Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[C-]#N.[CH3:28][N+:29](C)(C)C.C1CCN2C(=NCCC2)CC1>CC#N>[C:20]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:2]([C:28]#[N:29])=[N:3]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[N+](C)(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: [C-]#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: N#Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (5.0 g, 14 mmol) in CH3CN (50 mL) was added tetramethylammonium cyanide (4.5 g, 29 mmol) followed by DBU (4.39 g, 28.88 mmol). Upon completion of addition, the reaction mixture was heated to 80° C. where it stirred for 12 h. After this time, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was washed successively with water and brine, and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography using 28% ethyl acetate in petroleum ether to yield 5-phenyl-4-(pyridin-2-ylmethylamino)quinazoline-2-carbonitrile (2.1 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15-8.14 (d, J=4.0 Hz, 1H), 7.96-7.87 (m, 2H), 7.75-7.70 (dt, J=7.6, 2.0 Hz, 1H), 7.62-7.45 (m, 6H), 7.34-7.29 (m, 2H), 7.25-7.22 (m, 1H), 4.60 (d, J=3.6 Hz, 2H). LCMS Method O: retention time 1.52 min, [M+1]=338.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:24])=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH:23]=[CH:22][N:21]=[N:20]2)[N:14]=1)=O)C.[NH3:25]>CO>[Cl:24][C:9]1[N:8]=[N:7][C:6]([C:4]([NH2:25])=[O:3])=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[N:14]=2)[CH:10]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2ccnn2)n1
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2ccnn2)n1
Reaction time: 4 h
Yield: 100 %

Procedure:
6-Chloro-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (48 mg, 0.139 mmol) was suspended in 7M ammonia in methanol (23 mL). After 4 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (44 mg, 100%) as an off-white solid which was used directly in the next step without purification. MS (EI/CI) m/z: 317 [M+H].
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31][CH2:30]2)[CH:9]=1.[Br:51]N1C(=O)CCC1=O>C(#N)C>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:49])[CH3:50])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31][CH2:30]2)[C:9]=1[Br:51]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-5n, 512 mg, 715 μmol) in acetonitrile (15 mL) was added N-bromosuccinimide (153 mg, 858 μmol). The resulting solution was allowed to stir at room temperature for 18 hours. After 18 hours, the solvent was reduced in vacuo and the title compound was purified via silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:16][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[C:2]=1[Cl:1])=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:25])[CH3:24]
Reactant: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.8 g of 4-chloro-3-hydroxy-10H-phenothiazine (see Example 3) in 20 ml of acetic anhydride was added 1.2 ml of pyridine. The reaction mixture was then stirred at ambient temperature for 12 hours and then poured in water (75 ml). The resulting precipitate was filtered, washed with water and dried under vacuum to give 1.65 g of 3-acetoxy-4-chloro-10H-phenothiazine (m.p.: 173° C.).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH:14]1[C:19](O)=[CH:18][CH:17]=[C:16]([CH3:21])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[C:16]1([CH3:21])[CH:17]=[CH:18][C:19]([O:1][CH:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccc(C)cc2)cc1
Temperature: 20 °C
Yield: 37 %

Procedure:
A mixture of methyl 4-(1-hydroxyethyl)benzoate (180 mg, 1.0 mmol), p-cresol (130 mg, 1.2 mmol), triphenylphosphine (393 mg, 1.5 mmol) and tetrahydrofuran (15 mL) were stirred at 20° C. for half an hour. Then azodicarboxylic acid diisopropyl ester (303 mg, 1.5 mmol) was added. The mixture was stirred at 20° C. for 12 hours. The resultant mixture was washed with water (20 mL×3). The organic phase was separated, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to furnish methyl 4-(1-(p-tolyloxy)ethyl)benzoate as a colorless oil (100 mg, 37%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[N:6][CH:5]=1.[OH-].[Li+]>C1COCC1.O>[C:28]([O:27][C:25]([NH:24][CH:18]([C:19](=[O:23])[N:20]([CH3:21])[CH3:22])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=2)=[CH:12][CH:13]=1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
Amide 18 (1.0 g, 2.25 mmol) was dissolved in THF (10 mL) and diluted with water (10 mL). Lithium hydroxide (0.107 g, 4.5 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×100 mL). The organic layer was washed with water (1×100 mL) and brine (1×100 mL), dried and concentrated to yield the desired acid compound 19 (1.0 g, 97%). 1H NMR (400 MHz, DMSO-d6): 13.1 (s, 1H), 8.64 (br, 1H), 8.27 (dd, J=8.4 and 2.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.08 (m, 3H), 4.56 (m, 1H), 2.94 (s, 3H), 2.85-2.75 (m, 2H), 2.81 (s, 3H), 1.18 (s, 9H).
Reaction SMILES: [NH3:1].O[C:3]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]#[N:5]>O>[NH2:1][C:3]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]#[N:5]
Reactant: CC(C)CC(C)(O)C#N
Reactant: N
Solvent: O
Product: CC(C)CC(C)(N)C#N

Procedure:
To a 1-liter autoclave were added 7 moles of ammonia and then 3.5 moles of 90%-pure 2-hydroxy-2,4-dimethylpentanonitrile, and the mixture was reacted at 27° C. for 10 hours at a rate of 300 r.p.m. Thus, 2-amino-2,4-dimethylpentanonitrile was synthesized. After reaction, the reaction mixture was taken out of the autoclave, and 44 g of the water phase was separated. The residue was distilled in a wetted wall tower under the following conditions: Temperature of the heating portion 25° C.; pressure 30 mmHg; and residence time in the heating portion 1 minute or less. Low-boiling compounds were thus distilled off and purified 2-amino-2,4-dimethylpentanonitrile was withdrawn from the bottom. The yield of the purified product was 90.0 mole % based on cyanohydrin. This purified product contained 0.5% by weight of ammonia and 0.8% by weight of hydrogen cyanide, and its purity was 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:5]P(=O)(OCC)OCC.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O1CCCC1.[H-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:5]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diethyl 3-chloro-4-nitrobenzylphosphonate (2.80 mmol, 0.86 g), tert-butyl 4-oxopiperidine-1-carboxylate (2.80 mmol, 0.557 g) and tetrahydrofuran (4.89 mL) were stirred and sodium hydride (4.19 mmol, 0.168 g) was added. The reaction was stirred overnight at room temperature. Water was added and the reaction extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the intermediate tert-butyl 4-(3-chloro-4-nitrobenzylidene)-piperidine-1-carboxylate (0.85 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[CH:2]([CH3:4])[CH3:3].[Cl:18][CH2:19]OC.S(=O)(=O)(O)O>>[CH2:1]([C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:9][C:10]=1[CH2:19][Cl:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(CC(C)C)c([N+](=O)[O-])c1
Reactant: COCCl
Agent: O=S(=O)(O)O
Product: CC(C)Cc1cc(CCl)c(CC(C)C)c([N+](=O)[O-])c1

Procedure:
2,5-Diisobutylnitrobenzene is treated with chloromethylmethyl ether in the presence of 60% fuming sulfuric acid by the procedure of Example 29 to yield 2,5-diisobutyl-3-nitrobenzyl chloride. This is brominated by the procedure (of Example 11) to form 4-bromo-2,5-diisobutyl-3-nitrobenzyl chloride and 6-bromo-2,5-diisobutyl-3-nitrobenzyl chloride. This mixture is separated by fractional crystallization or chromatography and the 4-bromo-2,5-diisobutyl-3-nitrobenzyl chloride is treated with cuprous cyanide by the procedure of Example 22 to give 4-cyano-2,5-diisobutyl-3-nitrobenzeneacetonitrile.
Reaction SMILES: [H][H].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][CH:5]=1.[ClH:14]>CO.[Pt](=O)=O>[ClH:14].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6][CH2:5]1
Reactant: [H][H]
Reactant: Cc1cncc2ccccc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC1CNCc2ccccc21
Reaction time: 4 h

Procedure:
In a hydrogen atmosphere 0.50 g (3.5 mmol) 4-methyl-isoquinoline, 50 mg platinum dioxide in 50 mL methanol and 3.5 mL 1M aqueous hydrochloric acid solution were hydrogenated at RT and 3 bar for 4 h. After removal of the catalyst by suction filtering the reaction mixture was evaporated down. A mixture of educt and product was obtained, which was reacted further without any further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])=[C:4]([F:26])[CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1.Cl>O.O1CCOCC1>[F:26][C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: CC(CCc1ccc(Br)cc1F)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(CCc1ccc(-c2ccccc2)cc1F)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
4-(4-Bromo-2-fluorophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (250 mg, 0.558 mmol), phenyl boronic acid (91 mg, 0.747 mmol), sodium carbonate (216 mg, 2.04 mmol), and Pd (II) EnCat (144 mg, 0.056 mmol, 0.39 mmol/g loading) were combined in a 2-5 mL microwave vial followed by the addition of 2 mL of dioxane, and 2 mL of water. The reaction was irradiated in a microwave at 120° C. for 40 minutes, followed by neutralization through the addition of 5 mL of 4 N HCl in water and extracted with ethyl acetate (3×15 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a crude brown solid (206.7 mg, 67%). LC-MS m/z 448.3 (M−1)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].[C:34](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:11]([CH3:34])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1COCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1COCCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 40 °C
Yield: 68.4 %

Procedure:
To a slurry of 0.3 g (0.634 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid methyl ester (Example 24, Step 1) and potassium carbonate (0.176 g, 1.27 mmol) in DMF (10 mL) was added iodomethane (0.109 g, 0.765 mmol). The reaction was heated at 40° C. for 2 h and then the reaction was allowed to cool to 25° C. over 19 h. The DMF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL) and then washed with water (2×30 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude oil (0.170 g,). The crude product was purified by Biotage Flash 40S chromatography, eluting with 1:1 ethyl acetate:hexanes, to afford 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid methyl ester as an amorphous white solid (0.210 g, 68%). MS: 485 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:17])=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:18]=[C:19]([CH3:21])[CH:20]=[C:4]2[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CN(C)CCCO>>[NH2:25][CH2:24][CH2:22][O:23][C:2]1[C:7]2[C:8]([CH3:17])=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:18]=[C:19]([CH3:21])[CH:20]=[C:4]2[N:3]=1
Reactant: CCn1ncc2c1nc(C)c1c(Cl)nc3cc(C)nn3c12
Reactant: NCCO
Agent: CN(C)CCCO
Product: CCn1ncc2c1nc(C)c1c(OCCN)nc3cc(C)nn3c12

Procedure:
By substituting the 5-chloro-2,6-dimethyl-8-ethyl-8H pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine obtained in Example 37 in the procedure of Example 21 and substituting ethanolamine for the 3-(dimethylamino)propanol, 5-(2-aminoethoxy)-2,6-dimethyl-8-ethyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1F)[C:9]([O:11]C)=[O:10])(=O)C.NC1C=C(O)C(=CC=1F)C(O)=O>>[NH2:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(F)c(NC(C)=O)cc1O
Agent: Nc1cc(O)c(C(=O)O)cc1F
Product: Nc1ccc(C(=O)O)c(O)c1

Procedure:
Table 8 shows the results of the preliminary screening tests of the prodrug, compound 11 and the fluorinated analog of PAS, 4-Amino-5-fluorosalicylic Acid 12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1O[C:16]([NH2:18])=[N:15][N:14]=1)=[CH:7][CH:6]=2.O.[NH2:20][NH2:21]>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:20]([NH2:21])[C:16]([NH2:18])=[N:15][N:14]=1)=[CH:7][CH:6]=2
Reactant: NN
Reactant: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)o1
Solvent: O
Product: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)n1N
Temperature: 170 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A mixture of 5-(3-bromo-quinolin-6-ylmethyl)-[1,3,4]oxadiazol-2-ylamine (3.53 g, 11.6 mmol), hydrazine hydrate (30 mL) and water (15 mL) was heated in a microwave vial at 170° C. and 2 bar of pressure for 1 hour. After cooling the formed solid was collected via filtration and washed with cold methanol and dried to return the title compound as white solid (1.79 g, 5.6 mmol, 49%). 1H NMR (DMSO-d6): δ 4.13 (2H, s), 5.46 (s, 2H), 5.56 (s, 2H), 7.23 (d, 1H), 7.81 (s, 1H), 7.98 (d, 1H), 8.71 (d, 1H); 8.91 (d, 1H); MS (m/z) 319 [M+H+]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]O.[CH3:7][N:8]([CH3:12])[C:9]([NH2:11])=[S:10]>Br>[CH3:7][N:8]([CH3:12])[C:9](=[NH:11])[S:10][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: CN(C)CCO
Reactant: CN(C)C(N)=S
Agent: Br
Product: CN(C)CCSC(=N)N(C)C
Yield: 128 %

Procedure:
A mixture of 2-dimethylaminoethanol (2.23 g), N,N1 -dimethylthiourea (2.6 g) and aqueous hydrobromic acid (48%, 20 ml) was boiled under reflux for 50 hours and evaporated to dryness. The residue was recrystallised from a mixture of methanol and ethanol to give the dihydrobromide of the title compound (5.6 g) m.p. 198°-199°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][SH:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([S:31][CH2:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])(=[O:30])[CH3:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:17][C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][S:31][C:28](=[O:30])[CH3:29])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(CS)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 8 h

Procedure:
To a mixture of 3 g (0.01M) of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester, 1.2 g (0.012M) triethylamine in 100 ml methylene chloride was added a solution of 1.8 g (0.01M) of 3-acetylthio-2-methyl propanoyl chloride and stirring continued for 8 hours. It was then washed with water, dried over MgSO4 and evaporated to dryness leaving an oily residue which was purified by HPLC using ethyl acetate-hexane (1:3) as eluent.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:11][C@H:9]1[CH2:10][N:6]([CH3:4])[C@H:7]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8]1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(C)cc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(OCC[C@@H]2C[C@@H](O)CN2C)c(CCc2ccccc2)c1
Yield: 73.4 %

Procedure:
1410 mg of (2R,4R)-1-ethoxycarbonyl-4-hydroxy-2- {2-[4-methyl-2-(2-phenylethyl)phenoxy]ethyl}pyrrolidine [prepared as described in step (b) above], 20 ml of tetrahydrofuran and 400 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 884 mg (yield 73%) of the title compound as a colorless solid substance.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][O:13][C:14]([C:16]1([NH2:29])[CH2:27][C:26]2[C:28]3[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17]1)=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14]([C:16]1([NH:29][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[OH:1])[CH2:27][C:26]2[C:28]3[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17]1)=[O:15]
Reactant: COC(=O)C1(N)Cc2cccc3cccc(c23)C1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (1.12 g, 7.4 mmol), 2-amino-2,3-dihydro-1H-phenalene-2-carboxylic acid methyl ester (2.05 g, 7.4 mmol), HATU (3.38 g, 8.9 mmol) in anhydrous DMF (28 mL) is added DIPEA (4.89 mL, 29.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (300 g silica gel, gradient elution: 10%-80% EtOAc in heptane) to give the pure product (22) as white solid (353 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[C:11]([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([OH:12])[C:10]([CH2:20][O:21]COC)([CH3:19])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.CO>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:11]([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([OH:12])[C:10]([CH2:20][OH:21])([CH3:19])[CH2:9][CH2:8]2)=[CH:25][CH:26]=1
Reactant: COCOCC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Agent: Cl
Solvent: CO
Product: CC1(CO)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Reaction time: 48 h

Procedure:
5-(4-Chlorobenzyl)-2-methoxymethoxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound (VII), R1=CH3, Ym=4-Cl, G=CH2OCH3, A=N) (629 mg, 1.66 mmol) was dissolved in methanol (6.3 ml), 10% hydrogen chloride-methanol (6.3 ml, 1.73 mmol) was added and stirring was conducted at room temperature for 48 hours. After completion of the reaction, the solvent was distilled away, and water was added. After ethyl acetate (80 ml) was added, an aqueous solution of sodium hydroxide was added until the pH became 10. The organic layer was separated, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away to obtain the title compound (VI-1 (Compound (VI), (Ra2)Xa2na2 (OH)pa1=CH3, (Rb2)Xb2nb2 (OH)pb1=CH2OH, Ym=4-Cl, A=N, isomer type: C): VI-2 (Compound (VI), (Ra2)Xa2na2 (OH)pa1=CH2OH, (Rb2)Xb2nb2 (OH)pb1=CH3, Ym=4-Cl, A=N, isomer type: C): other isomers (isomer type: T)=6:3:1).