Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:10][CH:9]=[N:8][C:7]2[C:3]=1[N:4]=[CH:5][N:6]=2.O[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21].C(N(CC)C(Cl)=O)C>CC#N>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21]
Reactant: Clc1[nH]cnc2ncnc1-2
Reactant: CCCC1CC(=O)N(CO)C1
Agent: CCN(CC)C(=O)Cl
Solvent: CC#N
Product: CCCC1CC(=O)N(Cn2cnc3c(Cl)ncnc32)C1
Temperature: 100 °C
Yield: 99 %

Procedure:
A mixture of 6-chloro-1H-purine x165 (2 g, 12.93 mmol, 1 eq), 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (2.44 g, 15.53 mmol, 1.2 eq) and N,N-diethylcarbamoylchloride (332 mg, 1.293 mmol, 0.1 eq) in MeCN (30 ml) is heated at 100° C. in microwave apparatus during 5 hours. After cooling, the solvent is evaporated and the crude is purified on silicagel (CH2Cl2/MeOH (+NH4OH 10%) 95/5) to yield 3.8 g of 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x166 as a pale yellow solid.
Reaction SMILES: N([O-])=O.[Na+].Cl.C([NH:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])(=O)N>>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]([C:11]([OH:13])=[O:12])[NH2:9])=[CH:19][CH:18]=1
Reactant: NC(=O)NC(C(=O)O)c1ccc(O)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: NC(C(=O)O)c1ccc(O)cc1

Procedure:
The supernatant solution obtained by centrifuging the reaction mixture was lyophilized, and the residue was extracted with ethanol. After removing insoluble materials by filtration, to the ethanol solution was added ethyl acetate in the weight ratio of ethyl acetate to ethanol of 2:1, and further added about 1.5 equivalents of dicyclohexylamine to give a white precipitate of dicyclohexylamine salt of N-carbamoyl-2-(4-hydroxyphenyl)glycine. The white precipitate was taken out, and was caused to react with 1.1 equivalents of sodium nitrite in an aqueous medium under acidic conditions with hydrochloric acid at room temperature for 1 hour. Then the resulting reaction mixture was passed through a column of a strongly acidic cation exchange resin of H-type (commercially available under the registered trademark "Amberlite IR-120B" made by Rohm & Haas Co.) to adsorb the produced 2-(4-hydroxyphenyl)glycine on the resin. After eluting with 1.5 N NH4OH, crystalline 2-(4-hydroxyphenyl)glycine was isolated by concentrating the eluate under reduced pressure. These procedures were repeated on each reaction mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:21][CH2:20][CH2:19][C:16]3[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=3)=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Brc1ccc(C2CC2)cc1
Product: FC(F)(F)c1ccc(CCNc2ccc(C3CC3)cc2)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-cyclopropyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 307.2 [M+H]+) was prepared from 1-bromo-4-cyclopropyl-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.Cl>CCO.O.O>[CH2:3]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Yield: 62.3 %

Procedure:
KOH (6.16 g, 109.78 mmol) and benzyl bromide (9.42 g, 55.08 mmol) were added to a stirred solution of 4-hydroxy benzoic acid (6.9 g, 49.96 mmol) in EtOH:H2O (9:1, 176 mL) and the resulting mixture was heated to reflux for 20 hrs. 20% KOH solution (60 mL) was then added the mixture maintained at reflux for 4 hours. The reaction mixture was diluted with water (200 mL) and acidified with 20% HCl. The resulting white precipitate was filtered and washed with water followed by hexane to afford 7.1 g (62.2% yield) of 4-benzyloxy benzoic acid. 1H NMR (DMSO-d6): δ 12.6 (s, 1H), 7.9 (d, 2H), 7.4 (m, 5H), 7.1 (d, 2H), 5.2 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]=[CH:3][C:2]=1[C:12]([O:14]CC)=O.O.[NH2:18][NH2:19]>C(O)C>[NH:18]([C:12]([C:2]1[N:1]=[CH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1)=[O:14])[NH2:19]
Reactant: CCOC(=O)c1cnc(C(=O)OCC)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(C(=O)NN)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A mixture of diethyl pyrazine-2,5-dicarboxylate (1.75 g, 7.81 mmol) and ethanol (15 mL) was heated to 75° C. to obtain a homogeneous solution. After cooling to room temperature, a solution of hydrazine monohydrate (0.281 g, 7.03 mmol) in ethanol (3.5 mL) was added to the solution dropwise over 4 hours. After stirring at room temperature overnight, a solid had precipitated out of the reaction mixture. The solid was collected by filtration and dried under vacuum to give the title compound (1.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C@H:27]([NH2:30])[CH2:28][OH:29]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:30][C@@H:27]([CH3:26])[CH2:28][OH:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: C[C@H](N)CO
Solvent: CN(C)C=O
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and S-(+)-2-amino-1-propanol employing methods similar to those described in Example 2 and using N,N-dimethylformamide as the reaction solvent. The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ tautomers are observed 11.71 (1H, br s), 10.71 (1H, br s), 10.05 (1H, br s), 8.18 (0.59H, s), 8.14 (0.41H, s), 7.36-7.23 (3H, m), 7.14-7.08 (2H, m), 4.78 (1H, t, J=5 Hz), 3.98 (2H, s), 3.97-3.95 (1H, m), 3.49-3.41 (1H, m), 3.26-3.21 (1H, m), 1.13 (1.62H, d, J=6.6 Hz), 1.08 (1.388H, d, J=6.6 Hz); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1356.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7]([C@H:4]1[CH2:5][CH2:6][C@@H:2]([NH2:1])[CH2:3]1)=[O:9]
Reactant: CO
Reactant: N[C@@H]1CC[C@H](C(=O)O)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-aminocyclopentanecarboxylic acid (1.0 g, 7.4 mmol) in dry MeOH (10 mL) under N2 at 0° C. was added thionyl chloride (2.7 mL, 36.8 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo. The resultant residue was washed with anhydrous diethyl ether (3×30 mL) and dried under high vacuum to afford 1.87 g of (1S,3R)-3-amino-cyclopentanecarboxylic acid methyl ester as the HCl salt that was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:4]=1)[CH3:2].[H-].[Na+].CN(C=O)C.[CH3:26][N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[N:29]=[C:28]1S(C)(=O)=O>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:28]3[N:27]([CH3:26])[C:31]4=[N:32][CH:33]=[CH:34][CH:35]=[C:30]4[N:29]=3)=[CH:14][CH:13]=2)[N:4]=1)[CH3:2]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCc1nn(-c2ccc(O)cc2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1nn(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 4-(3-ethyl-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (120 mg) obtained in Example 8, step D), sodium hydride (60% in oil, 20.1 mg) and DMF (5.0 ml) was added 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (106 mg), and the mixture was stirred under microwave irradiation at 180° C. for 1 hr. The reaction mixture diluted with methanol, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[CH:4]1[C:3]2=[C:2]3[C:3]([C:10]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=5)[CH:13]=[CH:12][CH:11]=4)=[CH:2][CH:1]=[CH:6][C:1]3=[CH:6][CH:5]=1.[NH:8]1[CH:1]=[CH:2][N:7]=[CH:10]1
Reactant: Clc1cccc2ccccc12
Reactant: Nc1ccccc1N
Product: c1c[nH]cn1
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54

Procedure:
39.2 g of perylene-3,4,9,10-tetracarboxylic acid dianhydride, 32.4 g of o-phenylenediamine and 800 ml of α-chloronaphthalene were mixed, and the mixture was reacted at 260° C. for 6 hours. After the reaction product was left to cool, deposited crystals were collected by filtration, and were then repeatedly washed with methanol, followed by heating and drying to obtain 51.1 g of an imidazole perylene compound as a mixture of the compounds of Structural formulas 1 and 2. The product thus obtained was called a synthesized product, whose X-ray diffraction spectrum was as shown in FIG. 3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19]>>[C:21]([O:20][C:18](=[O:25])[NH:19][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cccc(-c2nc3cc(Br)ccn3n2)n1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Yield: 32.5 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.44 g, 4.91 mmol) and tert-butyl carbamate (691 mg, 5.9 mmol) as starting materials. The reaction affords [2-(6-fluoro-pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (526 mg, 32.5%), as off-white crystals. MS: m/z=330.0 (M+H+).
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]12([C:11]3[CH2:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2.[CH3:16][C:17](C)=O.O>CO.C(OCC)C>[CH:15]12[CH2:14][CH:13]([CH2:16][CH2:17]1)[CH2:12][CH:11]2[C:4]1[CH:9]=[CH:8][C:7](=[C:6]([CH3:5])[CH3:1])[CH:10]=1
Reactant: C1=CCC(C23CCC(CC2)C3)=C1
Reactant: CC(C)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC(C)=C1C=CC(C2CC3CCC2C3)=C1

Procedure:
Sodium methoxide (4.00 g, 74.0 mmol) was added to a solution of norbornylcyclopentadiene (8.00 g, 49.9 mmol) in 50 mL methanol. Acetone (15.8 g, 270 mmol) was added and the reaction stirred for 48 hours when 200 mL water and 100 mL diethyl ether were added. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (4×50 mL). The organic layers were dried over MgSO4, filtered, and rotavapped to provide the crude product as a yellow oil, which was purified by in vacuo drying and passing through a short column of alumina: 8.18 g (81.8%). MS (GC-MS) m/z 200.3 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH:7]=1)=[O:2].Cl>O1CCOCC1>[CH:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)Cn1cc(C=O)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1cnn(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl 2-(4-formylpyrazol-1-yl)acetate (0.67 g, 3.19 mmol) in dioxane (10 mL) was added a 4N solution of HCl in dioxane (10 mL) and the mixture was stirred at room temperature for three days. The solvent was removed by evaporation under reduced pressure to afford the title compound (0.41 g, 98%) as a yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[N:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:21]([NH:24][OH:25])=[NH:22])[CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C#N)n2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C(=N)NO)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A mixture of N-tert-butyl-3-(6-cyano-pyridin-2-yl)-benzenesulfonamide (example B.13) (1.03 g, 3.27 mmol), hydroxylamine hydrochloride (794 mg, 11.4 mmol) and sodium carbonate (692 mg, 6.53 mmol) in EtOH (20 ml) and water (20 ml) was stirred under argon atmosphere at 100° C. for 2 h. The EtOH was evaporated, the mixture was diluted with water and stirred for 1 h at 0° C. The crude product was filtered and dried in HV to give the pure title compound as a white solid (850 mg, 75%). MS (ISP) 349.3 [(M+H)+].
Reaction SMILES: [CH:1]1([C@H:7]([CH2:20][CH:21]=[CH2:22])[CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:23]#[N:24].[Na+].O>CS(C)=O>[CH:1]1([C@H:7]([CH2:20][CH:21]=[CH2:22])[CH2:8][C:23]#[N:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC[C@H](COS(=O)(=O)c1ccc(C)cc1)C1CCCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CC[C@H](CC#N)C1CCCCC1
Temperature: 90 °C

Procedure:
To the crude product, (S)-toluene-4-sulfonic acid 2-cyclohexyl-pent-4-enyl ester, in DMSO (40 mL) was added NaCN, and the resulting mixture was heated at 90° C. for 1.5 h. The reaction mixture was cooled to room temperature and treated with H2O (20 mL). The reaction mixture was then extracted with diethylether (3×25 mL), dried (MgSO4) and concentrated in vacuo to yield a residue which was purified by Kugelrohr distillation (0.19 mm Hg, 80-90° C.) to yield (R)-3-cyclohexyl-hex-5-enenitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:6]([CH:8]=1)[NH2:7].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:6]([NH:7][S:29]([C:21]2[O:20][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH:22]=2)(=[O:30])=[O:31])[CH:8]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1SCc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 69 %

Procedure:
Following General Procedure B, the title compound (485 mg, 69%) was prepared from 5-chloro-2-((2-nitrobenzyl)thio)aniline (435 mg, 1.48 mmol) and benzofuran-2-sulfonyl chloride (320 mg, 1.48 mmol) in pyridine (5 ml).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:24][C:23]4[N:25]=[C:26]5[C:31](=[CH:32][C:22]=4[CH2:21][C@H:20]2[CH2:19][N:18](C(OC=C)=O)[CH2:17][CH2:16]3)[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O>CO.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:24][C:23]4[N:25]=[C:26]5[C:31](=[CH:32][C:22]=4[CH2:21][C@H:20]2[CH2:19][NH:18][CH2:17][CH2:16]3)[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=COC(=O)N1CC[C@@]2(c3cccc(OCc4ccccc4)c3)Cc3nc4ccccc4cc3C[C@H]2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(COc2cccc([C@@]34CCNC[C@@H]3Cc3cc5ccccc5nc3C4)c2)cc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
(4aR, 12aR)-4a-(3-benzyloxyphenyl)-2-vinyloxycarbonyl-1,2,3,4,4a,5,12,12a-octahydroquinolino[2, 3-g]isoquinoline (181 mg, 0.369 mmol) was dissolved in a 10% hydrogen chloride methanol solution (6 ml), and the resultant solution was heated under reflux for 1 hour. After the solution was cooled to 0°C., an aqueous saturated sodiumbicarbonate solution (30 ml) and water (150 ml) were added to the solution, followed by extraction with chloroform (200 ml, 2 times). The organic layers were dried, and then concentrated to obtain the target compound (155 mg). The thus-obtained compound was supplied to next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][O:21][CH2:22][C:23]([CH3:27])([OH:26])[C:24]#[CH:25]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:25]#[C:24][C:23]([OH:26])([CH3:27])[CH2:22][O:21][CH3:20])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(O)COC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(O)COC)nc21

Procedure:
A suspension of 3 g (10.69 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 20 ml of a DMF/Et3N mixture (V/V; 1/1) is placed in an 80 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 1.83 g of (±)-1-methoxy-2-methyl-3-butyn-2-ol (16.03 mmol), 0.081 g of CuI (0.43 mmol) and 0.375 g of bis(triphenylphosphine) palladium(II)dichloride (0.53 mmol) are successively added.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[CH3:18][O:19][C:20](=[O:45])[N:21]=[C:22]([S:43][CH3:44])[C:23](=[N:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1)[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([OH:32])[C:25]=1[F:33].O>CN(C=O)C.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:45])[N:21]=[C:22]([S:43][CH3:44])[C:23]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:25]=1[F:33])=[N:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(O)c1F
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
After adding 1.8 g of potassium carbonate and 3 g of (2-bromoethoxy)-t-butyldimethylsilane to a solution of 3.45 g of [2-(4-cyanophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (163b)) in 10 ml of DMF, the mixture was stirred at 50° C. for 5 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (3.73 g, isomeric mixture) as a light yellow solid.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Br:26]Br.O>ClCCl>[Br:26][CH:9]([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: O=C(CCCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)CCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 11.5 g. of 1-(4-benzoylbutyryl)-L-proline (Example 41) in 115 ml. of acetic acid is added dropwise a solution of 6.4 g. of bromine in 25 ml. of acetic acid. The mixture is stirred for 18 hours, reduced to 1/3 its volume, poured into ice and water and extracted with dichloromethane. The organic extract is washed with water and saline, dried over magnesium sulfate and evaporated in vacuo to a yellow gum. This gum is dissolved in dichloromethane, placed on a 11/2"×24" column of silica gel which has been wet with dichloromethane and eluted with ethyl acetate:acetic acid (1:1) taking 100 ml. cuts. Cut number 7 gives 2.1 g. of solid which is dissolved in dichloromethane, filtered through celite and evaporated to dryness giving the desired product as 2.0 g. of an orange gum.
Reaction SMILES: C[N:2]([CH:4]=O)[CH3:3].P(Cl)(Cl)(Cl)=[O:7].[NH:11]1C2[C:14](=[CH:15][C:16]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>ClC(Cl)C>[OH:7][N:11]=[CH:12][C:13]1[C:14]2[C:3](=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:15]=2)[NH:2][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)COc1ccc2[nH]ccc2c1
Solvent: CC(Cl)Cl
Product: CCOC(=O)COc1ccc2[nH]cc(C=NO)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 31.2 %

Procedure:
To DMF (1.74 gm, 0.023 moles) cooled to 0° C. under nitrogen atmosphere, Phosphorous oxy chloride (3.5 gm, 0.022 moles) was added in portions and stireed for 15 mins. To this was added a solution of the product of step 1 (2.5 gm, 0.011 mole) in dichloro ethane (18 ml) at 0° C. and heated to 80° C. for 2 hrs. The solvents were evaporated under reduced pressure. The residue was dissolved in water, basified with NaOH and extracted with ethyl acetate. The ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography (eluent: 40% EtOAC in hexane) to yield 900 mg (31%) of product as solid.
Reaction SMILES: C(N(CCC)[C:5]([CH2:7][O:8][C:9](=[O:44])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([N:22]2[CH2:43][CH2:42][C:25]3([NH:29]/[C:28](=[N:30]/[C:31]([C:33]4[C:38]([NH2:39])=[N:37][C:36]([NH2:40])=[C:35]([Cl:41])[N:34]=4)=[O:32])/[NH:27][CH2:26]3)[CH2:24][CH2:23]2)=[O:21])=[CH:14][CH:13]=1)=[O:6])CC.BrCC([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=O>>[C:53]([O:52][C:5]([CH2:7][O:8][C:9](=[O:44])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([N:22]2[CH2:23][CH2:24][C:25]3([NH:29]/[C:28](=[N:30]/[C:31]([C:33]4[C:38]([NH2:39])=[N:37][C:36]([NH2:40])=[C:35]([Cl:41])[N:34]=4)=[O:32])/[NH:27][CH2:26]3)[CH2:42][CH2:43]2)=[O:21])=[CH:16][CH:17]=1)=[O:6])([CH3:56])([CH3:55])[CH3:54]
Reactant: CCCN(CCC)C(=O)COC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1

Procedure:
The title compound was prepared analogously to [4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid dipropylcarbamoylmethyl ester (Ex. 2.0) by replacing 2-chloro-N,N-dipropyl-acetamide with t-butyl bromoacetate; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (1H, br), 8.37 (1H, br), 7.16 (2H, d), 6.85 (2H, d), 6.8-6.6 (2H, br), 4.83 (2H, s), 4.64 (2H, s), 3.61 (1H, m), 3.58 (1H, m), 3.39 (2H, s), 3.38 (1H, m), 3.30 (1H, m), 2.75 (2H, t), 2.59 (2H, t), 1.60 (4H, m), 1.42 (9H, s). LC-MS Rt 4.27 mins; 645.3 [M+H]+, Method 10minLC_v002.