Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]=2[C:27]#[N:28])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:15]4[CH2:16][CH2:17][CH:29]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:3][CH2:4]4)=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]=2[C:27]#[N:28])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(F)ccc23)cc1Cl
Reactant: CN1CCCC1=O
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)ccc23)cc1Cl
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.37 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-fluoroquinoline-3-carbonitrile and 339 mg (2.20 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 9:1 methylene chloride/methanol) gives 66 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 125-130° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:9][C:10]([CH3:12])=O.[H][H]>C(O)C.[Pd]>[CH:10]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])([CH3:12])[CH3:9]
Reactant: [H][H]
Reactant: CC(C)=O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)N[C@H](C(=O)O)C(C)C
Reaction time: 2.5 h
Yield: 91.6 %

Procedure:
A mixture of L-valine (29.29 g, 250 mmol)6 and acetone (18.36 mL, 500 mmol, Malinckrodt Baker Inc., Paris, Ky. 40361) was agitated in an atmosphere of hydrogen (pressure, 41-50 psi) at room temperature in 500 mL ethanol in the presence of Pd/C (20%, 4 g) until the absorption of hydrogen had ceased. The mixture was filtered, and the filter cake washed with 450 mL 1 M HCl. The filtrate was treated with concentrated aqueous sodium hydroxide (29.8%) to adjust the pH to 5.5, and concentrated to dryness under reduced pressure. The white solid thus obtained was extracted by stirring 2 to 3 hours vigorously with 250 mL methanol followed by filtration. This process was repeated several times. The combined extracts were concentrated under reduced pressure, and the white solid thus obtained was recrystallized from methanol and dried under vacuum to give 36.48 g (92%) of the pure titled compound in two crops as a white solid: mp >300° C. APCI-MS m/z 160.2 (MH+).
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH:17]3[CH:13]([CH2:14][O:15][CH2:16]3)[O:12][CH2:11][C:10]2=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>O1CCCC1>[C:1]1([C@H:7]([N:9]2[C@H:17]3[C@@H:13]([CH2:14][O:15][CH2:16]3)[O:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)COC2COCC21
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H]2COC[C@H]21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 0° C. solution of (3aRS,7aSR)-7-((1R)-1-phenyl-ethyl)-tetrahydro-2,4-dioxa-7-aza-inden-6-one (1.46 g, 5.9 mmol) in tetrahydrofuran (20 ml), a 1 M-solution of boran tetrahydrofuran complex in tetrahydrofuran (18 ml, 18 mmol) was added dropwise under nitrogen atmosphere and the resulting mixture was warmed to room temperature. After the reaction mixture was stirred for 15 hours, methanol was added until disappearance of bubbles. The mixture was concentrated under reduced pressure and methanol (10 ml) and 1 N aqueous solution of sodium hydroxide (10 ml) were added to the obtained residue at room temperature. The white slurry was refluxed for 2 hours and cooled to room temperature. After evaporation of methanol, water (30 ml) was added to the residue and extractive workup with ethyl acetate was performed. The organic layer was dried over sodium sulfate and concentrated. (3aS,7aR)-7-((1R)-1-phenyl-ethyl)-hexahydro-2,4-dioxa-7-aza-indene was isolated as a diastereomerically enriched colorless crystalline by silica gel column chromatography (eluent; hexane/ethyl acetate=100/0 to 1/1) of the residue and subsequent recrystallization from ethanol (1.0 g, 4.9 mmol, 73%, 96% de determined by NMR analysis).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[K+].C(COC)OC>O.CN(C)P(N(C)C)(N(C)C)=O>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Yield: 94.3 %

Procedure:
A mixture comprising 90.5 grams (0.5 mole) of 2-chloro-6-trifluoromethylpyridine, 65 grams (0.55 mole) of 4-methoxyphenol and 36.4 grams (0.55 mole) of 85 percent potassium hydroxide was stirred in 1 liter of a 1:1 mixture of monoglyme and hexamethylphosphoramide for 1 hour at room temperature and thereafter heated overnight at reflux. The resulting mixture was diluted with water and extracted with hexane. The hexane extract was washed with a dilute sodium hydroxide solution followed by water washing. The extract was dried and concentrated under reduced pressure to give 127 grams (94 percent of theoretical) of 2-trifluoromethyl-6-(4-methoxyphenoxy)pyridine.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1>>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH3:22])([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:15]=1[Br:1]
Reactant: CCOC(=O)C(C)(C)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C(C)(C)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-aminophenyl)-2-methylpropionate (4.74 g in 40 mL dry methylene chloride) at 0° C. was added 4.08 g of N-bromosuccinimide and the mixture stirred at low temperature. After 1 hour, the mixture was warmed to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane:ethyl acetate, 9:1; then 8:2) gave the title compound, 5.46 g.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[O:14])[CH3:13]>>[CH3:3][N:4]([CH3:6])/[CH:5]=[CH:13]/[C:12](=[O:14])[CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(OC)N(C)C
Reactant: COC(OC)C(C)=O
Product: COC(OC)C(=O)/C=C/N(C)C
Temperature: 110 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110° C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1, pg 67.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:39])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:54])=[C:44]([CH:53]=2)[O:45][CH2:46][CH2:47][O:48]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55][NH:56][CH3:57].C1C[O:61]CC1>>[CH:47]([OH:48])=[O:61].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:39])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:54])=[C:44]([O:45][CH2:46][CH2:47][N:56]([CH3:57])[CH3:55])[CH:53]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: C1CCOC1
Reactant: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of Intermediate 78e (44 mg, 0.057 mmol) and dimethylamine (2M in THF, 0.57 mL, 1.14 mmol) in THF (1 mL) was heated at 60° C. for 18 h. The reaction mixture was cooled to RT and the solvent was removed under a stream of air, to leave a residue which was purified by MDAP (Method 7), to afford the title compound (16 mg, 38%). LCMS (Method 5): Rt: 3.42 min, m/z 726.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.10 (3H, d, J=6.2 Hz), 1.28 (9H, s), 1.54-1.65 (1H, m), 1.78-1.95 (3H, m), 1.95-2.08 (2H, m), 2.08-2.19 (2H, m), 2.21 (6H, s), 2.65 (2H, t, J=5.6 Hz), 3.09-3.16 (1H, m, obscured by water), 3.80-3.89 (1H, m), 4.06-4.14 (1H, m), 4.16 (2H, t, J=5.6 Hz), 4.75-4.84 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.34 (1H, s), 7.04-7.13 (3H, m), 7.22-7.39 (5H, m), 7.52-7.58 (2H, m), 7.79 (1H, d, J=1.9 Hz), 8.15-8.19 (2.2H, m).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=2)[N:14]=[CH:13][N:12]=1.[CH2:22]([C:24]1[NH:41][C:27]2=[N:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[C:26]2[N:25]=1)[CH3:23].C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]3[CH:31]=[C:26]4[N:25]=[C:24]([CH2:22][CH3:23])[NH:41][C:27]4=[N:28][CH:29]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: Ic1ccc2ncnc(N3CCc4ccccc4C3)c2c1
Reactant: CCc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2[nH]1
Yield: 19.1 %

Procedure:
0.25 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline, 0.35 g of 2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine, 0.52 g of sodium hydrogencarbonate and 0.29 g of Pd(PPh3)2Cl2 in 17 ml of dioxane and 2 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 3 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-45% in 16 min), giving 0.05 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline (“A10”) as white powder (yield 92%, content 94%); MS-FAB (M+H+)=407.2; Rf (polar method): 1.40 min;
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=O)=[N:4][N:3]=[N:2]1.[CH3:14]I.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:14][N:2]1[N:3]=[N:4][C:5]([C:6]2[S:18][C:17]([NH2:19])=[N:16][C:7]=2[C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:1]1
Reactant: CI
Reactant: O=C(Cc1nnn[nH]1)c1cccs1
Reactant: NC(N)=S
Product: Cn1nnc(-c2sc(N)nc2-c2cccs2)n1

Procedure:
Prepared from 2-(1H-tetrazol-5-yl)-1-thiophen-2-yl-ethanone and MeI and thiourea.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:22]3[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]3[CH3:16])[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 125 °C
Yield: 60.1 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-7-yl acetate (0.75 g, 3.3 mmol) in NMP (10 mL) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol). The mixture was heated to 125° C. for 60 hours. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.775 g, 60%). 1H NMR (CDCl3, 400 MHz) δ 8.60-8.59 (d, 1H), 6.07-5.89 (m, 1H), 4.73-4.60 (m, 1H), 4.30-3.80 (m, 3H), 3.60-3.35 (m, 1H), 3.22 (m, 1H), 3.02 (br, 1H), 2.78 (m, 1H), 2.35-1.60 (m, 5H), 1.49 (s, 9H), 1.32-1.20 (m, 6H). MS (APCI+) [M+H]+391. The resulting mixture of diastereomers was purified by chiral separation by HPLC (Chiralcel ODH column, 250×20 mm, 15 mL/min, Hexane/EtOH 50:50). The first peak (RT=3.864 min) gave (S)-tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.281 g, 36%) and the second peak (RT=5.064 min) gave (S)-tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.389 g, 50%).
Reaction SMILES: Cl[C:2](Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C[N:14](C)[NH:15][C:16]([NH:18][C:19]1[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][O:22][CH:23]=1)=[O:17].[CH2:29]([Cl:31])Cl>>[Cl:31][C:29]1[N:18]([C:19]2[C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][O:22][CH:23]=2)[C:16](=[O:17])[N:15]([CH3:2])[N:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: COC(=O)c1cocc1NC(=O)NN(C)C
Product: COC(=O)c1cocc1-n1c(Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (40.1 g) was added to a solution of crude title compound of Step C (15.4 g) in methylene chloride (550 mL) at 0° C. The mixture was heated at reflux for 4 h, cooled to room temperature and stirred overnight. The reaction mixture was concentrated to a brown oil which was dissolved in methylene chloride, washed with water and the aqueous layer extracted three times with methylene chloride. The combined organic extracts were dried (MgSO4), filtered and concentrated to a brown oil. Purification by flash chromatography (1:1 hexane:ethyl acetate) provided 5.34 g of the title compound of Step D as a yellow solid melting at 129-130° C. 1H NMR (CDCl3): δ 8.10 (d,1H), 7.72 (d,1H), 3.80 (s,3H), 3.52 (s,3H).
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][C:56]=1[CH3:57])[NH2:53]>C(O)(=O)C>[CH3:49][C:50]1[CH:51]=[C:52]([N:53]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:54]=[CH:55][C:56]=1[CH3:57]
Reactant: Cc1ccc(N)cc1C
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1C
Yield: 50 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (70 mg, 0.30 mmol), triethyl orthoformate (0.57 ml), 3,4-dimethylaniline (67.8 mg, 0.56 mmol), and acetic acid (0.07 ml) were used to give 49.2 mg (0.15 mmol, 50% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:19](=[O:20])[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[N:10][O:11][C:7]=2[CH2:6][CH2:5]1.[C:21](=[O:24])([O-])[O-:22].[K+].[K+].C(N(C(C)C)CC)(C)C.[F:36][C:37]1[CH:50]=[CH:49][C:40]([C:41]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:42])=[CH:39][CH:38]=1.[I-].[K+]>CN(C=O)C>[C:21]([OH:22])(=[O:24])[C:6]1[C:7](=[CH:8][CH:19]=[CH:4][CH:5]=1)[OH:11].[F:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([CH:43]2[CH2:48][CH2:47][N:46]([CH2:2][CH2:3][CH:4]3[C:19](=[O:20])[C:8]4[C:9]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[F:18])=[N:10][O:11][C:7]=4[CH2:6][CH2:5]3)[CH2:45][CH2:44]2)=[O:42])=[CH:49][CH:50]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1O
Product: O=C(c1ccc(F)cc1)C1CCN(CCC2CCc3onc(-c4ccccc4F)c3C2=O)CC1
Temperature: 80 °C

Procedure:
To a solution consisting of 5-(2-chloroethyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (2.5 g) and DMF (85 ml) was added anhydrous potassium carbonate (0.6 g), diisopropylethyl amine (2.2 ml), 4-(4-fluorobenzoyl)piperidine (2.3 g) and potassium iodide (70 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 19 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[N:14][CH:15]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:28]=[N+:29]=[N-:30].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:30][N:29]=[N:28][N:23]=3)=[N:14][CH:15]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C#N)nc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Product: CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Yield: 51.6 %

Procedure:
A mixture of 2-propyl-1-[[2-(2-cyanophenyl)-5-pyridinyl]methyl]-1H-benzimidazole (0.50 g, 1.42 mmol), NaN3 (0.18 g, 2.84 mmol), and tri-n-butyltin chloride (0.92 g, 2.84 mmol) in xylenes (10 mL) was heated under reflux for 48 h. The reaction mixture was concentrated and 2N HCl was added. The mixture was extracted with ether (discarded) and adjusted to pH 5 with 50% NaOH. The aqueous phase was extracted with CH2Cl2, and the extracts were washed with water, dried, and concentrated. Purification by flash chromatography (5% MeOH/CH2Cl2) and trituration with EtOH gave 0.29 g (51%) of product as a white solid, mp 240°-241° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:10](=[O:12])[N:11]=1.[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[C:10](=[O:12])[N:11]=1
Reactant: CN(C)CCCNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccccc1
Product: CN(C)CCCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 1-{4-[2-(3-dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 33) and (2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp 166-168° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 10 H), 1.60-1.80 (m, 2 H), 1.80-2.00 (m, 2 H), 2.19 (s, 6 H), 2.25 (t, J=6.8 Hz, 2 H), 2.55-3.00(m, 5 H), 3.50-4.05(m, 7 H), 6.65-6.95(m, 3 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.30 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.48 (s, 1 H); MS (ES) m/z: 269.6 ((M+2H)2+, 100%), 538.1(MH+, 10%); HRMS Calcd. for C29H40N5O3S (MH+): 538.2852. Found: 538.2885.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](N)[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.C(O)(=[O:26])C>[OH-].[Na+]>[NH2:1][C:2]1[N:3]=[C:4]([OH:26])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 25 °C
Yield: 88 %

Procedure:
A suspension of 1.0 g of 2,4-diamino-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 30 mL of 1N aqueous sodium hydroxide was heated under reflux under nitrogen for 3 hours. The resulting homogenous orange solution was cooled to room temperature, acidified with 6 mL of glacial acetic acid, and the resutling yellow precipitate collected by filtration. The filter cake was washed successively with water, methanol, acetone and ether and was then dried under reduce pressure to give 0.88 g (88%) of the title compound, which can be alternatively named as either 6-[2-(4-carboxyphenyl)ethenyl]-5-deazapterin or 6-(4-carboxystyryl)-5-deazapterin, as a microcrystalline yellow powder, mp >250° C.; NMR (TFA-d1 delta 6.8, 7.25 (AB q, 2H, J=12 Hz), 7.45, 8.2 (AB q, 4H, J=9 Hz), 8.55 (s, 1H), 8.85 (s, 1H); IR (Nujol) 3500-2500 (br), 1670, 1625, 1600 cm-1.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[C:25]1[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]1)=[N:19][CH:18]=2.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.[Pd]>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=[C:5]1[C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[C:25]1[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]1)=[N:19][CH:18]=2
Reactant: Clc1ccc2cnc3ccccc3c2c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2sc(-c3ccc4cnc5ccccc5c4c3)cc2c1
Yield: 78 %

Procedure:
Benzo[b]thiophene-2-ylboronic acid (884 mg, 5.0 mmol) and 9-chlorophenanthridin (1.0 g, 4.8 mmol) were dissolved in tetrahydrofuran (30 ml), and palladium catalyst (160 mg, 0.14 mmol) and 2M sodium carbonate solution (20 ml) were added, followed by refluxing under a N2 atmosphere for 5 hours. The reaction solution was added to H2O and the mixture was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 1.15 g, yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20])=[O:8]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of the 2,4,5-trichloro-phenoxy acetic acid (76.7 mg, 0.3 mmol), 3-amino benzamide (61.3 mg, 0.45 mmol), EDC (86.3 mg, 0.45 mmol) and HOBt (61.3 mg, 0.45 mmol) were dissolved in DMF (3 mL), and DIPEA (0.08 mL, 0.45 mmol) were added. The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (CH2Cl2:MeOH=6:3:1) gave 3-[2-(2,4,5-trichloro-phenoxy)acetyl-amino]-benzamide as a white solid (95.2 mg, 84.9% yield).