Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:13][CH2:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:16])=O)C1C=CC=CC=1.C(O)(=O)C.C([O-])=O.[NH4+]>CO.O.[C].[Pd]>[NH2:11][C@@H:12]([C:31]([OH:33])=[O:32])[CH2:13][CH2:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:16]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](N)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
An aliquot (5.0 g) of this ester was suspended in a mixture of 100 ml of methanol and 30 ml of water, and 5 ml of acetic acid, 4.6 g of ammonium formate and 0.5 g of 10% palladium-carbon were added to the suspension. The mixture was stirred at 50° C. for 1 hour. The catalyst was removed by filtration. The mother liquor was adjusted to pH 7 and concentrated. The residual solution was cooled. The precipitated crystals were collected by filtration and recrystallized from ethanol/water (1/1) to give 2.2 g of ethyl 1-(gamma-D-glutamyl)indoline-2(S)-carboxylate (mp. 197°-200° C., decomp.). An aliquot (2.0 g) of this ester and 0.66 g of sodium carbonate were dissolved in 25 ml of water, and a solution of 3.3 g of N2 -benzyloxycarbonyl-N6 -t-butoxycarbonyl-L-lysine N-hydroxysuccinimide ester in 25 ml of THF was added. The mixture was stirred overnight at room temperature. Tetrahydrofuran was evaporated, and 5% aqueous potassium hydrogensulfate solution was added. The precipitated crystals were collected by filtration and recrystallized from ethanol/ether to give 3.3 g of ethyl 1-(N2 -benzyloxycarbonyl-N6 -t-butoxycarbonyl-L-lysyl-gamma-D-glutamyl)indoline-2(S)-carboxylate. An aliquot (0.7 g) of this ester was stirred with 10 ml of trifluoroacetic acid under ice cooling for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to CHP20P column chromatography (0%→50% acetonitrile/water gradient). Fractions containing the desired product were concentrated, and the precipitated crystals were collected by filtration to give 0.34 g of the captioned compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[C:16]([OH:18])=O.[CH3:19][OH:20].[C:21]([O-])(O)=O.[Na+]>ClCCl.O.O>[CH3:19][O:20][C:16]([C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:21])=[O:14])[CH:11]=[CH:12][N:7]=1)=[O:18]
Reactant: CO
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccnc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
PCl5 (39 g; 0.186 mol; 3 eq) and pyridine-2,4-dicarboxylic acid (11.5 g; 6.2×10−2 mol) are introduced into a 500 mL flask. The mixture is stirred at ambient temperature for 45 minutes: it forms a green liquid. It is then diluted with dichloromethane (80 mL) then methanol is added (20 mL) with caution. The whole is poured into water H2O (300 mL) containing 60 g of NaHCO3, the aqueous phase is washed with dichloromethane (4×50 mL) and the organic phase is washed with 1M Na2CO3 (2×50 mL). The crude product is purified by flash chromatography (eluent: 75:25 AcOEt/cyclohexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:38][C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of the compound (1.2 g) obtained in step 4 in toluene (9 mL) were added DPPA (1.06 mL) and triethylamine (0.68 mL) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled, 8N aqueous sodium hydroxide solution (4.2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried, and the solvent was evaporated under reduced pressure to give tert-butyl (3S,4R)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (1.06 g, 96%) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]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:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1[C:35](OC)=[O:36].C(OCC)(OCC)OCC.COC1C(N)=CC=CC=1>C(O)(=O)C>[CH3:35][O:36][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: COc1ccccc1N
Product: COc1ccccc1-n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 71 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), o-anisidine (201 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 204 mg (0.61 mmol, 71% yield) of the title compound.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].C1C=CC2N(O)N=NC=2C=1.[NH2:40][C@H:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CC(C)N=C=NC(C)C>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C@H:2]([C:10]([NH:40][C@H:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccccc1
Reactant: CC(=O)NCSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)NCSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Fmoc-Cys(Acm)-OH (855 mg, 2 mmol) in 4 ml dry DCM at 0° C., HOBt (270 mg, 2 mmol) was added. Then an ice-cold solution of H-Phg-OtBu (415 mg, 2 mmol) in 4 ml of dry DCM was added. Subsequently, DIC (319 μl, 2 mmol) was introduced dropwise. After 1 h at 0° C. and 4 h at 4° C., the solution was evaporated under vacuum. The residue was dissolved in 50 ml EtOAc and washed with sat. aq. NaHCO3, 0.5 M HCl and water. After drying and evaporation of the organic phase, the residue was chromatographed on silica gel to give the protected dipeptide 1 as a foam. Yield 1.14 g (95%), Rf 0.35 (DCM/MeOH, 95:5). 1H NMR (CDCL3): δ1.45 (9H, s, tBu), 1.92 (3H, s, CH3 Acm), 2.71-3.1 (2H, m, CβH2 Cys), 3.8 (1H, m, CoH Cys) 4.2-4.5 (5H,m, CH2 Acm. CH—CH2 Fmoc), 4.56-4.85 (3H, m, CoH Phg, Fmoc), 5.4 (1H, d, J=7.3 Hz, NH) 6.47 (1H, d, J=8.4 Hz, NH), 7.2-8.05 (14H, Fmoc+Phg aromatic, NH Acm). 13C NMR (CDCl3): δ23.7 (CH2, Acm), 27.7 (3×CH3, tBu), 34.9 (Cβ, Cys), 41.1 (CH2, Acm), 41.9 (CH2, Fmoc), 57.4 (CαPhg), 83.7 (Cq tBu), 119.7-127.5 (aromatic, Fmoc, Phg), 141.0 and 143.6 (4C, Fmoc), 156.6 (CO, Fmoc), 170.2 (CO, Cys), 173.5 (2×CO, Acm, tBu ester).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@H:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].N1C=CN=C1>C(Cl)Cl>[Si:5]([O:9][C@H:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
tert-Butylchlorodimethylsilane (547 g, 3.63 mol) was added to a stirred solution of (R)-ethyl 3-hydroxybutanoate (400 g, 3.03 mol) in DCM (800 mL) under nitrogen at 0° C. Imidazole (412 g, 6.05 mol) was added portion wise over 20 min to the reaction mixture during which time the mixture became a thick white slurry. Additional DCM (175 mL) was added and the mixture was allowed to warm to room temperature and stirred for 16 h. The white solid was removed by filtration, rinsed with DCM (500 mL), partitioned between water (1 L) and DCM (500 mL), and the aqueous layer was further extracted with additional DCM (500 mL). The filtrate was combined with the organic layers and washed with water (500 mL) and brine, dried over MgSO4 and filtered. The product was concentrated and dried under high vacuum to yield (R)-ethyl 3-(tert-butyldimethylsilyloxy)butanoate (777.5 g), containing unidentified impurities. The analytical data of the crude product complied with data reported in the literature. The material was used without additional purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)CCCCl
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 107) and chloropropanesulfonyl chloride (Aldrich) in an analogous manner as described in Example 177. HR-MS (ES, m/z) calculated for C20H25N5O4SF2Cl [(M+H)+] 504.1279, observed 504.1284.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]1[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=1[O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O)[CH3:8].[OH2:32].C1C=CC=CC=1.[O:39]1CCCC1>>[C:11]([OH:12])(=[O:39])[C:10]([OH:9])=[O:32].[CH2:7]([O:9][C:10]1[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=1[O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:8]
Reactant: C1CCOC1
Reactant: CCOc1ccccc1OCCNCCC(=O)Nc1ccc(F)cc1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccccc1
Product: CCOc1ccccc1OCCNCCCNc1ccc(F)cc1
Product: O=C(O)C(=O)O

Procedure:
To a mixture of 0.35 g of lithium aluminum hydride and 15 ml of tetrahydrofuran, there was added dropwise a solution of 2.05 g of 3-{2-(2-ethoxyphenoxy)ethylamino}-p-fluoropropionanilide in 20 ml of tetrahydrofuran. Then, the resulting mixture was refluxed for 3 hours. To the reaction mixture cooled in ice, there were gradually added water and benzene. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was dissolved in isopropanol, and a warm solution of 0.8 g of oxalic acid in 10 ml of isopropanol was added thereto. After cooling, the precipitate was collected by filtration and dried to give N-{2-(2-ethoxyphenoxy)ethyl}-3-(4-fluoroanilino)propylamine hydrogen oxalate, M.P. 193°-196° C (decomp.). Recrystallization from methanol gave white crystals, M.P. 218°-219° C (decomp.).
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[C:8]([F:13])=[CH:7][CH:6]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>>[F:13][C:8]1[C:9]([CH:11]=[O:12])=[N:10][C:5]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1nc(Br)ccc1F
Reactant: OB(O)c1ccco1
Agent: OBO
Product: O=Cc1nc(-c2ccco2)ccc1F

Procedure:
3-fluoro-6-(furan-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure with 6-bromo-3-fluoropicolinaldehyde and furan-2-ylboronic acid (41 mg, 94 mg theoretical, 43.6%). LC-MS m/z 192 (M+1).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28])=O)(=O)OC.O.[NH2:32][NH2:33]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:32]=[N:33][C:2]3[CH:1]4[CH2:8][CH2:7][CH:4]([C:3]=3[CH:17]=2)[CH2:5][CH2:6]4)=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=1
Reactant: COP(=O)(CC(=O)c1ccc(F)cc1C(F)(F)F)OC
Reactant: O=C1C(=O)C2CCC1CC2
Reactant: NN
Solvent: O
Product: Fc1ccc(-c2cc3c(nn2)C2CCC3CC2)c(C(F)(F)F)c1

Procedure:
White solid MS (ESI): 323.1 (MH+). Prepared from bicyclo[2.2.2]octane-2,3-dione, [2-(4-fluoro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]([C:5]1[N:6]([C:20]([OH:22])=[O:21])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[C:8]=2[CH3:19])([CH3:4])([CH3:3])[CH3:2].BrN1C(=[O:29])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]([C:20]([OH:22])=[O:21])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([C:15]([F:17])([F:18])[F:16])[C:8]=2[CH:19]=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(F)(F)F)c(Br)cc2cc(C(C)(C)C)n(C(=O)O)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc2cc(Br)c(C(F)(F)F)c(C=O)c2n1C(=O)O
Temperature: 90 °C
Reaction time: 18 h
Yield: 20.9 %

Procedure:
To a mixture of tert-butyl 5-bromo-7-methyl-6-(trifluoromethyl)-1H-indole-1-carboxylic acid (1.2 g) and carbon tetrachloride (20 mL) were added N-bromosuccinimide (0.70 g) and 2,2′-azobis(2-methylpropionitrile) (20 mg) at room temperature. The reaction mixture was stirred at 90° C. for 18 hours. The reaction mixture was left to be cooled to room temperature and filtered through Celite to remove the insoluble materials. The filtrate was evaporated under reduced pressure, and to the residue was added acetonitrile (20 mL), followed by addition of 4-methyl morpholine-4-oxide (0.50 g) under ice-cooling. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain tert-butyl 5-bromo-7-formyl-6-(trifluoromethyl)-1H-indole-1-carboxylic acid (0.26 g).
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([O:36]CC)=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][C:34]([OH:36])=[O:35])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc21
Yield: 85 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide dihydrochloride and sodium hydroxide solution. Yield: 85% of theory, C24H22N6O4 (458.5); EKA mass spectrum: (M+H)+=459; (M+Na)+=481; (M+2Na)++=252.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2CC2C=CC(OC)=CC=2)=[CH:4][CH:3]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 23.9 using 4-(4-chlorophenyl)-1-cyclopropyl-5-(4-methoxybenzyl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.5) under MW irradiation 140° C. for 2 hr. tR: 4.22 min (HPLC 1); tR: 0.94 min (LC-MS 2); ESI-MS: 288 [M+H]+ (LC-MS 2); Rf=0.31 (Hexane/EtOAc 1:1).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h

Procedure:
To a mixture of NaH (60% in oil, 60.9 g, 1.52 mol) in DMF (1500 mL) is carefully added crude (1,4-dioxa-spiro[4.5]dec-8-yl)methanol (150 g) in DMF (50 mL) at 10° C. under argon atmosphere and the mixture is stirred for 1 hour at the same temperature. To the mixture is added benzyl bromide (181 mL) 10° C., and stirring is continued for 3 hours at room temperature. After addition of H2O (70 mL) over 10 min, the mixture is poured into the mixture of H2O (4500 mL) and EtOAc (2000 mL). The water layer is extracted with EtOAc and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford crude 8-benzyloxymethyl-1,4-dioxa-spiro[4.5]decane as a yellow oil. The crude product is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1.[H][H]>C1COCC1.CO.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cn1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2c(N)cnc3ccc(Br)cc23)cn1

Procedure:
6-bromo-N-(6-methoxypyridin-3-yl)-3-nitroquinolin-4-amine (compound of step 2, 13.3 mmol) was hydrogenated using Raney-Ni (1 g) in THF-MeOH [(1:1), 50 mL] under 40 psi of hydrogen for 4 h at RT. After completion of the reaction, the reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 3H), 7.47 (dd, J=2.1, 9.0 Hz, 2H), 6.93 (dd, J=3.0, 8.7 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 5.42 (s, 2H), 3.85 (s, 3H); MS (m/z): 345.0 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCc2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
To 9.5 g of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (42 mmol), prepared according to the method described in Synth. Comm. 1994, 2777, dissolved in 100 ml of ethanol, there are added, at 0° C. and in two portions, 0.8 g of sodium borohydride (21 mmol). The reaction mixture is then allowed to come back up to ambient temperature over 30 minutes, and then the ethanol is evaporated off. The residue is taken up in 100 ml of toluene and 100 ml of water. After separation, the aqueous phase is extracted with 50 ml of toluene. The toluene phases are combined, washed with a saturated aqueous solution of sodium chloride and are then evaporated to yield 7-bromo-1,2,3,4-tetrahydronaphth-1-ol in the form of an oil.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][CH2:9][CH:7]([OH:8])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: O=CC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(CCN)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CCNCC(O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
Phenyl glyoxal (0.8 g) and 2-(4-carbomethoxyphenyl) ethanamine (1.1 g) were heated in refluxing benzene (100 ml) under a Dean and stark head until the theoretical amount of water had been collected. The solvent was replaced with methanol and sodium borohydride (2.0 g) was added portionwise with ice cooling. The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The dried organic extract was evaporated and crystallised from benzene/hexane, mp 105°-106°. (CDCl3) 6.80-7.60 (8H, m), 6.18 (3H, s), 5.34 (1H, m), 2.94 (2H, d, J=8 Hz), 2.77 (5H, m), 2.09 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[NH:9][CH:8]=[CH:7][C:6]2=O.S(Cl)([Cl:26])=O>CN(C=O)C>[ClH:26].[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Product: Cl
Yield: 93 %

Procedure:
A solution of 6-methoxy-7-(3-morpholinopropoxy)-1,4-dihydroquinolin-4-one (200 mg, 0.63 mmol) in thionyl chloride (10 ml) containing DMF (3 drops) was heated at reflux for 1 hour. After removal of the volatiles by evaporation, the residue was azeotroped with toluene, triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride (240 mg, 93%).