Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH2:30].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:30][O:29][CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][O:23]4)=[O:19])=[CH:21][CH:22]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 4-[4-(phenylmethyl)-1-piperazinyl]-benzoic acid (0.0145 mol), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (0.029 mol), N,N-methanetetrayl-biscyclohexanamine (0.0145 mol) and 1-hydroxy-1H-benzotriazole (0.021 mol) in DCM p.a. (200 ml) was stirred at room temperature over the weekend. The reaction mixture was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from EtOAc, filtered off and dried, yielding 3.5 g and another crop: 2.0 g total yielding 5.5 g (95%) of 4-[4-(phenylmethyl)-1-piperazinyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-benzamide (interm. 8).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([NH:16]C(=O)OCC2C=CC=CC=2)=[N:14][CH:15]=1>CO.C1COCC1.[C].[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1
Reactant: O=C(Nc1cnc(CCOC2CCCCO2)cn1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc(CCOC2CCCCO2)cn1
Reaction time: 2 h
Yield: 117.4 %

Procedure:
To a solution of benzyl {5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazin-2-yl}carbamate (416 mg) in methanol (20 mL) and THF (10 mL) was added 10% palladium carbon (100 mg), followed by stirring for 2 hours under a hydrogen atmosphere. It was filtered through Celite and concentrated to obtain 5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazin-2-amine (305 mg) as a pale yellow oily substance.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:55])[CH2:13][CH2:14][NH:15][CH2:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>O1CCOCC1.CO>[C:43]([C:42]1[CH:46]=[CH:47][C:39]([C:26]2[C:27]([CH3:38])([CH3:37])[C@H:28]3[C@:23]([CH3:48])([CH2:24][CH:25]=2)[C@@H:22]2[C@:31]([CH3:36])([C@@:32]4([CH3:35])[C@H:19]([CH2:20][CH2:21]2)[C@H:18]2[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:17]2([CH2:16][NH:15][CH2:14][CH2:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[O:55])[CH2:34][CH2:33]4)[CH2:30][CH2:29]3)=[CH:40][CH:41]=1)([OH:45])=[O:44]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 240 h
Yield: 52.4 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(4-(ethoxycarbonyl)piperidin-1-yl)-3-oxopropylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (16 mg, 0.021 mmol) in dioxane (1 ml) and methanol (2 ml) was added 1N sodium hydroxide (0.3 ml, 0.1 mmol) and H2O (0.5 ml). The resulting mixture was stirred at rt for 10 days. The reaction mixture was neutralized with 1N HCl and concentrated in vacuo. The crude product was purified by prep. HPLC to afford the title compound (8 mg). MS: m/e 727.6 (MH+), 1.69 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.95 (s, 3H) 0.97 (s, 3H) 1.04 (s, 3H) 1.08 (s, 3H) 1.17 (d, J=2.76 Hz, 3H) 1.73 (s, 3H) 0.87-1.86 (m, 23H) 1.92-2.10 (m, 3H) 2.15 (dd, J=17.32, 6.53 Hz, 1H) 2.47-2.56 (m, 1H) 2.57-2.67 (m, J=7.34, 7.12, 7.12, 3.76 Hz, 1H) 2.83-2.94 (m, 4H) 3.16-3.41 (m, 4H) 3.82-3.91 (m, 1H) 4.35-4.44 (m, 1H) 4.64 (s, 1H) 4.76 (d, J=1.51 Hz, 1H) 5.30 (d, J=5.27 Hz, 1H) 7.22 (d, J=8.28 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:8]=[C:4]2[CH:3]=1.[NH2-].[Li+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)([CH3:23])[CH3:24])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:11][CH2:10][CH2:9][CH2:20][CH2:19][CH2:22][CH3:23])=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
The compound prepared in Example 47 is refluxed in toluene in the presence of lithium amide and EXXAL® 8 (mixture of octanols, Exxon-Mobil) for four hours. The title compound is obtained.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:50]=[CH:49][C:14]([CH2:15][NH:16][C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:51]([O:58][CH2:59][C:60](Cl)=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]([CH2:60][CH2:59][O:58][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:17]3[CH:22]=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=3[CH:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH:37]=4)[CH2:32]3)=[CH:49][CH:50]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Reactant: O=C(Cl)COCc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCOCc1ccccc1)Cc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 94.7 %

Procedure:
Synthesized from [4-(2-azepan-1-ylethoxy)benzyl]{5-(tert-butyldimethylsilyloxy)-2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]phenyl}amine (400 mg) and benzyloxyacetyl chloride (520 mg) according to an analogous synthetic method to Example 152, the title compound (450 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH3:26])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:27]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([N:29]1[CH:33]=[C:32]([C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[O:25][CH3:26])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH:31]=[N:30]1)[CH3:28]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCn1cc(-c2nccc3cnc(Nc4ccc(-c5cnn(C)c5)cc4OC)nc23)cn1
Yield: 69.1 %

Procedure:
A solution of 8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Example 94, 35 mg, 0.095 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32 mg, 0.144 mmol) and Pd(dppf)Cl2.DCM (8 mg, 9.79 μmol) was dissolved in THF (0.6 mL) and 2M sodium carbonate in water (0.2 mL) and heated to 65° C. for 18 hours. The mixture was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM three times. The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 5% MeOH in EtOAc to give the title compound (28 mg, 68%).
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])=[N:5]1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (108 mg; compound B82) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (88 mg; compound C10) and HBTU (183 mg) in DCM/DMF (18 ml/1 ml) in the presence of DIPEA (227 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc, 60/40 to 40/60 (v/v)] and by preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluation gradient: EtOAc/methanol/triethylamine, 91/5/4 (v/v/v)] as a solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].O1CCOCC1.O.C(N(CC)CC)C.[C:24](=O)([O:30]C(Cl)C(Cl)(Cl)Cl)[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O>[C:26]([O:25][C:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(Cl)C(Cl)(Cl)Cl
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Yield: 60 %

Procedure:
To a solution of 1.33 g (10 mmol) of L-aspartic acid in a dioxane/water (1:1) mixture (30 ml), 4.2 ml (30 mmol) of triethylamine are added, and the mixture is stirred until solution is complete (approximately 10 min). 2.85 g (10 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate are then added and the mixture is stirred for 6 hours at 20° C. 50 ml of water are then added and the mixture is extracted with 2×20 ml of ethyl acetate. The aqueous phase is acidified (pH 2-3) with NHCl, and then extracted with 3×30 ml of ethyl acetate. The extract is washed with saturated NaCl solution, dried over MgSO4 and evaporated. The product obtained is crystallised in ethyl acetate and petroleum ether. 1.4 g (60% yield) of the expected acid is obtained. ##STR60##
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:35])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[N:9]=[C:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)([CH3:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[F:45])[CH:40]=[O:41].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[F:45][C:44]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][C:37]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)[N:7]([CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:35])[C:16]2=[O:17]
Reactant: COc1cccc(-c2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ccc(-c4cc(C=O)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 80 °C
Yield: 26.7 %

Procedure:
To a solution of N-isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-4H-quinazolin-3-yl]acetamide (70 mg, 0.15 mmol) in DMF (3 mL) was added 3-bromo-4-fluorobenzaldehyde (70 mg, 0.34 mmol), followed by tetrakis(triphenylphosphine)palladium (Pd[P(C6H5)3]4) (24 mg, 0.02 mmol) and 2M K3PO4 (aq.) (0.38 mL, 0.76 mmol). The mixture was heated at 80° C. under argon for 20 h, then cooled to room temperature and DMF evaporated in vacuo. The crude product was purified by preparative thin layer chromatography on silica gel with methanol:dichloromethane (1:9, v/v) as eluent to provide 2-[6-(2-fluoro-5-formylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (19.3 mg, 0.04 mmol, 27% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5](O)=[C:4]([F:10])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:26])=[O:25])[CH:19]=2)=[C:4]([F:10])[CH:3]=1
Reactant: Nc1cc(F)c(O)cc1F
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(-c2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 78.6 %

Procedure:
4-Amino-2,5-difluorophenol (4.95 g) was dissolved in dimethyl sulfoxide (50 ml) under a nitrogen stream, and potassium tert-butoxide (4.05 g) was added at room temperature, and the mixture was stirred for 25 minutes. 4-Chloropyridine-2-carboxamide (2.70 g) was added to the mixture, which was stirred at 80° C. for 2.5 hours. The reaction mixture was allowed to cool down to room temperature, and a 1N aqueous solution of sodium hydroxide (74.25 ml) was added, and the mixture was stirred for 10 hours. The precipitated solid was collected by filtration, and the resultant solid was washed with water. The solid was dried by hot air at 100° C. for 24 hours to give the title compound (3.38 g, 74%) as purple powder.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[C:10](Cl)(=[O:14])C(Cl)=[O:12].[N:16]1[CH:21]=NC=NC=1>[N+](C1C=CC=CC=1)([O-])=O>[N-:9]=[C:8]=[O:12].[N-:1]=[C:10]=[O:14].[N-:16]=[C:21]=[O:12].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ncncn1
Agent: Nc1nc(N)nc(N)n1
Solvent: O=[N+]([O-])c1ccccc1
Product: [N-]=C=O
Reaction time: 72 h

Procedure:
To a suitable reactor equipped with an efficient reflux condenser and CaSO4 drying tube was charged 2.52 grams of melamine, 60 ml of oxalyl chloride and 60 ml of nitrobenzene and the mixture was brought to reflux with good stirring. The reaction mixture became homogeneous within 72 hours. The excess oxalyl chloride was first removed under slight vacuum at a bath temperature of 80° C. and then the nitrobenzene was removed at less than 1 mm of Hg, allowing the bath to rise to 140° C. The product obtained after stripping was a very light tan, clear semi-solid which showed an intense NCO band in the IR spectrum at 2250 cm-1 and also had other expected bands for s-triazine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]#[N:17])[CH:12]([NH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1)[CH2:11][CH2:10]2)=O.C([OH:34])C.OO.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]1[NH:17][C:16](=[O:34])[C:15]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:30][CH:31]=4)[C:13]=3[CH:14]=2)[N:6]=1
Reactant: COCC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1nc2cc3c(cc2c(=O)[nH]1)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of tert-butyl 4-[N-(5-methoxyacetamido-6-cyanoindan-1-yl)amino]benzoate (0.295 g, 0.70 mmol), ethanol (3.2 ml), and water (0.64 ml) was cooled in an ice-bath, then 30% aqueous H2O2 solution (0.60 ml) was added followed by granulated sodium hydroxide pellets (0.047 g, 1.19 mmol). The reaction mixture was stirred at ˜0° C. for 10 min, then it was placed in an oil bath preheated to 55° C. and stirred at this temperature for 30 min. The reaction mixture was allowed to cool to room temperature, then the solvents were removed in vacuo and the residue was suspended in water (˜15 ml). The pH of this mixture was adjusted to ˜12 with 1N NaOH (got a clear solution), then to ˜4 with 1N hydrochloric acid. The off white precipitate was collected by filtration, washed with water, dried in vacuo over P2O5: 0.262 g (89%), m.p. >122° C. (softens); 1H-NMR (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(CH3)3), 1.87, 2.56 (2×m, each 1H, 7-H), 3.00 (m, 2H, 8-H), 3.34 (s, 3H, OCH3), 4.30 (s, 2H, 2-CH2), 5.16 (m, 1H, 6-H), 6.78 (d, J=8.55 Hz, 2H, 3′,5′-H), 6.89 (d, J=8.10, N10—H), 7.52, 7.90 (2×s, each 1H, 5-H, 9-H), 7.67 (d, J=8.45 Hz, 2′,6′-H), 12.12 (s, 1H, N3—H); MS (ESI, m/z) 444 {(M+Na)+, 40%}; Found: C, 67.19; H, 6.31; N, 9.69; C24H27N3O4 0.5H2O requires C, 66.96; H, 6.50; N, 9.76%.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[OH:14][C:15]1[C:16]([C:33](O)=[O:34])=[CH:17][C:18]2[C:23]([CH:24]=1)=[C:22]([O:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:21]=[CH:20][CH:19]=2.C(Cl)(=O)C(C)(C)C.[CH:43]([N:56]1[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][NH2:64])[CH2:58][CH2:57]1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(N(CC)CC)C.C(Cl)Cl>[CH:43]([N:56]1[CH2:57][CH2:58][N:59]([CH2:62][CH2:63][NH:64][C:33]([C:16]2[C:15]([OH:14])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:17]=2)=[O:34])[CH2:60][CH2:61]1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(O)c1cc2cccc(OCc3cccnc3)c2cc1O
Reactant: NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc2cccc(OCc3cccnc3)c2cc1O
Reaction time: 2 h
Yield: 78 %

Procedure:
19.1 g (40.0 mM) of dicyclohexylamine salt of 3-hydroxy 5-(3-pyridylmethoxy)-2-naphtoic acid was dissolved in 11.2 ml (80.0 mM) of triethylamine and 500 ml of anhydrous methylene chloride. Thereto was dropwise added, at -20° C., a solution of 9.6 ml (80.0 mM) of pivaloyl chloride in 10 ml of anhydrous methylene chloride. The resulting mixture was stirred for 2 hours. Thereto was dropwise added a solution of 17.4 g (56.0 mM) of 2-(4-benzhydrylpiperazino)ethaneamine in 20 ml of anhydrous methylene chloride. The mixture was stirred for 2 hours. The reaction mixture was washed with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 600 ml of methanol. Thereto was added 160 ml of an aqueous solution containing 16.56 g (120.0 mM) of potassium carbonate. Stirring was conducted at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 1000 ml of ethyl acetate. The solution was washed with water, a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 18.3 g of the title compound at a yield of 78%. The properties of the compound are shown in Table 7.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([Si:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([CH3:15])([CH3:13])[CH3:14]
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a solution of 1,4-butanediol (4.0 g, 44.4 mmol) in 250 mL THF was added imidazole (3.7 g, 54.3 mmol) followed by tert-butyl(chloro)diphenylsilane (10 g, 36.4 mmol) at room temperature. The mixture was stirred for 3 h and then quenched by the addition of saturated aqueous NH4Cl (200 mL) and then diluted with ethyl acetate (200 mL). The mixture was extracted with ethyl acetate (3×200 mL) and the combined organic layers washed with brine (3×60 mL) and dried over Na2SO4. The solvent was evaporated and the product isolated by flash column chromatography eluting with 0 to 50% EtOAc/hexanes to give 10.6 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:15][N:16]([CH3:34])[C:17]([C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[C:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([C:17]([N:16]([CH3:34])[CH3:15])=[O:18])=[N:20][CH:21]=2)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.38 g, 1.4 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (from PepTech, 0.46 g, 1.6 mmol) in 1,4-dioxane (6 mL), potassium carbonate (0.38 g, 2.7 mmol) in water (2 mL) was added. The reaction mixture was bubbled with N2. Tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.082 mmol) was added and the reaction was stirred overnight at 100° C. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-100% EtOAc in hexanes) to give the desired product. LCMS calculated for C18H20ClN2O3 (M+H)+: m/z=347.1; Found: 347.1