Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[NH:5][C:6](OCC1C=CC=CC=1)=[O:7].[N:22]1[NH:23][N:24]=[N:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:51]=[CH:50][C:36]2[N:37]([CH:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])C(O)=O)[CH:38]=[N:39][C:35]=2[CH:34]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[O:7]=[C:6]([NH:5][C@H:4]([C:3]([OH:21])=[O:2])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:40]([N:37]1[C:36]2[CH:50]=[CH:51][C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]3[N:25]=[N:24][NH:23][N:22]=3)=[CH:34][C:35]=2[N:39]=[CH:38]1)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: COC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Product: CCCCCCC(C(=O)N[C@@H](CCCCN)C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Yield: 13.9 %

Procedure:
N-carbobenzyloxy-L-Lysine methyl ester (1.0 mmoles, 0.295 g) and 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.0 moles, 0.405 g) were reacted with 1.0 moles of hydroxybenzotriazole and dicyclohexylcarbodiimide as in Example 37. The stereoisomers were separated on silica gel eluted with 5% EtOH in chloroform with 1% acetic acid. Each was hydrolyzed with sodium hydroxide as in Example 37 and hydrogenated to remove the carbobenzyloxy group in ethanol over 5% Pd/C for 4 hours. The catalyst was removed by filtering through celite. The solvent was removed in vacuo to yield 74 mg of N-[1-Oxo-2-[5-[2-(2H-tetrazol-5-yl]phenyl]-1H-benzimidazol-1-yl]octyl]-lysine. Isomer A (MS)
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:19]=1.[Br:20][CH2:21][CH2:22][CH2:23]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[Br:20][CH2:21][CH2:22][CH2:23][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:19]=1
Reactant: Oc1ccc2c(c1)C(N1CCCCC1)CCO2
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: BrCCCOc1ccc2c(c1)C(N1CCCCC1)CCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Crushed potassium hydroxide (1.15 g) and tetrabutyl ammonium chloride (0.61 g) are added to a solution of the product obtained in Step 3. (4.8 g) in 1,3-dibromopropane (21 ml). The reaction mixture is stirred under nitrogen at RT for 48 hours, diluted with diethyl ether, washed with water and extracted into 5% aq. HCl. The aqueous solution is washed with ether and made alkaline yielding a yellow oil which is taken up in ether, washed, dried, filtered and evaporated to give the desired product as an oil.
Reaction SMILES: [OH-].[Na+].[S].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[N+:16]([C:19]1C=[C:21](C)[C:22](C)=[CH:23][CH:24]=1)([O-])=O.C(OC(C)C)(C)C.[CH:34]([OH:37])([CH3:36])C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:16][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:36]=1[CH:34]=[O:37]
Reactant: CC(C)O
Reactant: Cc1ccc([N+](=O)[O-])cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O
Product: Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
In a 2-l flask, place 48.0 g (1.2 m) of sodium hydroxide pellets, 25.65 g (0.8 m) of sulfur powder, 72.0 g (0.3 m) of sodium sulfide nonahydrate, and 640 ml of distilled water. Heat the mixture with good stirring to about 70 C. to make an orange-red solution. In a 400-ml beaker, place 90.7 g (0.6 m) of 4-nitro-o-xylene, 9.6 g (0.03 m) of tetrabutylammonium bromide and 120 ml of isopropyl alcohol. Warm it to 50 C. with occasional stirring to make a clear pale-yellow solution. Add the solution in the beaker to the mixture in the 2-l flask and use 40 ml of isopropyl alcohol to rinse the beaker and add to the reaction mixture. Heat the mixture with vigorous stirring under gentle reflux (pot temperature 83 C.) for 4.5 hours. Distill off isopropyl alcohol till approximately 200 ml of distillate is collected and pot/vapor temperature reaches to 100 C. Cool the reaction mixture to 20 C. Add 400 ml of propyl acetate and stir vigorously at room temperature for 5 minutes, and let layers settle. Separate off bottom water layer. Add 400 ml of cold water and stir vigorously at room temperature for 5 minutes, and let layers settle. Separate bottom water layer. The propyl acetate solution contains 4-amino-2-methylbenzaldehyde intermediates. Add 61.1 g (0.54 m) of ethyl cyanoacetate, 1.6 g of piperidine, and 4.8 g of acetic acid. Stir the reaction mixture at room temperature for 30 min and then distill off propyl acetate under aspirator vacuum at pot/vapor temperature of 35-40 C. till no distillate comes off. Distillate comes out as an azeotropic mixture of propyl acetate and water with excess of propyl acetate. Add 120 ml of propyl acetate with gentle stirring while cooling to room temperature to get a fine yellow slurry. Add 300 ml of isopropyl ether slowly with a little faster stirring. Stir the product mixture for 20 minutes and let it stand at room temperature for 1 hour. Collect product, wash isopropyl ether, and dry to give 100.5 g (72.7%) of blocked aminobenzaldehyde intermediate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.O(C(C)C)C(C)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), 4-aminothiophenol (8.8 g, 68 mmol) and K2CO3 (11.8 g, 85 mmol) in DMF (150 mL) was heated at 90° C. for 1.5 hours, cooled to room temperature, and then poured into H2O (450 mL) under stirring. The aqueous mixture was extracted with ethyl acetate (400 mL). The extract was washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give the crude produce as orange crystal. The crude product was suspended in 150 mL of i-Pr2O and stirred at room temperature for 1 hour. The crystal was collected by filtration, washed with i-Pr2O and dried at 60° C. for 3 days under reduced pressure gave purified title compound as orange crystal (18.6 g, 90% yield).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:2]4[CH:6]=[CH:5][S:4][C:3]=4[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1sccc1Br
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ccsc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(3-bromo-thiophen-2-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br-].[CH2:2]([NH:6][S:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][PH3+])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]([CH3:5])[CH3:4].[H-].[Na+].[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)(=[O:23])=[O:22]>CN(C=O)C.CCOC(C)=O>[CH2:2]([NH:6][S:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:27]2[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CNS(=O)(=O)c1ccc(C[PH3+])cc1
Reactant: CS(=O)(=O)N1CCC(=O)CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CNS(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of 4-isobutylsulfamoyl-benzyl-phosphonium bromide (1.87 g, 3.29 mmol) in DMF (10 mL) was treated with NaH (60% dispersion in mineral oil, 329 mg, 8.22 mmol) and stirred at room temperature for 1 hour. 1-(Methylsulfonyl)piperidin-4-one (758 mg, 4.28 mmol) was added and the mixture stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) gave N-isobutyl-4-(1-methanesulfonyl-piperidin-4-ylidenemethyl)-benzenesulfonamide (392 mg, 31%). 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 6.43 (s, 1H), 4.40 (t, J=6.5 Hz, 1H), 3.37 (t, J=5.7 Hz, 2H), 3.25 (t, J=5.8 Hz, 2H), 2.82-2.76 (m, 5H), 2.60 (t, J=5.7 Hz, 2H), 2.53 (t, J=5.7 Hz, 2H), 1.80-1.66 (m, 1H), 0.88 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 523.1 [M+Na]+.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[O:11])=[CH:5][CH:4]=1.F[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>CN(C=O)C.C(Cl)Cl.O>[NH:9]([C:10](=[O:11])[CH:12]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
To a suspension of NaH (32 mg, 60% wt. dispersion in mineral oil, 0.80 mmol) in DMF (0.5 mL) at room temperature was added malondianilide (169 mg, 0.67 mmol). The solution was stirred for 20 min and a solution of methyl 6-fluoronicotinate (129 mg, 0.62 mmol) in DMF (1 mL) was added. The reaction mixture was heated to 100° C. for 1 h, cooled to room temperature, and diluted with CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (3×) and the combined extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by reverse phase HPLC (40% to 90% MeCN in water) gave methyl 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinate (66 mg, TFA salt, 21%) as a white solid: ESIMS calcd 390.1 (M++H), found 390.1 (M++H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:7]([C:5]5[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:25]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)c1cn(C)nc1C(F)(F)F
Yield: 59.7 %

Procedure:
In the same manner as in Example 55 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (85.2 mg, 0.439 mmol), tetrahydrofuran (5 mL), thionyl chloride (77.0 μL, 0.888 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (129 mg, 0.399 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (119 mg, 60%) was obtained as a white solid.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][SH:34]>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:34][CH2:33][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: SCCc1ccccn1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(SCCc3ccccn3)C(=O)O2)cc1Cl
Yield: 5 %

Procedure:
The title compound was prepared analogously to Example F(7), Step 6, substituting 3-chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.201 g, 0.52 mmol, described below) in place of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione, and 2-Pyridin-2-yl-ethanethiol in place of 2-mercaptothiazole. Yield: 12.6 mg, 5% yield. 1H NMR (CDCl3) δ: 1.48-1.73 (m, 8H), 1.92-1.98 (m, 2H), 2.34 (p, J=8.32 Hz, 1H), 2.56-2.62 (m, 4H), 2.80-3.01 (m, 4H), 3.80 (s, 3H), 6.76 (d, J=8.32 Hz, 1H), 6.95 (dd, J1=8.48 Hz, J2=2.08 Hz, 1H), 7.09 (d, J=2.24 Hz, 1H), 7.41-7.48 (m, 2H), 7.93 (t, J=7.52 Hz, 1H), 8.52 (d, J=5.12 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].C(N(CC)CC)C>CN(C=O)C.CO.[Cu]I.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>[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[C:25][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(Br)ccc21
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 65 °C
Yield: 68.2 %

Procedure:
To a mixture of 3-(5-bromo-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (467 mg, 1.42 mmol), 1-dimethylamino-2-propyne (473 mg, 5.69 mmol), copper(I) iodide (48 mg, 0.25 mmol), triethylamine (287 mg, 2.84 mmol) in DMF (5 ml), was added tetrakis(triphenylphosphine)palladium (100 mg, 0.086 mmol). The mixture was heated at 65° C. under argon for 16 hours, and then cooled to room temperature. The mixture was diluted with MeOH (100 ml). The insoluble material was removed by filtration, and the filtrate solution was concentrated and then diluted with EtOAc (200 ml). The resulting mixture was washed with brine (3×100 ml), dried over anhydrous Na2SO4, and concentrated to give a dark-brown residue. Purification of the residue by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3, afforded 3-[5-(3-dimethylamino-prop-1-ynyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a brown solid (320 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:10])=[C:4]([F:24])[CH:3]=1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]2[NH:30][C:31](=[O:33])[O:32][C:28]=2[CH:27]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:33]=[C:31]1[NH:30][C:29]2[CH:34]=[CH:35][C:26]([NH:25][C:21]([C:19]3[CH:18]=[CH:17][C:15]4[N:16]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:24])[S:13][C:14]=4[CH:20]=3)=[O:22])=[CH:27][C:28]=2[O:32]1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(Cc1ccc(Cl)cc1F)Nc1nc2ccc(C(=O)O)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1F)Nc1nc2ccc(C(=O)Nc3ccc4[nH]c(=O)oc4c3)cc2s1
Temperature: 25 °C
Yield: 20 %

Procedure:
Starting material 37 (60 mg, 0.2 mmol, 70% content) and 6-Amino-3H-benzooxazol-2-one (30, 25 mg, 0.2 mmol) were dissolved in 2 ml DMF. Then EDCl (38 mg, 0.2 mmol) and HOBt (31 mg, 0.2 mmol) were added. The reaction was stirred over night at ambient temperature, concentrated in vacuo and purified by prep HPLC (Method 1). By concentration of the pure fractions the desired product 38 (23 mg, 0.04 mmol, 24%) could be isolated.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH:10]1[C:22]2[N:21]3[CH:23]=[CH:24][N:25]=[C:20]3[C:19](=[O:26])[NH:18][C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C)C=O>[C:1]([O:5][C:6]([CH:8]=[C:10]1[C:22]2[N:21]3[CH:23]=[CH:24][N:25]=[C:20]3[C:19](=[O:26])[NH:18][C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(O)C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reaction time: 8 h
Yield: 61.2 %

Procedure:
5.85 g of 10-(1-tert-butoxycarbonyl-1-hydroxymethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are heated to 90°-100° C. in 300 ml of dimethylformamide, filtered immediately and 150 ml of methanol and 200 ml of water are added to the filtrate, which is left overnight at a temperature in the region of 5° C. The crystals formed are filtered off, washed with 20 ml of water and dried at 80° C. under vacuum (2 mmHg; 0.26 kPa) to give 3.4 g of 10-(tert-butoxycarbonylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in the form of a red solid melting above 260° C. (Analysis, % calculated C: 68.05, H: 5.11, N: 12.53, O: 14.31, % found C: 68.0, H: 5.6, N: 12.5, O: 14.3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.S(Cl)(Cl)=O.[CH3:36]O>>[CH3:36][O:30][C:29]([CH:25]1[CH2:26][C:27](=[O:28])[N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])=[CH:22][CH:21]=2)[CH2:24]1)=[O:31]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CC(=O)N(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-{4-[4-(2,4-Dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (1.54 g) described in Example 333 was dissolved in methanol (10 mL), thionyl chloride (0.29 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture, and the residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.39 g).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[N:7]=1.O>C1C=CC=CC=1.O.OO.[Ni]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[N:7]=1
Reactant: c1cc(C2=NCCS2)nc(C2OCCO2)c1
Agent: [Ni]
Agent: OO
Solvent: O
Solvent: c1ccccc1
Product: c1cc(-c2nccs2)nc(C2OCCO2)c1
Yield: 31.5 %

Procedure:
10 g of nickel peroxide hydrate are added in 1 g portions over 20 hours to a solution of 1.33 g of 2-(4,5-dihydrothiazol-2-yl)-6-[1,3]dioxolan-2-yl-pyridine (5.62 mmol) in 50 ml of benzene maintained under reflux with removal of the water formed continuously. The insoluble matter is removed by filtration on celite and then the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform/ethyl acetate; 85:15). 0.42 g of a white solid is recovered.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][N:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:16]4)=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN1CCCC(c2ccccc2)C1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CCCC(c5ccccc5)C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-3-phenyl-piperidine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.Cl[CH2:14][C:15](=[O:17])[CH3:16].[I-].[K+]>CC(C)=O>[CH2:14]([O:11][C:4]1[C:3]([F:12])=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[C:15]([CH3:16])=[O:17]
Reactant: CC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(Cl)c(F)c1O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1c([N+](=O)[O-])ccc(Cl)c1F
Yield: 54.5 %

Procedure:
A mixture of 3 g (15.7 mmols) of 3-chloro-2-fluoro-6-nitrophenol, 3 ml of chloroacetone and 300 mg of potassium iodide in 50 ml of acetone was refluxed for 6 hours while vigorously stirring. After cooling, any insoluble substance was removed by filtration, and the filtrate was concentrated and purified by silica gel (20 g) column chromatography using chloroform as an eluant to provide 2.5 g (54.5% yield) of 2-acetonyloxy-4-chloro-3-fluoronitrobenzene as an oil.
Reaction SMILES: C[C:2]1([O:23][C@@H:22]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:4]1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3].[BH4-].[Na+].CC(C)=O.C(O)(=O)C>C(O)C>[CH2:6]([O:5][C@@H:4]([C@@H:13]([C@H:22]([CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:23])[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:2][OH:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1(O)O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Methyl 2,3,5-tri-O-benzyl-L-xylofuranose (11.7 g, 27.92 mmol) is dissolved in ethanol (150 mL) and sodium borohydride (0.844 g, 30.5 mmol) was added. The mixture is stirred 2 hours at 0° C. The reaction is treated successively by acetone and acetic acid. The mixture is concentrated under reduced pressure. The residue is taken with water, extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 1:1 mixture of hexane and ethyl acetate yield 2,3,5-tri-O-benzyl-L-xylitol (10.2 g, 86.5%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15](=[S:17])[NH2:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.Br[CH2:22][C:23](=O)[CH2:24][CH3:25]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[S:17][CH:22]=[C:23]([CH2:24][CH3:25])[N:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: NC(=S)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: CCC(=O)CBr
Solvent: C1COCCO1
Product: CCc1csc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)n1
Reaction time: 2 h

Procedure:
57.5 mg (0.19 mmol) of 4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine (see Example 10) and 34 ml of 1-bromo-2-butanone (Aldrich; Milwaukee/USA) in 3 ml of dioxane are heated to boiling for 2 h. Cooling, filtering the suspension and washing with isopropanol/diethyl ether yields 4-(3-chloroanilino)-6-(4-ethylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=13.6; FAB-MS: (M+H)+=356.