Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][CH:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][CH:38]([NH:45][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1

Procedure:
(3-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methane sulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) by following the method in Example 61.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH2:22][O:21]1>CN(C)C=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([OH:21])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[CH2:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CN1NCc2ccccc21)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a suspension of Indazole (0.27 g, 2.32 mmol) in N, N-dimethylformamide (10 ml) was slowly added sodium hydride (0.093 g, 2.32 mmol) at 0° C., followed by stirring for 30 min and then for an additional 30 min at room temperature. Then, 1-((2-(2,4-difluorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole (0.50 g, 2.11 mmol) was added, followed by stirring for 2 hrs at 60° C. The reaction was quenched with the addition of water (1 ml) at 0° C. Following dilution with ethyl acetate (20 ml), the reaction mixture was washed with saturated ammonium chloride solution (20 ml) and then with brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum condition. The product was purified by chromatography on silica gel to give the title compound (Yield 44%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.Br.Cl[C:20]([O:22][CH:23]=[CH2:24])=[O:21]>>[CH:23]([O:22][C:20]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)=[O:21])=[CH2:24]
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: C=COC(=O)Cl
Agent: Br
Product: C=COC(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1

Procedure:
2-Amino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide and vinyl chloroformate were treated in the same manner as in Example 49 to obtain 2-vinyloxycarbonylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([C:35](O)=[O:36])[CH:34]=1)[NH:31][CH:30]=[CH:29]2.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[C:35]([C:33]2[CH:34]=[C:26]([Cl:25])[CH:27]=[C:28]3[C:32]=2[NH:31][CH:30]=[CH:29]3)=[O:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Yield: 62.4 %

Procedure:
167 mg (0.5 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine, 97 mg (0.5 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 115 mg (0.6 mmol) of EDC.HCl were stirred over night at rt in 10 ml DCM. The product was purified by column chromatography (20 silica gel; DCM) to yield 160 mg (64%) product as a white solid. MS (EI) 512.2 (60), 514.2 (25) (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:28]1[CH:29]=[C:30]([NH:34][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cccc(F)c1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3cccc(F)c3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 49 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), 3-Fluoro-phenylamine (0.28 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give (3-Fluoro-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine as brown solid in 49% yield.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]([F:35])([F:34])[C:24]([NH:26][C@H:27]1[C@@H:31]([CH2:32][F:33])[CH2:30][NH:29][CH2:28]1)=[O:25]>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:29]4[CH2:30][C@H:31]([CH2:32][F:33])[C@H:27]([NH:26][C:24](=[O:25])[C:23]([F:35])([F:34])[F:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: O=C(N[C@@H]1CNC[C@@H]1CF)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3C[C@H](CF)[C@H](NC(=O)C(F)(F)F)C3)c(F)c(F)c2c1=O
Yield: 57.6 %

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.32 g), cis-3-trifluoroacetylamino-4-fluoromethylpyrrolidine (1.41 g), and pyridine (10 ml) was refluxed for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and the resulting precipitate were collected. Recrystallization from dimethylformamide gave 1-cyclopropyl-5,6,8-trifluoro-7-(cis-3-trifluoroacetylamino-4-fluoromethyl-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.25 g), m.p. 283°-284° C.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:35]([C:34]1[CH:37]=[CH:38][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=1)[OH:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 5.65 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.3 g, 12.5 mmol) in THF (126 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-tert-butylbenzaldehyde (1.68 g, 10.4 mmol) in THF (42 mL) was added at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.17 g, 60%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)CC1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (45 mg, 64%), MS (ISP) m/z=443.5 [(M+H)+], mp 173.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) rac-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:33]=[CH:32][C:11]([O:12][C:13]2[C:14]([C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1>[OH-].[OH-].[Pd+2].C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:14]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Reaction time: 48 h

Procedure:
To a N2 purged flask containing tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10.0 g, 22.45 mmol) and pearlman's catalyst (4.1 g, 5.84 mmol) was added THF (350 mL). H2 was bubbled through the solution for 4 minutes, then the solution was capped with a balloon of H2. After 48 hours, LC-MS shows complete conversion. The solution was filtered over a pad of celite, and the celite washed with EtOAc (150 mL). The filtrate was concentrated in vacuo. The residue was taken up in DCM (50 mL) and loaded onto a plug of silica gel (800 mL frit) and eluted with 0% to 50% EtOAc in hexanes to give tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as a light yellow foam. MS (ESI, pos. ion) m/z: 448.1 (M+1).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+]>CO>[N:1]1([CH2:6][CH:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cn1ccnc1)c1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(Cn1ccnc1)c1nccs1
Yield: 60 %

Procedure:
2-(Imidazol-1-yl)-1-(thiazol-2-yl)ethanone was reduced with sodium borohydride in methanol to give 2-(imidazol-1-yl)-1-(thiazol-2-yl)ethanol in 60% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]([C@H:12]([OH:17])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]([O:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[C:11]([C@H:12]([O:17][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]([O:22][CH:23]([CH3:24])[CH3:25])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](C)[C@@H](O)c1c(O)cc(OC(C)C)c2c(CCC)cc(=O)oc12
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=C[C@@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)c1c(O)cc(OC(C)C)c2c(CCC)cc(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
To a solution of 4a (500 mg, 1.44 mmol) in dry CH2Cl2 (20 mL) at 0° C. was added DMAP (88 mg, 0.72 mmol), imidazole (196 mg, 2.88 mmol) and tert-butylchlorodimethylsilane (239 mg, 1.59 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 24 h. Water (10 mL) was then added, the organic layer was separated, dried (MgSO4), concentrated and submitted to silica gel chromatography (Solvent B) to obtain 5a (583 mg, 88%) as a syrup: [α]D20 +38.0° (c 1.1, CHCl3); 1H NMR (CDCl3): δ -0.04 (s, 3 H, --SiCH3), 0.14 (s, 3 H, --SiCH3), 0.87 [s, 9 H, --C(CH3)3 ], 0.97 (d, 3 H, J=6.88 Hz, --CHCH3), 1.00 (t, 3 H, J=7.44 Hz, --CH2CH2CH3), 1.38 and 1.40 (2d, 6 H, J=6.0 Hz, --CH(CH3)2), 1.62 (m, 2 H, --CH2CH2CH3), 2.59 (q, 1 H, J=6.9 Hz, --CHCH3), 2.86 (bt, 2 H, --CH2CH2 CH3), 4.62 [m, 1 H, J=6.06 Hz, --CH(CH3)2 ], 4.95-5.05 (m, 2 H, --CH=CH2), 5.29 [d, 1 H, J=6.5 Hz, --CHOSi(CH3)2 --], 5.85 (m, 1 H, --CH=CH2), 5.89 (s, 1 H, H-3), 6.24 (s, 1 H, H-6), 9.15 (s, 1 H, ArOH); 13C NMR (CDCl3): δ -0.33, -0.15, 13.91, 16.27, 18.06, 21.76, 21.85, 23.08, 25.68, 25.88, 38.96, 44.62, 70.67, 74.28, 97.54, 103.39, 106.57, 109.86, 115.71, 139.60, 152.98, 156.13, 158.95, 160.17, 160.75. Anal. Calcd for C26H40 O5Si: C, 67.78; H, 8.75. Found C, 67.91; H, 8.71.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[N:18]1[C:27]2[C:22](=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](O)=[O:29].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[N:24][CH:23]=2)[N:18]=1)=[O:29]
Reactant: NCc1ccccc1Br
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Br)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
To a stirring solution of 2-bromobenzylamine hydrochloride (80.7 mg, 95%, 0.345 mmol) in anhydrous DMF (5 ml) was added triethylamine (51.8 ul. 0.345 mmol), After 5 min, 2-[1,6]naphthyridinecarboxylic acid (40 mg, 0.229 mmol), 1-hydroxybenzotriazole hydrate (34.2 mg, 0.253 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (48.5 mg, 0.253 mmol) was sequentially added. The resulting mixture was allowed to stir at room temperature for 4 h and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (70 mg, 89%): m.p. 129-130° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1.[NH4+:18].[OH-]>C1COCC1.CO>[NH2:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc(CN)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(bromomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide (500 mg) in THF/MeOH (1:1, 15 ml) was added NH4OH (4.5 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between EtOAc/H2O and the aq phase was extracted by EtOAc (3×). The organic phase was then combined, washed with brine, dried over Na2SO4 and concentrated to give 4-(aminomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: O=Cc1cc(O)ccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Oc1ccc(Br)c(C2OCCO2)c1
Yield: 90.2 %

Procedure:
A mixture of 2-bromo-5-hydroxybenzaldehyde (60.0 g, 299 mmol), ethylene glycol (56 mL, 1.00 mol), and p-toluenesulfonic acid (1.14 g, 5.98 mmol) in toluene (450 mL) was refluxed with Dean-Stark head for overnight. Potassium carbonate (3 g) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-bromo-3-(1,3-dioxolan-2-yl)phenol (66.1 g, 90%).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].F[C:13]1[C:18]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH:7][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[N:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: Nc1cccc(OC(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cccc(OC(F)F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 3-(difluoromethoxy)aniline (0.038 mL, 0.303 mmol) (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.090 g, 0.202 mmol) in THF (3.0 mL) at 0° C. was treated with LiHMDS 1.0 M in THF (0.606 mL, 0.606 mmol) (Aldrich) dropwise. The solution was stirred at 0° C. for 1.5 h and was then quenched with a saturated solution of NH4Cl at 0° C. The mixture was extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to give 4-(2-(3-(difluoromethoxy)phenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.121 g, 0.207 mmol, 99% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 12.12 (br. s., 1H); 8.84 (d, J=8.2 Hz, 1H); 8.35 (br. s., 1H); 7.72 (br. s., 1H); 7.31 (d, J=8.4 Hz, 1H); 7.20 (d, J=7.8 Hz, 5H); 7.11 (t, J=8.0 Hz, 4H); 6.84-6.90 (m, 4H); 6.80 (d, J=7.8 Hz, 1H); 6.71 (d, J=8.4 Hz, 1H); 6.65 (br. s., 1H); 6.45-6.54 (m, 10H); 6.42 (br. s., 4H); 6.28 (br. s., 1H); 4.84 (br. s., 4H); 3.80 (d, J=3.5 Hz, 7H); 2.60 (br. s., 3H). m/z (ESI, +ve ion) 585.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc(F)c(Cl)c1
Product: O=C(NCc1ccc(F)c(Cl)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3-chloro-4-fluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[S:15](Cl)(=[O:18])(=[O:17])[OH:16].CCN(C(C)C)C(C)C>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)CCCSSc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Yield: 48.7 %

Procedure:
4-(pyridin-2-yldisulfanyl)butanoic acid (102 mg, 0.445 mmol) was coevaporated with 1,2-dichloroethane, (2×6 ml) (to remove moisture) and re-dissolved in 6 ml of 1,2-dichloroethane. The resulting solution was then placed in a preheated oil bath (75˜80° C.). To this solution, sulfurochloridic acid (100 μL, ˜3 eq) was added and the resulting mixture was stirred for 5˜8 min. DIPEA (117 iμL, 1.5 eq) was then added (to precipitate the product) and the resulting mixture was stirred for 5 min. Another portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for ˜15 min, followed by addition of DIPEA (63 μL, 0.81 eq) and stirred for 5 min. A third portion of sulfurochloridic acid (40 ul, 1.33 eq) was added and the mixture was stirred for 15˜20 min. The resulting mixture was removed from the oil bath and cooled (on ice bath). Aqueous NaOH (0.5 M) or concentrated Na2CO3 was added to raise the pH ˜12 and the reaction mixture was stirred for 10 min. The organic phase was separated, washed with water (2×10 ml), and neutralized with H3P04 to pH 7. The organic phase was then concentrated to ˜5 ml and acidified with HCl to pH ˜4. The crude product was purified by passing through a C-18 column using eluting with a gradient of 100% water (containing 0.5% HAc) to 75% of water (containing 0.5% HAc)/25% of MeOH. Fractions containing the desired product (eluted out at 5-10% of MeOH) were pooled, evaporated to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (67 mg, 0.217 mmol, 48.7% yield). 1H NMR (D2O) 8.41 (dd, 1H, J=1.5, 4.9 Hz), 7.89 (m, 2H), 7.31 (m, 1H), 3.75 (dd, 1H, J=5.1, 9.6), 2.97 (m, 1H), 2.82 (m, 1H), 2.28 (m, 2H); 13C NMR 176.60, 160.28, 150.60, 140.27, 123.39, 122.92, 69.07, 37.56, 29.45; ESI MS m/z −307.8 (M-H).