Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][CH:17]([C:18](=[O:19])[NH:20][CH3:21])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CNC(=O)C(N)Cc1ccccc1
Product: CNC(=O)C(Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-methyl-3-phenyl-propionamide to provide the title compound in good yield. LCMS m/z 384 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>C(OCC)C.O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1cccc(F)c1
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a suspension of 3.07 gm (81 mMol) lithium aluminum hydride in 115 mL diethyl ether at 0° C. were added dropwise a solution of 7.0 gm (45 mMol) 3-fluorophenylacetic acid in 26 mL tetrahydrofuran dropwise. The reaction was allowed to warm to ambient and then stirred 18 hours. The reaction mixture was quenched by the addition of 3.0 mL 2N NaOH dropwise with cooling. To this mixture was then added 9.0 mL water and the resulting suspension stirred for 1 hour at ambient. The suspension was filtered and the filter cake rinsed well with diethyl ether, The filtrate was concentrated under reduced pressure to give 6.26 gm (100%) of the title compound as a clear oil. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20](OCCCC)=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:28]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([NH2:28])=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl (5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 350 mg, 0.910 mmol) is treated with 7N ammonia in methanol (9.1 mL) under N2, and the mixture is stirred at ambient temperature for 30 mins. The reaction mixture is then concentrated under reduced pressure, and the residue is recrystallized from EtOAc/hexanes to give the title compound, mp 181–183° C.; MS (ESI+) for C14H15N3O4F2 m/z 328 (M+H)+; [α]25D−23 (c 0.94, DMSO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:18])=[C:10]([C:15](=[O:17])[CH3:16])[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:10]2[CH:11]=[C:12]([O:14][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)[CH:13]=[CH:16][C:15]=2[OH:17])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: CC(=O)c1cc(O)cc(-c2cccc(Br)c2)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(Cc1cccc(Br)c1)c1cc(OC2CCCCO2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a mixture of 3-(3-bromophenyl)-1-(2,5-dihydroxyphenyl)ethanone (4.79 g, 16.2 mmol) and pyridinium p-toluene sulfonate (815 mg, 3.24 mmol) in DCM (100 mL), 3,4-dihydro-2H-pyran (2.2 mL, 24.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and diluted with DCM (100 mL). The solution was washed (100 mL sat'd aqueous NaHCO3), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified on a silica gel column to give 2-(3-bromophenyl)-1-(2-hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone (5.28 g, 83%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.23 (s, 1H), 7.56 (d, 1H), 7.51 (m, 1H), 7.46 (dt, 1H), 7.32-7.24 (m, 3H), 6.92 (d, 1H), 5.42 (t, 1H), 4.46 (s, 2H), 3.80 (m, 1H), 3.55 (m, 1H), 1.96-1.68 (m, 3H), 1.68-1.48 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 70.2 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline (0.087 g, 0.168 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.056 g, 0.118 mmol, 70%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[CH2:15][C:16]([OH:18])=[O:17])=[O:8])=[CH:3][CH:2]=1.[CH3:25][O:26][NH3+:27].[Cl-].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:27][O:26][CH3:25])[CH2:11][C@H:10]2[CH2:15][C:16]([OH:18])=[O:17])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)C[C@@H]1CC(=O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 48.7 %

Procedure:
A solution of [(2S)-1-(biphenyl-4-ylcarbonyl)-4-oxopyrrolidin-2-yl]acetic acid (Intermediate 5, 1.50 g, 6.64 mmol), hydroxylamine methyl ether hydrochloride (0.58 g, 6.96 mmol) and triethylamine (1.62 ml, 11.60 mmol) in chloroforme (30 ml) was stirred at RT for 2 days Solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. Organic phase was washed twice with a solution of citric acid 10% and once with brine. Organic phase was then dried on MgSO4, filtered, and concentrated to give [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid as a cream solid (1.14 g). Yield: 45%. HLPC purity: 92%
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=2)[N:37]=[CH:36][N:35]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:34]2[C:43]3[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(F)c(F)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.27 g, 5.23 mmol) in dry THF (2 mL) was added dropwise over 2 minutes with stirring to 1.01M LiHMDS/THF (5.75 mL, 5.81 mmol) at −78° C. under argon. After 5 min at −78° C., the cold bath was removed and the reaction was allowed to stir at “rt” for 30 min. A portion of this enolate solution (5.1 mL, ˜3 mmol enolate) was added dropwise over 2-3 min to a stirred homogeneous solution of 4-chloro-6,7-difluoroquinazoline (600 mg, 2.99 mmol) in dry THF (3 mL) at 0° C. under argon. The reaction was stirred for 30 min at 0° C., and was then quenched with 1M NaH2PO4 (50 mL) and extracted with EtOAc (1×50 mL). The organic layer was washed with 4M NaCl (1×50 mL), dried (Na2SO4), and concentrated. The residue was purified with silica flash chromatography (3:1 hexanes/EtOAc) to afford the title compound as a yellow oil (451 mg, 37%). LC/MS (ESI): calcd mass 407.2, found 408.2 (MH)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:36]([CH:37]=O)=[C:30]2[CH:29]=1>CO.C1(C)C=CC=CC=1>[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:36]([CH:37]=[CH:2][O:3][CH3:4])=[C:30]2[CH:29]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC=Cc1c(-c2ccc(OC)cc2)nn2ccc(Br)cc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of methoxymethyltriphenylphosphonium chloride (298 mg, 0.87 mmol) in methanol (3 ml) was added a solution of sodium methoxide 25% wt. in methanol (0.20 ml, 0.87 mmol). The resulting white suspension was stirred at 20° C. for 30 minutes. The mixture was concentrated to dryness and azeotroped with toluene (6 ml) twice. The resulting solid was suspended in toluene (2 ml). A suspension of 5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (180 mg, 0.54 mmol) in toluene (4 ml) was added to the ylide suspension. Heated the resulting mixture to 85-90° C. and stirred for 1.25 h. Cooled to 20° C. and stirred 17.5 h. In a separate flask, to a solution of methoxymethyltriphenylphosphonium chloride (298 mg, 0.87 mmol) in methanol (3 ml) was added a solution of sodium methoxide 25% wt. in methanol (0.20 ml, 0.87 mmol). The resulting white suspension was stirred for 30 minutes, concentrated and azeotroped with toluene (6 ml) twice. The resulting solid was suspended in toluene (2 ml) and added to the reaction mixture which was heated to 90° C. for 2 h at which time monitoring the reaction by LC indicated all starting material had converted to the title compound. to the mixture was cooled to 20° C., filtered through a 0.45 μm filter and rinsed with toluene (2 mL). The filtrate was concentrated under reduced pressure to afford a residue that was purified by automated ISCO chromatography (ethyl acetate/hexane; 25/75). The title compound was obtained as a bright yellow solid (168 mg, 86%). LCMS m/z 359.0 (M+H)+, ret. time=2.31 (cis isomer) and 2.34 min (trans isomer).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39](=[O:46])[NH:40][C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35].[Br:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([C:63](O)=[O:64])[CH:61]=3)[C:56]([S:66][CH3:67])=[CH:55]2)=[N:52][CH:53]=1>CN(C=O)C>[Br:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[C:62]3[C:57](=[CH:58][CH:59]=[C:60]([C:63]([N:43]4[CH2:44][CH2:45][C@@H:41]([NH:40][C:39](=[O:46])[O:38][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:42]4)=[O:64])[CH:61]=3)[C:56]([S:66][CH3:67])=[CH:55]2)=[N:52][CH:53]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (2.41 g, 6.363 mmol), diisopropylethylamine (3.02 ml, 17.355 mmol) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.18 g, 6.363 mmol) were added to an ice cooled suspension of 223a) (2.1 g, 5.787 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 16 h and then diluted with ice cold water (40 mL). The precipitate was filtered off, washed with water and hexane (3 times) and dissolved in dichloromethane. The solution was successively washed with saturated ammonium chloride solution (2×30 mL), saturated sodium hydrogen solution (2×30 mL), and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with ether. White solid. Yield: 3 g (97% of theory)
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:17]([O:21][C:22](=[O:23])[NH:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCC1(O)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 12 h
Yield: 36.6 %

Procedure:
To a solution of 4-aminomethyl-1-benzyl-piperidin-4-ol (264 mmol, 58 g) in DCM (200 mL) and saturated NaHCO3 (200 mL) was added di-tert-butylcarbonate (396 mmol, 86.4 g). The reaction mixture was stirred for 12 hours. The layers were separated and the organic layer was washed with brine (50 mL) and evaporated. The product was purified on 1 L of SiO2 using a mixtures of ethyl acetate and DCM to give (1-benzyl-4-hydroxy-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (31 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10])#[N:2].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1C#N
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4C#N)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-cyano-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([S:20](Cl)(=[O:22])=[O:21])=[CH:9][CH:8]=1)(=O)C.[NH3:24].CO>>[OH:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([S:20]([NH2:24])(=[O:22])=[O:21])=[CH:9][CH:8]=1
Reactant: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc12
Reactant: N
Solvent: CO
Product: NS(=O)(=O)c1ccc(CCO)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Solid 4-(2-acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride (39.64 g, 111 mmol) was added to an ice-cold, 6.8 M solution of ammonia in methanol (408 mL, 277 mmol). The cooling bath was removed, the reaction flask was stoppered, and the reaction was stirred at room temperature. After 4 days, the dark amber solution was concentrated under vacuum to a dark gum. The residue was triturated vigorously shaken with water (300 mL) to give a solid which was washed with water (150 mL) then ether (150 mL) and dried under vacuum. The resulting brown solid was recrystallized from isopropanol (300 mL) to afford 4-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide (27.79 g) as tan flakes.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C(O)(=O)C>[C:8]1(=[O:13])[N:1]([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O

Procedure:
A 2 liter nitrogen flushed flask fitted with a mechanical stirrer and a reflux condenser was charged with 103 g (1 mole) of 4-aminobutyric acid (GABA), 148 g (1 mole) of phthalic anhydride and 250 ml of glacial acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ncnn1-c1ccc(N)cc1F
Yield: 75.2 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-5-methyl-1H-[1,2,4]triazole (120 mg, 0.54 mmol) was dissolved in tetrahydrofurane (6 mL) and triethylamine (10 mL) and stirred for 4 hours with 10% palladium on carbon (50 mg) under 3 bar of hydrogen. The reaction mixture was filtered and the solvent was removed in vacuo to yield the title compound (78 mg, 75%) as a yellow solid. MS ISP (m/e): 193.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.93 (s, 1H), 7.16 (dd, 1H), 6.51 (m, 2H), 4.03 (s broad, 2H), 2.38 (s, 3H). Mp 106-108° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[S:7])[NH:4][C:3]1=[O:8].Cl.[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.O.[OH-].[Na+]>CS(C)=O>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:7][C:5]1[NH:6][C:2]([CH3:9])([CH3:1])[C:3](=[O:8])[N:4]=1
Reactant: CC1(C)NC(=S)NC1=O
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)c1ccccc1CSC1=NC(=O)C(C)(C)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 1 g of 5,5-dimethyl-2-thiohydantoin was dissolved in 20 mL of dimethylsulfoxide, and 1.7 g of 2-dimethylaminobenzylchloride hydrochloride was added to the solution. The reaction mixture was stirred at the room temperature for one hour, and poured into 50 mL of water. The pH value of the solution was adjusted to 7-8 with diluted aqueous solution of 2N sodium hydroxide (NaOH). A precipitated sediment was extracted from the liquid, two times, using 50 mL of ethyl acetate (AcOEt). The AcOEt layer was successively washed with 50 mL of water and 50 mL of brine, dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The thus obtained residue was purified by column chromatography [developing solvent=CHCl3 :MeOH=20:1 (volume ratio, v/v)]. Recrystallized from diethyl ether gave the desired compound in the form of needle-like crystal. The yield of the compound was 1.2 g with a yield ratio of 62.4%, and its melting point was 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:5]=[CH:6][CH:7]=1.[C:25]1([S:35](Cl)(=[O:37])=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:35]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][CH:26]=4)(=[O:37])=[O:36])[CH:7]=[CH:6][CH:5]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=C1CC(=O)N(c2cccc(NS(=O)(=O)c3cccc4ccccc34)c2)c2ccc3ccccc3c2N1
Yield: 100 %

Procedure:
By using 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 53, (1), and naphthalene-1-sulfonyl chloride, the title compound (yield 100%) was obtained in the same manner as that of Example 150.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[OH:30])=[C:23]([O:31][CH3:32])[N:22]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:59]([O:66][CH2:67][CH:68](O)[CH2:69][CH2:70][P:71](=[O:78])([O:75][CH2:76][CH3:77])[O:72][CH2:73][CH3:74])([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60]>O1CCCC1>[C:36]([O:35][C:33]([N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[O:30][CH:68]([CH2:67][O:66][Si:59]([C:62]([CH3:64])([CH3:63])[CH3:65])([CH3:60])[CH3:61])[CH2:69][CH2:70][P:71]([O:72][CH2:73][CH3:74])([O:75][CH2:76][CH3:77])=[O:78])=[C:23]([O:31][CH3:32])[N:22]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Reactant: CCOP(=O)(CCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Diethyl azodicarboxylate (0.43 ml, 2.75 mmol) was added to a cooled mixture of 2-[bis-(t-butoxycarbonyl)-amino]-9-hydroxy-6-methoxypurine (0.71 g, 1.83 mmol), triphenylphosphine (0.72 g, 2.75 mmol) and diethyl 4-(t-butyldimethylsilyloxy)-3-hydroxybutylphosphonate (0.623 g, 1.83 mmol) in dry tetrahydrofuran (20 ml). The reaction mixture was stirred at ambient temperature for 1 hour, and then evaporated to dryness. The residue was dissolved in diethyl ether, the solution filtered, and the filtrate evaporated to give a yellow oil. This oil was partially purified by column chromatography on silica gel (eluting with dichloromethane:ethanol 97:3) to give 2-[bis-(t-butoxycarbonyl)amino]-9-[1-(t-butyldimethylsilyloxymethyl)-3-(diethoxyphosphoryl)propoxy]-6-methoxypurine as a yellow oil (1.20 g, 98%).