0.031 mole) of chloromethyl pivalate in 25 ml of glyme dropwise and a catalytic amount of potassium iodide. The reaction mixture was heated at reflux overnight, then poured onto water. The aqueous mixture was extracted with ether. The combined ether extracts were washed, then dried and concentrated to give 13.4 g of crude oily product. The product was purified by chromatography on silica gel, eluting with toluene, to give 4.1 g of crystals, mp 121°-123.5° (from methyl cyclohexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Brc1ccccn1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-bromopyridine according to the general procedure C. Obtained as a yellow solid (407 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:28]1[S:32][N:31]=[CH:30][N:29]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1I)[N:14]=[CH:13]2)(=[O:9])=[O:8].CC1(C)C(C)(C)OB([CH2:47]/[CH:48]=[CH:49]/[NH:50]C(=O)OC(C)(C)C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[NH2:50][CH2:49]/[CH:48]=[CH:47]/[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:8])=[O:9])=[C:18]([F:19])[CH:17]=2)[CH:13]=[N:14]1
Reactant: CC(C)(C)OC(=O)N/C=C/CB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3cnn(Cc4ccccc4I)c3cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: NC/C=C/c1ccccc1Cn1ncc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-6-fluoro-1-(2-iodobenzyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indazole-5-sulfonamide (2-3, 0.068 g, 0.103 mmol, 1.0 equiv) in THF (0.94 mL) was added (E)-tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)carbamate (0.088 g, 0.310 mmol, 3.0 equiv) and Pd(Cl)2dppf (0.008 g, 10.34 μmol, 0.1 equiv) followed by 1M cesium carbonate (0.094 mL) and the system was irradiated at 120° C. for 10 min. The reaction contents were extracted with EtOAc and water and the organic phase was dried over Na2SO4, filtered and concentrated. To this residue was added DCM (0.69 mL) followed by TFA (0.17 mL) and the system was stirred at room temperature for 1 h. The reaction contents were then concentrated in vacuo and purified by reverse phase chromatography (10%→70% 0.1% TFA in ACN: 0.1% TFA in water) to yield compound Ex-5 as a mono TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.30-8.43 (m, 3H), 8.00 (br s, 2H), 7.80 (m, 1H), 7.50 (m, 1H), 7.18-7.39 (m, 3H), 6.80 (m, 1H), 6.20 (m, 1H), 5.70 (s, 2H), 2.45 (m, 3H). HRMS [M+H] C19H17FN6O2S2 calc'd 445.0911. found 445.0910.
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=O)=O)C1C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH:36]([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccccc1
Reactant: O=C1N(c2ccccc2Br)Cc2cnc(S(=O)(=O)Cc3ccccc3)nc2N1CC1CCCCC1
Product: O=C1N(c2ccccc2Br)Cc2cnc(Nc3ccccc3)nc2N1CC1CCCCC1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
A mixture of 240 mg (0.4 mmol) of 7-benzylsulfonyl-3-(2-bromophenyl)-1-cyclohexylmethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.39 ml (4.3 mmol) of aniline was heated at 150° C. for 2 hours. The reaction mixture was cooled to room temperature then partitioned between 2M hydrochloric acid (20 ml) and dichloromethane (20 ml). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 1:2 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 80 mg (42%) of 7-anilino-3-(2-bromophenyl)-1-cyclohexylmethyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 200-202° C. [Mass spectrum (ESI) MH+ =492].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CSc1nccc(-c2ccccc2F)n1
Yield: 89.8 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-pyrimidine (1.00 g, 6.22 mmol), 2-fluoro-phenyl-boronic acid (1.04 g, 6.84 mmol), Na2CO3 (790 mg, 7.45 mmol), triphenylphosphine (163 mg, 0.62 mmol) in nPrOH (50 ml), Pd(OAc)2 (42 mg, 0.187 mmol) was added and the mixture was refluxed for 3 hours. The solvent was evaporated under vacuum, and the crude was dissolved in ethyl acetate and washed with water. The organic phase was dried (Na2SO4) and evaporated; the crude was purified by flash chromatography with petroleum ether-ethyl acetate (97-3 to 95-5) to give the title compound (1.23 g, 90% yield).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH3:19])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[ClH:21]>>[ClH:21].[CH3:19][O:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:20])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1
Reactant: COCCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: Cl
Product: COCCN1CCC(c2ccc(C(=O)O)cc2)CC1

Procedure:
4-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-benzoic acid methyl ester (47 mmol) is dissolved in 4N HCl (80 ml) and heated under reflux for 12 hours. After cooling the solvent is evaporated and the residue is suspended in acetone and the solid filtered of, washed with acetone and dried (vacuum). A white powder with mp. >270° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:8]=[CH:9][S:10][C:11]=2[NH:12][C:13](=O)[CH3:14])[CH:6]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>P(Cl)(Cl)(Cl)=O>[CH3:14][C:13]1[C:6]2[N:5]([CH:4]=[N:3][C:2]=2[CH3:1])[C:7]2[N:8]=[CH:9][S:10][C:11]=2[N:12]=1
Reactant: CC(=O)Nc1scnc1-n1cnc(C)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncn2c1c(C)nc1scnc12
Temperature: 160 °C
Yield: 31.9 %

Procedure:
N-(4-(4-methyl-1H-imidazol-1-yl)thiazol-5-yl)acetamide (50 mg, 0.23 mmol) was suspended in phosphorus oxychloride (5 mL) and P2O5 (326 mg, 2.3 mmol) was added quickly. The resulting mixture was heated at 160° C. in a sealed tube for 24 hr. After POCl3 was evaporated, the residue was quenched with ice water very carefully. The mixture was neutralized with saturated Na2CO3 solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated (the crude product can also be directly used for next step), purified by prep-HPLC to give 15 mg of the title compound (yield: 33%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH2:4].[C:14](Cl)(Cl)=[O:15]>O1CCOCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[N:4]=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Temperature: 100 °C
Reaction time: 1.17 h

Procedure:
To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg, 0.56 mmol; Preparation 2) in 2 ml of dioxane under a nitrogene atmosphere, phosgene (0.52 ml 20% in toluene, 0.98 mmol) is added. The mixture is stirred for 70 min at 100° C., cooled to RT and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenylisocyanate. The resulting solid is added portion-wise to a boiling solution of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (140 mg, 0.47 mmol) in 8 ml of toluene during 20 min. After 3 h, another 2 eq of 2,6-dichloro-3,5-dimethoxyphenylisocyanate are added and stirring is continued for totally 5 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM/MeOH/NH3aq, 97:3:0.2) gives the title compound: ESI-MS: 547/549 [MH]+; tR=3.5 min (purity: 100%, gradient J); TLC: Rf=0.40 (DCM/MeOH+1% NH3aq, 95:5).