Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:62]=[CH:61][C:55]([O:56][CH2:57][CH2:58]CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:58][CH2:57][O:56][C:55]2[CH:61]=[CH:62][C:52]([Cl:51])=[CH:53][CH:54]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCCCOc1ccc(Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCOc4ccc(Cl)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 55 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-chlorophenoxy)-1-propanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (71 mg, yield 51%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH:34]([C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][C:45]=3[F:46])[N:42]=[CH:41][CH:40]=[CH:39]4)[CH3:35])=[CH:32][N:33]=2)[N:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:46][C:45]1[CH:44]=[C:43]2[C:38]([CH:39]=[CH:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[CH:34]([C:31]1[N:29]2[N:30]=[C:25]([C:13]3[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:14]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1)[CH3:35]
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 72.5 mg, 0.225 mmol), (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-7-fluoro-quinoline (Stage 255.2, 49 mg, 0.15 mmol), and 2 M K2CO3 (0.203 mL) in DME (1 mL) stirred at 80-90° C. under argon atmosphere was added PdCl2(PPh3)2 (3.2 mg). After 1.5 h and cooling to rt the RM was taken-up in DCM and water, the aqueous phase was extracted with DCM, the combined organic layers were dried over MgSO4, filtered, evaporated to dryness and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH=100:0->80:20) to afford the title compound as a white solid (tR 4.14 min (conditions 3), MH+=487.2).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH3:26][C:27]([NH2:44])([CH3:43])[CH2:28][CH2:29][N:30]1[C:34]([CH3:35])=[N:33][C:32]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)=[N:31]1>>[CH3:43][C:27]([NH:44][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=1)[OH:25])([CH3:26])[CH2:28][CH2:29][N:30]1[C:34]([CH3:35])=[N:33][C:32]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)=[N:31]1
Reactant: Cc1ccc(-c2nc(C)n(CCC(C)(C)N)n2)cc1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Product: Cc1ccc(-c2nc(C)n(CCC(C)(C)NCC(O)c3ccc(O)c(CO)c3)n2)cc1

Procedure:
The compound is prepared analogously to the general working method A from 241 mg (0.7 mmol) of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 181 mg (0.7 mmol) of 1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propylamine.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:40]=[CH:39][C:14]2[N:15]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][C:28]([C:30]4[CH:35]=[C:34]([Br:36])[C:33]([NH2:37])=[C:32]([Br:38])[CH:31]=4)=[O:29])[CH2:21][CH2:20]3)[C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1.C(N(CC)CC)C>C1COCC1>[NH2:37][C:33]1[C:34]([Br:36])=[CH:35][C:30]([C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][CH:19]([N:15]3[C:14]4[CH:39]=[CH:40][C:11]([NH:10][C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])=[CH:12][C:13]=4[NH:17][C:16]3=[O:18])[CH2:24][CH2:23]2)=[CH:31][C:32]=1[Br:38].[CH:1]([O:29][CH:28]([CH3:27])[CH3:30])([CH3:6])[CH3:2]
Reactant: Nc1ccc2c(c1)[nH]c(=O)n2C1CCN(CCCC(=O)c2cc(Br)c(N)c(Br)c2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: Nc1c(Br)cc(C(=O)CCCN2CCC(n3c(=O)[nH]c4cc(NC(=O)C5CCCCC5)ccc43)CC2)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
58.64 mg (0.40 mmol) of cyclohexanecarboxylic acid chloride were added to a solution of 200 mg (0.363 mmol) of 5-amino-1-{1-[4-(4-amino-3,5-dibromophenyl)-4-oxobutyl]-4-piperidinyl}-1,3-dihydro-2(2H)-benzimidazolone and 0.056 ml (0.40 mmol) of triethylamine in 10 ml of THF at a reaction temperature of 0° C. and the suspension formed was then stirred for 2 hours at ambient temperature. The mixture was evaporated down in vacuo, the residue was purified by column chromatography on silica gel (30–60 μm) using dichloromethane/methanol/cyclohexane/conc. ammonia 400/40/40/2.5 v/v/v/v as eluant. By working up the appropriate fractions. 106 mg (44% of theoretical) of the desired compound were obtained in the form of colourless crystals (diisopropyl-ether), Rf 0.67 (El B). IR (KBr): 1695.3 (C═O) MS: (M-H2O)+=641/643/645 (Br2)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([N:11]([CH:25]2[CH2:27][CH2:26]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:6]1)=[O:4].[BH-](O[C:42]([CH3:44])=O)(OC(C)=O)OC(C)=O.[Na+].Cl[CH2:47]CCl>>[CH:25]1([N:11]([CH:7]2[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH:42]([CH3:44])[CH3:47])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:6]2)[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:26][CH2:27]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)C[C@H](N)C(=O)N1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: ClCCCl
Agent: [Na+]
Product: CC(C)C[C@H](NC(C)C)C(=O)N1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2S)N-Cyclopropyl-N-[1-(2-isopropylamino-4-methylpentanoyl)-piperidin-3-yl]-3-trifluoromethylbenzenesulfonamide (18) was prepared as follows. A solution of compound 8 prepared in Example 2 (100 mg, 0.22 mmol), compound 17 (12 mg, 0.22 mmol, Aldrich) and 4 Å molecular sieves (500 mg) in 2 mL of 1,2-dichloroethane was shaken at room temperature for 10 minutes, and then, NaB(OAc)3H (43 mg, 0.22 mmol) was charged. The resulting mixture was shaken at room temperature for 24 hours. The reaction mixture was quenched with MeOH (0.2 mL), water (2 mL) was added, and the mixture was extracted with DCM (3×4 mL). The organic layers were combined and then washed with brine, dried over Na2SO3, concentrated under vacuum and purified by column (silica gel, EtOAc, then EtOAc/MeOH 10/1) to give the title compound 18 as a free base, which was converted to its HCl-salt by treating with HCl (1 N aqueous) and drying under vacuum (white solid, 60 mg, yield 65%). 1H NMR (400 MHz, CD3OD): δ 8.10-8.22 (m, 2H), 8.06 (dd, j=7.7, 7.8 Hz, 1H), 7.91 (dd, j=7.8, 7.9 Hz, 1H), 4.45-4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.35-3.45 (m, 1H), 3.3-3.35 (m, 1H), 2.9-2.95 (m, 0.5H), 2.55-2.64 (m, 0.5H), 1.35-2.15 (m, 14H), 0.75-1.20 (m, 10H); LC: 100%; MS: m/z=504 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24]/[N:25]=[C:26](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+].Cl>CN(C)C=O.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24]/[N:25]=[C:26](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)c1ccccc1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a stirred solution of 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (1.65 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (1.04 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 200 mg) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:4, v/v) gave methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate (1.60 g, yield 64%) as crystals. Recrystallization from ethyl acetate-hexane gave pale-yellow prisms. m.p. 67-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=O)[CH2:13][CH2:14][C:6]=3[C:5]=2[CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CCO.O>[OH:18][N:17]=[C:12]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]c3c(c2c1)CCC3=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CCC3=NO
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A stirred solution of 1,2-cyclopentadione mono-4-methoxyphenylhydrazone (6.0 g) in 100 ml of 10% aqueous H2SO4 was heated on a steam bath for 4 hours and thereafter allowed to cool to room temperature and filtered to give 1,4-dihydro-7-methoxycyclopent[b]indol-3(2H)-one as a solid. To the indole (2.6 g) in 25 ml of 95% EtOH was added hydroxylamine hydrochloride (1.7 g) in 15 ml water followed by sodium acetate (2.1 g) in 15 ml water. The mixture was heated at reflux for 2.5 hours and allowed to stand overnight. The EtOH was removed in vacuo and the solid material which formed was collected and purified by flash chromatography to give 0.8 g of a mixture of oxime isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][O:31][CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COCC(=O)O
Reactant: COc1cc(OC[C@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COCC(=O)N1C[C@@H](O)C[C@@H]1COc1cc(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Yield: 60 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (120 mg) with methoxyacetic acid (24 μl) to give the title compound as a white solid in 60% yield; NMR spectrum (DMSO-d6) 9.96 (s, 1H), 8.45 (s, 1H), 8.17-8.14 (m, 1H), 7.76-7.72 (m, 1H), 7.45 (t, 1H), 6.83 (s, 2H), 5.10 (m, 1H), 4.73-4.69 (m, 1H), 4.47-4.38 (m, 2H), 4.25 (dd, 1H), 4.10-3.98 (m, 2H), 3.94 (s, 3H), 3.51 (dd, 1H), 3.40 (s, 1H), 3.29 (s, 3H), 2.05-2.02 (m, 2H); Mass spectrum MH+ 491.
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:23]([O:22][C:14]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1)=[O:21])[CH3:24]
Reactant: Brc1nsc2nc3ccccc3n12
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)c1nsc2nc3ccccc3n12
Yield: 53.8 %

Procedure:
A mixture of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (0.2 g, 0.78 mmole), diethyl malonate (0.15 g, 0.94 mmol) and triethylamine (0.13 mL, 0.94 mmole) in 8 mL of THF was refluxed under a nitrogen atmosphere for 36 h. The resulting mixture was extracted with ethyl acetate, washed with water and 10% aqueous sodium sulfate. The organic layer was dried over magnesium sulfate to give the crude product, which was purified by flash chromatography (35% ethyl acetate: 65% hexane) to afford 0.14 g (54%) of the title compound as a yellow oil:
Reaction SMILES: CC(OC(=O)[N:7]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)C.[ClH:52].C(O)(C)C.CCOCC>CO>[ClH:52].[ClH:52].[ClH:52].[ClH:52].[NH2:36][CH2:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([C:19]3[CH:18]=[N:17][CH:16]=[C:15]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)[CH:20]=3)=[O:22])[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(N(Cc4cccnc4)C(=O)OC(C)(C)C)c3)CC2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CO
Product: NCc1cccc(C2CCN(C(=O)c3cncc(NCc4cccnc4)c3)CC2)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
{5-[1-(4-{3-[N,N-Bis-(tert-butoxycarbonyl)amino-methyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-pyridin-3-ylmethyl-carbamic acid dimethyl-ethyl ester (0.0250 g, 0.0356 mmol) was treated with 5-6 M HCl in isopropanol (1.0 mL, 8.0 mmol) and stirred at ambient temperature. After 90 minutes the reaction mixture was diluted with methyl alcohol (0.5 mL) and stirring was continued for an additional 75 minutes. Dripping the reaction solution into ether (40 mL) with vigorous stirring afforded a white precipitate which was collected by filtration, washed with fresh ether (3.0 mL), and dried to afford 1-[4-(3-aminomethyl-phenyl)-piperidin-1-yl]-1-{5-[(pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-methanone tetrahydrochloride (0.0160 g): 1H NMR (300 MHz, DMSO-d6) δ 8.60-8.95 (m, 2H), 8.39 (br s, 2H), 8.29 (d, J=8.0 Hz, 1H), 7.97-8.25 (m, 2H), 7.65-7.85 (m, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.20-7.38 (m, 3H), 4.63 (s, 2H), 4.43-4.61 (m partially obscured, 1H), 4.00 (AB q, J=5.8 Hz, 2H), 3.05-3.25 (m partially obscured, 1H), 2.72-2.95 (m, 2H), 1.80-1.88 (m, 1H), 1.47-1.77 (m, 3H); MS (CI) m/z 402 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15](O)=[O:16])[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:66]([NH:73][CH2:74][CH2:75][CH2:76][NH2:77])([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67].Cl>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:77][CH2:76][CH2:75][CH2:74][NH:73][C:66](=[O:67])[O:68][C:69]([CH3:71])([CH3:70])[CH3:72])=[O:16])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (300 mg, 0.66 mmol), HATU (277 mg, 0.73 mmol) and N,N-diisopropylethylamine (187 mg, 1.45 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of N-Boc-1,3-propanediamine (172 mg, 0.99 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate as light yellow solid. Yield: 345 mg, 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[O:18]1[C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=[N:19]1>>[O:18]1[C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:21][CH:20]=[N:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccno1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccno4)cc23)CC1
Yield: 57.3 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 8.21 mg (0.062 mMol) isoxazole-5-carbonyl chloride, 10.4 mg (57%) of the title compound were recovered.
Reaction SMILES: N1C=CC=CC=1.[CH:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])[CH3:8].[Cl:17]C(Cl)(Cl)C([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:23][CH2:22]1)=O>ClCCl>[ClH:17].[CH:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][S:35]([C:29]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([N:24]2[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]2)[CH:28]=1)(=[O:36])=[O:37])([CH3:9])[CH3:8]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Reactant: CC(C)c1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2C(C)C)cc1N1CCNCC1
Product: Cl
Reaction time: 18 h
Yield: 76.4 %

Procedure:
Pyridine (0.28 ml) was added to a stirred solution of 2-isopropylaniline (98 mg) and 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D4) (300 mg) in dichloromethane (4 ml) at room temperature. After 18 h the solution was washed with 1M hydrochloric acid (5 ml) then water (5 ml). The organic phase was stirred vigourously with 20% aq. potassium hydroxide (0.5 ml) for 18 h. A 10% aqueous solution of KH2PO4 (8 ml) was then added to the mixture and after 0.25 h stirring the layers were separated. The organic layer was dried (Na2SO4), acidified with 1M ethereal hydrogen chloride (2 ml) and concentrated to an oil which was stirred with acetone/diethyl ether to afford the title compound (E79) as a white solid (0.224 g, 83%). MH+ 390.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:6]=2)=[O:16])[CH:11]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)cc1)c1cccnc1
Product: CN(C(=O)Oc1ccc(NC(=O)c2cccnc2)cc1)c1ccccc1

Procedure:
The title product was prepared from N-(4-Hydroxy-phenyl)-nicotinamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (1%, light yellow crystals). HPLC-MS: m/z=348.1 (M+1); Rt: 2.96 min.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[O:12]=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C:19]([NH2:21])=O.N1C=CC=CC=1>C(#N)C>[O:12]=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C:19]#[N:21]
Reactant: NC(=O)CN1CCCC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#CCN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethylformamide (4.65 mL, 60 mmol) was taken up in acetonitrile (100 mL) and the solution cooled to 0° C. with an ice bath. Oxalyl chloride (4.8 mL, 55 mmol), diluted with acetonitrile (20 mL) was added to the reaction dropwise. The mixture was stirred for 30 min, then 2-(2-oxopyrrolidin-1-yl)acetamide (7.11 g, 50 mmol) in 30 mL of acetonitrile was added slowly to the reaction. The mixture was allowed to stir for 30 min and pyridine (6.1 mL, 100 mmol) was added to the reaction in one portion. The reaction was stirred for an additional 30 min and the volatiles were removed in vacuo. Water was added to the residue which was extracted with ethyl acetate. The aqueous layer was acidified to pH 2 with 1 N HCl and further extracted with ethyl acetate. All the organic layers were combined, washed with brine, dried with sodium sulfate, concentrated and placed on a high vacuum line to afford a clear oil. Yield=4.4 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:38][C:39]1[CH:51]=[CH:50][CH:49]=[CH:48][C:40]=1[CH2:41][N:42]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[Cl:38][C:39]1[CH:51]=[CH:50][CH:49]=[CH:48][C:40]=1[CH2:41][N:42]1[CH2:46][CH2:45][CH:44]([NH:47][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][C:18]=2[N+:23]([O-:25])=[O:24])=[O:29])[CH2:43]1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: NC1CCN(Cc2ccccc2Cl)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5Cl)C4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Chloroform (13 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) to prepare a solution. Triphosgene (96 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(2-Chlorobenzyl)-3-pyrrolidinamine (92 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (66 mg, yield 39%).