Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:26][C:27]1[CH:42]=[CH:41][C:30]([O:31][C@H:32]([CH3:40])[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])=[CH:29][CH:28]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O:26][C:27]3[CH:28]=[CH:29][C:30]([O:31][C@H:32]([CH3:40])[C:33]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])=[CH:41][CH:42]=3)=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCOC(=O)[C@@H](C)Oc1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1Cl
Solvent: CCCCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(O[C@H](C)C(=O)OCCCC)cc3)cc2)cc1Cl
Yield: 15 %

Procedure:
This was prepared by the methods of Examples 2(b) and 2(c) using butanol instead of propanol and using 4-(3-chloro-4-octoxyphenyl)benzoyl chloride and Butyl (R)-2-(4-hydroxyphenoxy)propanoate (BHPP) in place of the OPBC and PHPTB used in Example 2(c), (yield 15%, SOR: +16°). The results of IR, 1H-NMR and mass spectroscopy and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Cl[CH2:15][CH2:16][N:17]([CH2:25][CH2:26]Cl)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CS(C)=O>[C:21]([O:20][C:18]([N:17]1[CH2:25][CH2:26][C:11]([C:12]#[N:13])([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:15][CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc2ccccc2c1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc3ccccc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine naphth-2-ylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol) in DMSO (30 mL). Add portionwise, NaNH2 (22 mmol). After the addition, stir for an additional 0.5 h. Pour the contents of the flask over ice (150 g). Extract the mixture with dichloromethane. Dry the organic phase over MgSO4, filter, and concentrate in vacuo to give a residue. Purify to give the title compound.
Reaction SMILES: [N:1]1([CH2:10][C:11](OC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)Cn1ccc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1ccc2ccccc21
Yield: 99.4 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 6.20 g of methyl indol-1-yl-acetate (prepared as described in Preparation 12), 1.50 g of lithium aluminum hydride and 220 ml of anhydrous tetrahydrofuran were used, to give 5.25 g of the title compound having Rf=0.33 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[CH:7][CH:6]=1>O.O1CCOCC1>[OH:3][NH:2][S:22]([C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=3)=[CH:12][C:13]([C:26]([F:29])([F:28])[F:27])=[N:14]2)=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NO)cc2)cc1
Yield: 74 %

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (2.74 g, 40 mmol) in dioxane (25 ml) sodium acetate (3.25 g, 40 mmol) in water (15 ml) was added dropwise at room temperature, followed by dropwise addition of 4-(5-p-methylphenyl-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonyl chloride (4.11 g, 10 mmol) in dioxane (40 ml). The obtained reaction mixture was poured into water (100 ml), extracted with ethyl acetate (2×50 ml), the organic layers were washed with water (3×50 ml) and brine (1×50 ml), dried over MgSO4, filtered and concentrated in vacuo. The obtained oil was crystallized from 75% aqueous ethanol (75 ml) to yield 2.94 g (75%) of the title compound as white crystals. Mp: 203° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:25][CH2:26][CH2:27][OH:28].[Na+].[I-]>O1CCCC1.C(OCC)(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: OCCCBr
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (151 mg, prepared following the procedure reported in WO 2005080382) in dry tetrahydrofuran (3.3 mL), triethylamine (0.112 mL), 3-bromo-1-propanol (0.073 mL) and NaI were added and the resulting mixture was heated at reflux for 4 hours. After cooling at room temperature it was diluted with ethyl acetate (20 mL), washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (10 g) eluting with dichloromethane/methanol from 99/1 to 97/3 to give the title compound as a colourless oil (144 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:15][CH:14]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[CH:35][N:36]=[C:6]12.Cl.[NH2:41][O:42][CH3:43].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:43][O:42]/[N:41]=[C:3](/[C:2]([CH3:1])([CH3:39])[CH3:38])\[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:17][CH:18]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[CH:35][N:36]=[C:6]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(C)(C)C)c2ncnn12
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N\OC)C(C)(C)C)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
A mixture of 4-(3,3-dimethyl-2-oxobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.1 g), (aminooxy)methane hydrochloride (0.32 g) and pyridine (5 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.022 g, 21%).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=[N:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[N:22]1[N:21]=[C:20]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14])[C:2]([Br:1])=[CH:3][CH:4]=3)[N:9]=2)[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=NNc3ccccn3)nc12
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(-c3nnc4ccccn34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To the product from Step D (2.95 g, 6.45 mmol) was added CH2Cl2 (60 mL). Iodobenzene diacetate (2.28 g, 7.09 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the product purified directly by column chromatography (1 to 8% MeOH/CH2Cl2) to afford 2.87 g (88%) of the product.
Reaction SMILES: [Si]([O:8][CH:9]1[CH:15]2[CH:13]([O:14]2)[CH2:12][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][CH:9]1[CH:15]2[CH:13]([O:14]2)[CH2:12][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1
Reactant: CCOC(=O)N1CC2OC2C(O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CC(O)C2OC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of Compound 239F (13.6 g, 45.1 mmol) in 10 mL of dry THF was added a solution of TBAF (67.6 mL, 67.6 mmol) in THF. The mixture was stirred overnight at room temperature. Water was added and the reaction mixture was extracted with EtOAc (250 mL×3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 1:1 to 1:2) on silica gel afforded 6.03 g (Yield: 75%) of 239H as an oil.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][CH:3]=[CH2:4].C1COCC1.[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][C:23]=1[F:29])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:4][CH2:3][CH2:2][CH2:1][N:5]2[CH:9]=[CH:8][N:7]=[N:6]2)=[CH:24][C:23]=1[F:29])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=CCCn1ccnn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CCCCn2ccnn2)cc1F
Reaction time: 2 h

Procedure:
To a solution of 1-but-3-enyl-1H-[1,2,3]triazole (0.85 g, 6.9 mmol) in THF (15 ml) 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 30.3 ml, 15.2 mmol) was added dropwise at 0° C. and stirring continued for 2 h. This mixture was then added to a solution of (4-bromo-2-fluoro-phenyl)-carbamic acid tert-butyl ester (2 g, 6.89 mmol), Pd(dppf)Cl2 (0.56 g, 0.69 mmol) and aqueous cesium carbonate (6.89 ml, 3M) in DMF (30 ml) and stirred for 3 h at 70° C. Water (100 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified on silica gel (ethyl acetate) to yield [2-Fluoro-4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-carbamic acid tert-butyl ester as light yellow solid. Yield 1.93 g (84%)
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CO.[Pd]>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: CCCCCCN(CCCCCC)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 2-fluoro-N,N-di-n-hexyl-4-nitroaniline (2.79 g, 8.64 mmol) in MeOH (50 mL) was added catalyst Pd/C (0.28 g). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as pale yellow oil (1.60 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][OH:7]
Reactant: COc1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc(CO)c1

Procedure:
A solution of 50 g. of m-methoxybenzoic acid in 500 ml. of dry tetrahydrofuran is slowly added to a stirred solution of 15 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran. When the addition is complete the reaction mixture is refluxed for 1 hour, cooled and then treated with 50 ml. of saturated sodium chloride solution. The resultant slurry is filtered and the insoluble material washed with 200 ml. of ether. The combined filtrates are evaporated to dryness to yield an oil which is distilled under reduced pressure, to yield m-methoxybenzyl alcohol as a colourless oil; I.R.: νmax/film 3630 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.C(O)C.N>O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: N
Solvent: CCO
Solvent: O
Product: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Yield: 48 %

Procedure:
5-Amino-3-phenyl-1H-indazole can be obtained as described in Example 4 from 5 g of 5-nitro-3-phenyl-1H-indazole, 75 ml of ethanol, 77.5 g of ferrous sulfate, 65 ml of water and 50 ml of 32% aqueous ammonia. 2.1 g of 5-amino-3-phenyl-1H-indazole are thus obtained in the form of a white powder melting at 62° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CCOc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CCOc5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-3-nitro-4-[4-(2-phenoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.037 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 5.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted with 1 to 2.5% gradient of methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.011 g, 23%); %); 1H-NMR (500 Mz, DMSO-d6) 2.72 (br s, 4H, piperazine N(CH2)2), 2.79 (t, J=5.46 Hz, 2H, NCH2CH2O), 3.68 (br s, 4H, piperazine N(CH2)2), 4.15 (t, J=5.70 Hz, 2H, NCH2CH2O), 6.82 (d, J=10.17 Hz, 2H) and 8.00 (d, J=8.93 Hz, 2H) (3,5-C6H4—NMe2 and 3,5-C6H4—NMe2) 6.93 (t, J=6.7 Hz, 1H, p-ArH), 6.99 (d, J=8.92 Hz, 2H, o-ArH), 7.30 (t, J=8.16 Hz, 2H, m-ArH), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.10 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) 5.57 min—477, 479 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 477.2162, calculated for C26H30N6OCl (M+H)+: 477.2170.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=[C:3]1[C:12]([O:14]CC)=[O:13].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C.O.C(OCC)(=O)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([C:12]([OH:14])=[O:13])=[N:4]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1n[nH]c2ccccc2c1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(C(=O)O)c(=O)c3ccccc32)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of ethyl 4-oxo-1,4-dihydrocinnoline-3-carboxylate (2.0 g), potassium iodide (1.5 g) and potassium carbonate (2.5 g) in DMF (50 mL) was added 1-(chloromethyl)-4-methoxybenzene (1.4 mL), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in ethanol-THF (1:1, 30 mL), 1 N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with water, neutralized with 1 N hydrochloric acid (15 mL), and the precipitate was collected by filtration, washed with water, and dried to give the title compound (1.1 g).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@@H:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1>CO.C(O)C.[Pd]>[CH2:17]([O:16][C@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH:8])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1CO

Procedure:
1.409 g of dl-cis-2-benzyloxymethyl-3-hexadecyloxytetrahydropyran (prepared as described in Preparation 45) was dissolved in 100 ml of a 1:1 by volume mixture of methanol and ethanol. 0.70 g of a 10% w/w palladium on activated carbon catalyst was then added to the resulting solution. Catalytic reduction using the same procedure as described in Preparation 44 yielded 1.116 g of a crude substance, which was then subjected to column chromatography through 30 g of silica gel. Those fractions eluted with mixtures of diethyl ether and hexane ranging from 1:20 to 1:5 by volume gave 1.031 g of the title compound, melting at 42°-43° C. (after recrystallisation from cold hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[N+:26]([O-:28])=[O:27])[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[N+:26]([O-:28])=[O:27])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(Oc2ccc(C(=O)OCC)cc2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(Oc2ccc(C(=O)OCC)cc2)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 74.7 %

Procedure:
A mixture of 1.78 g (4.39 mmol) of N-[4-(4-ethoxycarbonylphenoxy)-5-fluoro-2-nitrophenyl]glycine ethyl ester, 896 mg of imidazole and 20 ml of DMF was stirred with heating on an oil bath of 70° C. for 12 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate. The resulting solution was washed successively with water and brine, dried over anhydrous sodium sulfate and then, concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (developing solvent: chloroform+0 to 1% methanol) to give 1.49 g (75%) of N-[4-(4-ethoxycarbonylphenoxy)-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[NH:11][C:10]2=[S:25])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(Cl)cccc1Cn1c(=S)[nH]c(=O)c2sc(N3CCOCC3)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(SCC(=O)OC(C)(C)C)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a solution of 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-thioxo-5,6-dihydro[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (Example 107) (150 mg, 0.367 mmol) in N,N-Dimethylformamide (DMF) (2 mL) in a 20 mL Scintillation vial stirred at rt was added sodium hydride (27.8 mg, 1.100 mmol). After stirring at rt for 10 minutes, 1,1-dimethylethyl bromoacetate (0.108 mL, 0.734 mmol) was added and the reaction mixture was capped. Upon addition a precipitate immediately formed and the reaction mixture became a thick almost solid suspension. A portion of the solid was checked by LC/MS and it indicated that the reaction had gone about 80%. The reaction mixture was quenched with saturated NH4Cl solution and diluted with 15 mL water. The yellow-orange solid was isolated by filtration, washed with water and dried in a vacuum oven at 65 C for two hours providing 182 mg of solid that was used without further purification in the next step LC/MS (ES) m/z=524 (M+H).
Reaction SMILES: Cl.[CH:2]([N:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH2:7][Cl:8])([CH3:4])[CH3:3].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[ClH:8].[CH3:3][CH:2]([N:5]([CH2:6][CH2:7][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17])[CH:9]([CH3:11])[CH3:10])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)N(CCN1C(=O)c2ccccc2C1=O)C(C)C
Yield: 6.7 %

Procedure:
A solution of 2-diisopropylaminoethyl chloride hydrochloride (40.0 g, 0.2 mole) and potassium phthalimide (74.0 g, 0.4 mole) as stirred overnight at 85° C. in 500 ml of dimethyl formamide. The reaction mixture was stirred to dryness on a rotary evaporator, and the residue was partitioned between chloroform and water. The chloroform layer was extracted with 10% sodium hydroxide. After drying and removal of solvent, a brown oil was obtained which slowly crystallized. A portion of the oil was converted to the hydrochloride salt and recrystallized from methanol/diethyl ether to give 4.18 g (62.3%) of white crystalline product, m.p. 209°-211° C.
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Reactant: CCOC(=O)CBr
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(CC(=O)OCC)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl bromoacetate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained, mp 38°-40° C.