Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([N:9]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH3:10])=[O:8])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7]([N:9]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH3:10])=[O:8])(=[O:3])[NH2:2]
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(N)=O)c1
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 3-(2-(2-(2-(3-(carbamoyl)-N-methylbenzamido)ethoxy)ethoxy)ethoxy)propanoate (120 mg, 0.14 mmol, 1.00 equiv, 90%) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) dropwise with stirring and the resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum and the crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford 45 mg (45%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): 10.95 (s, 1H), 10.87 (s, 1H), 9.19 (s, 2H), 8.35-8.38 (t, 2H), 8.04-8.07 (d, J=9 Hz, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.51-7.60 (m, 5H), 7.34 (s, 1H), 3.43-3.62 (m, 17H), 3.98 (s, 3H), 2.38-2.42 (t, J=6, 6 Hz, 2H), 1.51-1.71 (m, 6H). MS (ES, m/z): 739 [M+11]+.
Reaction SMILES: [BrH:1].C(OC([NH:12][CH:13]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[C:14]([O:16][CH3:17])=[O:15])=O)C1C=CC=CC=1.CCOCC>C(O)(=O)C>[BrH:1].[NH2:12][CH:13]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)c1ccco1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C(N)c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To magnetically stirred 33 wt % hydrogen bromide (2.00 ml, 11.04 mmol) in acetic acid was added methyl 2-(((benzyloxy)carbonyl)amino)-2-(furan-2-yl)acetate (579 mg, 2 mmol). After stirring at room temperature for 1 hr, 25 mL of anhydrous ether was added to give methyl 2-amino-2-(furan-2-yl)acetate hydrobromide (468 mg, 1.983 mmol, 99% yield) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 7.81 (dd, J=1.8, 0.8 Hz, 1H), 6.69 (m, 1H), 6.57 (dd, J=3.3, 1.9 Hz, 1H), 5.61 (s, 1H), 3.78 (s, 3H).
Reaction SMILES: CO[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([N:17]2[CH2:21][C@@H:20]([CH:22]3[CH2:24][CH2:23]3)[C@H:19]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH:8]=[CH:7]1.C1(=O)[NH:43]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[NH2:43][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([N:17]2[CH2:21][C@@H:20]([CH:22]3[CH2:24][CH2:23]3)[C@H:19]([CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:30][CH2:31]3)[CH2:18]2)=[O:16])[CH:8]=[CH:7]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
A mixture of 1 g (4 mmol) of 7-carboethoxy-N-(3-hydroxypropyl)indole (Example 20, Step 1), 1.23 g (8.4 mmol) of phthalimide, 2.12 g (8 mmol) of triphenylphosphine and 1.28 g (8 mmol) of diethylazodicarboxylate in 15 mL of THF was stirred for 12 h at rt. The reaction mixture was concentrated and partitioned between ether and water that had been made basic. The combined organic fractions were dried over MgSO4, filtered andthe filtrate was concentrated. The residue was purified by chromatography (silica, EtOAc:hexanes, 1:4) to give 1.09 g of the title compound. 1H NMR (CDCl3) δ7.8 (m, 2H), 7.7 (m, 4H), 7.2 (d, 1H), 7.1 (t, 1H), 4.45 (t, 2H), 4.2 (q, 2H), 3.7 (t, 2H), 2.1 (m, 2H), 1.35 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(Cl)Cl>[CH2:34]([NH:36][C:37]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][C:19]2[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]3=[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)[N:18]=2)[CH2:29][CH2:30]1)=[O:38])[CH3:35]
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1

Procedure:
1-(2-Phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolved in 2.00 mL of CH2Cl2. At four 15 min. increments, 10 μL (0.47 equiv), 5 μL (0.24 equiv), 2.1 μL (0.1 equiv) and 2.1 μL (0.1 equiv) of ethylisocyanate were added dropwise, respectfully. The crude product was purified by 5 g Jones silica gel (wetted with 100% CH2Cl2; dry loaded with silica gel, eluted with 2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1 H, d, J=1.64), 8.29 (1 H, d, J=8.38), 8.20 (2 H, dd, J=1.52, J=1.10), 7.97 (2 H, m), 7.87 (1 H, dd, J=1.71, J=1.71), 7.53 (4 H, m), 7.24 (1 H, d, J=5.26), 7.08 (1 H, d, J=5.23), 4.38 (1 H, t), 3.97 (2 H, d, J=13.44), 3.28 (2 H, m), 2.96 (2 H, d, J=7.12), 2.79 (2 H, t), 2.20 (1 H, m), 1.80 (2 H, d, J=10.60), 1.36 (2 H, m); MS (ES+): m/z 506.07/507.08 (50/25) [MH+]; HPLC: tR=2.17 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:19][CH:20]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (6.34 g, 34.0 mmol), 1 eq.), 4-bromomethyl-2'-cyanobiphenyl (9.25 g, 34.0 mmol, 1 eq.), potassium carbonate (5.17 g, 37.4 mmol., 1.1 eq.) and DMF (100 mL) were mixed and stirred at 25° C. overnight. The solids were filtered and the filtrate evaporated. The residue wash chromatography over silica gel in 9:1 to 1:1 hexane/ethyl acetate and crystallized from methylcylcohexane/n-butyl chloride yielding 9.70 g of a solid; m.p. 96.0°-97.0° C. NMR (CDCl3): δ 9.78 (s, 1H); 7.83-7.40 (m, 6H); 7.19 (d, 2H, J=9Hz); 5.63 (s, 2H); 2.71 (t, 2H, J=7Hz); 1.72 (t of t, 2H, J=7,7Hz); 1.38 (t of q, 2H, J=7,7Hz); 0.90 (t, 3H, J= 7Hz). Anal. calcd. for C22H20ClN3O: C, 69.93; H, 5.34; N, 11.12. Found: C, 69.64; H, 5.37; N, 11.21.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.06 mL) was added 2-methoxypyridin-3-ylboronic acid (0.925 g, 6.05 mmol), potassium carbonate (1.67 g, 12.1 mmol) and palladium tetrakistriphenylphosphine (0.466 g, 0.403 mmol). The reaction was stirred at 100° C. and stirring continued for 18 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with (0-50% EtOAc in hexanes) to provide 4-chloro-5,7-difluoro-2-(2-methoxy-3-pyridinyl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=321.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)=[O:21]>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH:17][C:30]3[N:29]=[C:28]([NH:27][C:26]4[CH:25]=[CH:24][S:23][C:22]=4[C:20](=[O:21])[NH:19][CH3:18])[C:33]([Cl:34])=[CH:32][N:31]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CCOC(=O)N1CCCOc2ccc(N)cc21
Product: CCOC(=O)N1CCCOc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21

Procedure:
2-[5-Chloro-4-(2-methylcarbamoyl-thiophen-3-ylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester was prepared from 2-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as a tan solid (138 mg, 61%). m.p.=222-224° C.; LCMS (m/e) 503 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.62 (s, 1H), 9.50 (s, 1H), 8.52-8.38 (m, 1H), 8.30-8.20 (m, 2H), 7.74 (d, 1H, J=5.4 Hz), 7.70-7.59 (m, 1H), 7.50-7.38 (m, 1H), 6.98 (d, 1H, J=8.6 Hz), 4.20-3.91 (m, 4H), 3.79-3.55 (m, 2H), 2.77 (d, 3H, J=4.2 Hz), 2.01-1.86 (m, 2H), 1.33-0.90 (m, 3H).
Reaction SMILES: O.[NH2:2]N.C(O)(=O)C.[Br:8][C:9]1[CH:21]=[CH:20][C:12]([C:13](/[N:15]=[CH:16]/[N:17](C)C)=O)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]2[NH:2][N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(-c2ncn[nH]2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution of hydrazine hydrate (1.96 mL, 40.4 mmol) in acetic acid (91.9 mL, 36.8 mmol) was added (E)-4-bromo-N-((dimethylamino)methylene)benzamide (9.38 g, 36.8 mmol) and the mixture stirred at 90° C. for 1.5 hours. The reaction mixture was concentrated to about 10 mL and diluted with ether (50 mL). The resulting white solid was collected by vacuum filtration, rinsing with excess ether, and dried to afford 5-(4-bromophenyl)-1H-1,2,4-triazole (5.48 g, 66%) which was carried on without further purification. LCMS (APCI+) m/z 224, 226 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:52][CH2:51][C:50]([C:58]([O:60][CH2:61][CH3:62])=[O:59])([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:49][CH:48]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:52][CH2:51][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:49][CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 11.3 %

Procedure:
To a sealable vial containing (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-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 trifluoromethanesulfonate (0.25 g, 0.448 mmol) was added diethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1,1-dicarboxylate (0.374 g, 0.531 mmol), sodium carbonate hydrate (0.167 g, 1.345 mmol), and palladium tetrakis (0.016 g, 0.013 mmol). The mixture was diluted with 1,4-dioxane (4 mL) and water (1 mL) then was flushed with nitrogen and was sealed and heated to 85° C. in an oil bath. After 5 h of heating, the mixture was cooled to rt, was diluted with water (20 mL), and was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10-50% ethyl acetate in hexanes gradient. diethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-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)cyclohex-3-ene-1,1-dicarboxylate, a white solid, was recovered as the minor isolate (0.032 g, 0.05 mmol, 11.3% yield). LCMS: m/e 634.6 (M+H)+, 2.10 min (method 1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CN(C)C=O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccsc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-thiophenemethanol (1.0 g; 8.76 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (0.42 g; 10.51 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 600 milligrams of 2-fluoro-6-(thiophen-3-ylmethoxy)benzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 72.2 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[(dimethylamino)methyl]phenylamino}quinolin-3-yl)(cyclopropyl)methanone (44 mg, 0.104 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.156 mmol) to afford the desired product (38 mg, 73%) as a yellow solid: 1H NMR (300 MHz, CD3OD+Acetic Acid-d4) δ 9.26 (s, 1H), 7.99 (d, J=10.0 Hz, 2H), 7.94 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.29 (s, J=9.9 Hz, 3H), 7.25 (s, 1H), 4.32 (s, 2H), 2.94-2.85 (m, 1H), 2.82 (s, 6H), 1.17-1.01 (m, 4H); ESI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC 94.4% (AUC), tR=11.19 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[O:6]=[C:7]1[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[S:12][C:11]=2[C:10](=[O:20])[CH:9]=[CH:8]1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:8]1[C:7](=[O:6])[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[S:12][C:11]=2[C:10](=[O:20])[CH:9]=1
Reactant: COC(=O)c1cc2c(s1)C(=O)C=CC2=O
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNC1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Temperature: 25 °C
Reaction time: 27 h

Procedure:
2-Methoxyethylamine (1.6 ml) was added to a solution of methyl 4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (2.4 g) in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 27 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography (elution with chloroform) to give methyl 4,7-dihydro-5-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (1.5 g) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cncc(-c2ccc(C#N)c(Cl)c2)c1
Yield: 46.6 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1.1 eq) in anhydrous pyridine (500 μl) was added propane-1-sulfonyl chloride (10.8 μl, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)propane-1-sulfonamide (13.6 mg, >95% purity, yield: 46.5%).
Reaction SMILES: [CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([O:41]C(C)(C)C)=[O:40])=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([OH:41])=[O:40])=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)O)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
The mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (657 mg), trifluoroacetic acid (3 ml) and methylene chloride (10 ml) is stirred overnight at room temperature. The reaction mixture is washed with a saturated sodium hydrogen carbonate solution and brine, dried, and evaporated. The crude product is purified by silica gelcolumn chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-3-(2'-carboxybiphenyl-4-yl)methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (516 mg).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1nc2c(Br)cc(Cl)cc2[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(Br)cc(Cl)cc2n1C1CCCCO1
Temperature: 75 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A mixture of 4-bromo-6-chloro-2-methyl-1H-benzo[d]imidazole (3.5 g, 14.26 mmol), p-TsOH.H2O (272 mg, 1.43 mmol), and 3,4-dihydro-2H-pyran (5.9 g, 71.30 mmol) in THF (20 mL) was stirred at 75° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0 to 9% MeOH) to afford 4-bromo-6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a white solid (3.2 g, 69.6%). MS (ESI): m/z=329.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29])=[O:19]>O1CCCC1>[C:24]1(=[O:29])[N:23]([CH2:22][CH2:21][O:20][C:18]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:19])[C:27](=[O:28])[CH:26]=[CH:25]1
Reactant: O=C(Cl)OCCN1C(=O)C=CC1=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC(=O)N1CCOC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
500 mg (3.84 mmol) 5-fluorouracil were dissolved in 100 ml of tetrahydrofuran and diluted with 505 mg (696 μl; 4.99 mmol) of triethylamine. To this solution, 1016 mg (4.99 mmol) of 2-maleinimidoethyl chloroformate, dissolved in 100 ml of tetrahydrofuran, were added drop-wise and the set-up was stirred for 15 h at room temperature. Then, the solvent was removed under the water jet vacuum and the residue purified using column chromatography (LOBAR®-column; running medium: acetic acid/hexane 1.5/1; yield: 61%); melting point: 132° C., Rf-value: 0.64 (diol; acetic acid/hexane 2/1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[N:25]([CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([S:42]([N:19]2[CH2:20][CH2:21][CH:17](/[CH:16]=[CH:15]/[C:13]3[CH:12]=[CH:11][C:10]([N:22]4[S:26](=[O:27])(=[O:28])[N:25]([CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:24](=[O:35])[CH2:23]4)=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:14]=3)[CH2:18]2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCNC3)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCN(S(=O)(=O)c4ccccc4)C3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 5-[2-benzyloxy-4-((E)-2-pyrrolidin-3-yl-vinyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and benzenesulfonyl chloride analogous to Example 192, step B.