Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:31]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:31])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:25][CH:24]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(F)c2)C(=O)O1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: C[C@@H](c1cccc(F)c1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(3-fluorophenyl)ethyl)-1,3-oxazinan-2-one (80 mg, 0.392 mmol) in dry THF (4 mL) was added dropwise BH3.THF (0.2 mL, 0.2 mmol, 1 M) at 0° C. After stirring for 2 h at rt, the reaction mixture was cooled to 0° C. and water (1 mL), aqueous NaOH (0.5 mL, 3 M) and H2O2 (0.3 mL, 30%) were added successively. The mixture was stirred for 2-3 h at rt and diluted with water (8 mL). The pH was adjusted to 6-7 with 0.5 N aq HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×6 mL). The combined organic layers were washed with a satd aq NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford (R)-6-(4-fluorophenyl)-3-((S)-1-(3-fluorophenyl)ethyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (40 mg, 48%). LC-MS Method 2 tR=2.151 min, m/z=332.1; 1H NMR (CDCl3): 1.31 (m, 1H) 1.49 (m, 3H), 1.64 (m, 1H), 1.81-1.93 (m, 2H), 2.14-2.26 (m, 3H), 2.88 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.96 (m, 2H), 7.13 (m, 1H), 7.19 (m, 4H), 7.37 (m, 1H).
Reaction SMILES: [OH-].[Cr+3:2].[OH-].[OH-].[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].CCCCCC>O>[NH2:5][C@H:6]([C:12]([O-:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[Cr+3:2].[NH2:5][C@H:6]([C:12]([O-:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[NH2:5][C@H:6]([C:12]([O-:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Cr+3]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: NCCCC[C@H](N)C(=O)[O-]
Reaction time: 3 h

Procedure:
The recovered chromium hydroxide was then placed into a beaker provided with a reflux condenser and Dean Stark water trap. 43.8 grams (0.3 Mole) of lysine was added and thereafter 100 ml hexane was added to this mixture and stirred and boiled at atmospheric pressure for 3 hours. In the course of the reaction about 5.3-5.5 ml of water was removed from the reaction media and acquired in the Dean Stark apparatus. The reaction mixture was then cooled and filtered yielding 48.2 grams of chromium lysinate in the form of a fine blue-gray powder.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[S:12]([S:16]([O-:18])=[O:17])([O-:15])(=[O:14])=[O:13].[Na+].[Na+]>O>[S:12]([S:16]([OH:18])=[O:17])([OH:15])(=[O:14])=[O:13].[CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=CC1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(O)S(=O)(=O)O
Yield: 116.2 %

Procedure:
100 gms of cyclohexane carboxaldehyde was dissolved in 400 ml of industrial spirit (denatured ethanol) and a solution of sodium metabisulphite (95 gms) in water (150 ml) was added under stirring. The resulting precipitate was filtered and washed with industrial spirit and dried under vacuum at a temperature of about 50-60° C. to obtain 150 gms of the titled complex having 99.5% purity.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([C:15]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:16]=3[F:24])=[C:10]([F:25])[CH:9]=2)[CH2:4][CH2:3]1>CCO.[Pd]>[O:26]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[C:10]([F:25])[C:11]([C:15]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:16]=3[F:24])=[C:12]([F:14])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3=CCS(=O)(=O)CC3)cc2F)n1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(F)c(-c2c(F)cc(C3CCS(=O)(=O)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a degassed solution of 6-(4-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinic acid (1.0 equiv.) in EtOH (0.10 M) was added Pd/C (0.1 equiv.). The mixture was stirred at rt under H2 for 16 hrs. Add Pd/C (0.1 equiv.) and the reaction was stirred for additional 16 hrs. The reaction was filtered and concentrated to yield 6-(4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinic acid in 100% yield. LC/MS=386.0 (M+H), Rt=0.64 min.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[OH:12][C:13]1[CH:38]=[CH:37][C:16]([NH:17][C:18]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:19]=2[C:20]([NH:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])=[CH:15][CH:14]=1>O1CCOCC1>[OH:12][C:13]1[CH:38]=[CH:37][C:16]([N:17]2[C:18]3[C:19](=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[C:20](=[O:21])[N:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1]2=[O:2])=[CH:15][CH:14]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Temperature: 25 °C

Procedure:
A 2N solution of phosgene in toluene (2.5 mL, 5 mmol) was added to a solution of crude 2-(4-hydroxyanilino)-N-benzyloxy-4,5-difluoro-benzamide (Example I-1, 0.35 g, 0.95 mmol) in 20 mL of dioxane. The solution was heated at reflux for 2 hours, cooled down to room temperature and poured into ice water, and extracted with ethyl acetate (3×30 mL). Combined extracts were washed with water, brine, and dried over sodium sulfate to give 0.065 g of the title product as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C1(O)CCCCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: OC1CCCCC1
Product: CCOC(=O)N1CCC(Nc2ccc(C)cc2[N+](=O)[O-])CC1
Temperature: 150 °C
Yield: 43.1 %

Procedure:
A mixture of 69 g of 4-chloro-3-nitro-toluene, 50 g of ethyl 4-amino-1-piperidinecarboxylate, 24 g of sodium carbonate, 0.1 g of sodium iodide and 120 mL of cyclohexanol was heated to 150° C. for 72 h. After cooling the cyclohexanol was distilled off under reduced pressure and the residue partitioned between 1 L of ethyl acetate and 1 L of water. The organic extract was dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel, eluting with 20% ethyl acetate in cyclohexane gave 38.5 g (42.3%) of ethyl 4-(4-methyl-2-nitroanilino)-1-piperidinecarboxylate as an orange crystalline solid. 1H NMR (400 MHz, CDCl3) 8.0 (s, 1H), 7.27 (t, J=9 Hz, 1H), 6.8 (d, J=9 Hz, 1H), 4.15 (q, J=7 Hz, 2H), 4.05 (br m, 2H), 3.67 (br m, 1H), 3.10 (br t, J=11 Hz, 2H), 2.27 (s, 3H), 2.06 (br d, J=11 Hz, 2H), 1.6 (m, 2H), 1.27 (t, J=7 Hz, 4H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[C:8]([CH3:14])=[CH:7][C:6]=1[CH3:15].[OH-].[Na+]>CO>[CH:11]1([C:9]2[C:8]([CH3:14])=[CH:7][C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:10]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)Cc1cc(C2CC2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c(C2CC2)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
2.5 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid methyl ester in 30 ml of methanol was kept at ice bath temperature and treated with 0.5 g of sodium hydroxide in 5 portions. The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed in vacuo, the residue poured into water and extracted with diethyl ether. The combined organic phases were dried with sodium sulfate, filtered and concentrated to afford 2.3 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][C@H:9]1[C:31]([O:33][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a suspension of (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (1 g, 2.21 mmol) in methanol (6 mL) was added a solution potassium carbonate (153 mg, 1.1 mmol) in water (6 mL) dropwise. The mixture was stirred at room temperature for 1 hour, concentrated, and the residue slurried in toluene and evaporated to dryness 3 times and once from diethyl ether to give a white solid. The solid was mixed with DMF (6 mL), and bromomethyl-benzene (289 μL, 2.43 mmol) was added dropwise at room temperature. After 16 hours the mixture was diluted with water extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to give (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (0.92 g, 77%) as a foam.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-])=O)C>[Pt].Cl.C(OCC)(=O)C>[Cl:13][C:10]1[CH:9]=[C:8]2[C:7]([CH2:6][CH2:5][C:4](=[O:3])[NH:14]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(Cl)cc2N1

Procedure:
A mixture of the product from step (i) (4.95 g) and 5% platinum on carbon (0.400 g) and a few drops of 2M hydrochloric acid in ethyl acetate (30 ml) was hydrogenated under a pressure of 3 bar. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure to a brown solid, which was triturated with diethyl ether to give a pink solid. Yield 1.28 g
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[CH:5][CH:4]=1)#[N:2].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CSc2cccc[n+]2[O-])cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CS(=O)c2cccc[n+]2[O-])cc1

Procedure:
The procedure employed is identical to that of Example 68 using 3.6 gm (0.015 mol) 2-(4-cyanophenylmethylthio)pyridine N-oxide in 50 ml of chloroform with 3 gm (0.015 mol) MCPBA in 50 ml chloroform.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1.C(OCC)C.[ClH:39].O1CCOCC1>>[NH2:1][C@@H:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1.[ClH:39]
Reactant: COC(=O)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)n1cc(C[C@@H](N)C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Boc-DTrp-OBzl (12.19 g) in dichloromethane (60 ml) were added methyl chloroformate (4.8 ml), pulverized sodium hydroxide (4.1 g) and TBAHS (9.2 g), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from dichloromethane and hexane to give Boc-DTrp(COOMe)-OBzl (12.57 g). Boc-DTrp(COOMe)-OBzl (4.52 g) was dissolved in 4N-hydrogen chloride/1,4-dioxane (50 ml) and the mixture was stirred at room temperature for 45 min. Ethyl ether (50 ml) was added to the mixture to complete the precipitation. The precipitate was collected by filtration and dried in vacuo to give H-DTrp(COOMe)-OBzl·HCl (3.71 g). To a suspension of H-DTrp(COOMe)-OBzl·HCl (1.94 g) in dichloromethane (50 ml) were added NMM (0.55 ml), 2,6-dimethylpiperidinocarbonyl-γMeLeu-OH (1.42 g), HOBT·H2O (0.84 g) and EDCI·HCl (1.05 g) under ice cooling. The mixture was stirred at the same temperature for 2 h and at room temperature over night. The reaction mixture was washed with sat. aq NaHCO3 (50 ml), 10% aq. citric acid (50 ml) and brine (50 ml) successively, dried over MgSO4 and evaporated. The residue was purified by MPLC (Merck, LiChroprep Si 60) with hexane/ethyl acetate=2/1 for elution to give 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.17 g). A solution of 2,6-dimethylpiperidinocarbonyl-γMeLeu-DTrp(COOMe)-OBzl (1.10 g) in methanol (30 ml) was hydrogenated over 10% Pd/C (50 mg) at an atmospheric pressure of hydrogen for 1.5 h. After removal of the catalyst by filtration, the filtrate was evaporated in vacuo to give the product (0.93 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[C:26]#[N:27])[CH:5]=[CH:6][C:7]=1[Cl:8]>O1CCCC1>[NH2:27][CH2:26][CH:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][N:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:18][CH2:17]2)=[O:15])[CH2:11]1
Reactant: CS(=O)(=O)N1CCN(C(=O)N2CC(C#N)C(c3ccc(Cl)c(Cl)c3)C2)CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(C(=O)N2CC(CN)C(c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 569.2 %

Procedure:
To a stirred solution of (3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidine-3-carbonitrile (0.1 g, 0.23 mmol) in tetrahydrofuran (1.0 mL) at 0° C. was added BH3 in tetrahydrofuran (0.55 mL, 0.55 mmol). After 2 hours of stirring at ambient temperature the reaction mixture was quenched with MeOH and the volatiles were removed under vacuo. The residue was taken up in H2O, extracted with EtOAc and the combined organic phases were dried over Na2SO4. Flash chromatography (SiO2, EtOAc, then CH2Cl2/MeOH 19:1) yielded the title product (0.57 g, 56%) as a colorless oil. ES-MS m/e: 436.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([NH2:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>C1COCC1>[NH2:17][C:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:27]4[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=4[F:25])=[O:38])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[NH:14][N:15]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(-c2ccc3c(N)n[nH]c3n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1n[nH]c2nc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.44 mmol) of 6-(4-aminophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine are partially solubilized in 2.5 ml of anhydrous THF. The mixture is then degassed for 15 minutes with argon. 61.55 μl (44.93 mg, 0.44 mmol, 1 eq.) of triethylamine are subsequently added. The solution is once again degassed for 15 minutes. Finally, 64.22 μl (91 mg, 0.44 mmol, 1 eq.) of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate are added dropwise. The mixture is stirred for 2 hours at ambient temperature under an inert atmosphere. After reaction, the mixture is filtered. The filtrate is concentrated. A beige solid is isolated. This crude product is subsequently purified on a C18 reverse-phase silica (13 g) column with an eluent gradient of 5% to 95% of acetonitrile in water. The fractions containing the expected product are lyophilized. A white solid is isolated (10 mg).
Reaction SMILES: [OH:1][C:2]([CH:18]([CH3:20])[CH3:19])([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6]C)=[O:5].[CH3:21]O.Cl>O>[CH3:21][CH:3]([C:2]([OH:1])([CH:18]([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(O)(CCCCc1ccccc1)C(C)C
Reactant: CO
Agent: Cl
Solvent: O
Product: CC(C)C(O)(CCCCc1ccccc1)C(C)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 0.88 g (3.17 mmol) of the methyl 3-hydroxy-3-isopropyl-7-phenylheptanoate in 30 mL of 1:1:1-THF:MeOH:H2O is added 1.08 g (25.36 mmol, 8 eq) of LiOH monohydrate and this is stirred at 25° C. for 1 month. This mixture is then acidified to pH=6 with 1 N HCl and then partitioned between ethyl acetate and water. The organics are dried (Na2SO4) and concentrated in vacuo to afford methyl 3-hydroxy-3-isopropyl-7-phenylheptanoic acid in the form of a pale yellow crystalline solid. (0.59 g, 70%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 0.98(d, 6H), 1.35(m, 1H), 1.55(m, 5H), 2.1(m, 1H), 2.35(t, 1H), 2.6(t, 2H), 3.88(m, 1H), 6.08(bs, 2H), 7.15(m, 3H), 7.25(m, 2H).
Reaction SMILES: C(OC1C=CC=CC=1C([NH:10][CH:11]([CH3:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1)=O)CCC.N1CCOCC1.[S].Cl>>[NH2:10][CH:11]([CH3:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1
Reactant: CCCCOc1ccccc1C(=O)NC(C)Cc1ccc(CC(=O)OCC)cc1
Agent: Cl
Agent: [S]
Solvent: C1COCCN1
Product: CC(N)Cc1ccc(CC(=O)O)cc1

Procedure:
The preparation of the ethyl 4-(2-aminopropyl)-phenylacetate used as starting material is carried out in the following manner: 4-(2-acetamidopropyl)-acetophenone (m.p. 99°-100° C.) is reacted with morpholine and sulfur to give the thiomorpholide of 4-(2-acetamidopropyl)-phenyl-acid acid (m.p. 147° C.). By boiling with 6 N hydrochloric acid, there is obtained 4-(2-aminopropyl)-phenylacetic acid (oily), which is esterified with hydrogen chloride and ethanol. By treating the initially formed hydrochloride with dilute aqueous sodium hydroxide solution, there is obtained the free amino compound in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.CCCCCCC.[CH3:22][N:23](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[OH:14][C:4]1[CH:3]=[C:2]([C:22]#[N:23])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(Br)cc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCCCCCC
Product: N#Cc1cc(O)cc(-c2ccccc2)c1
Temperature: 200 °C
Yield: 38 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol) was added to 5-bromobiphenyl-3-ol (250 mg, 1 mmol) and zinc cyanide (117 mg, 1.0 mmol) dissolved in DMF (5 mL) in a microwave vessel. The reaction vessel was sealed and then heated at 200° C. for 300 seconds. The reaction was quenched with water and the product was extracted into DCM. The solution was filtered and then concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded 5-hydroxybiphenyl-3-carbonitrile (74 mg, 0.379 mmol, 38%). M.S. (ESI) (m/z): 194 [M−H]−.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]2.Cl>C(OCC)(=O)C>[O:5]=[C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)[CH2:3][NH:2][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)=[O:22]
Reactant: NCC(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
2-Amino-1-thiazolidin-3-yl-ethanone hydrochloride (3.1 mmol) and 5-chloro-1H-indole-2-carboxylic acid (3.4 mmol) were coupled according to Procedure A (0-25° C., 120 hour reaction time) substituting the following work up: the reaction mixture was stirred with ethyl acetate and 2N HCl, filtered, and the filtered solid washed with 2N HCl, 2N NaOH and ether. Yield 988 mg, 98%; HPLC (70/30) 3.25 minutes (99%); mp 253-255° C. (dec, darkening at 243° C.); PBMS 324/326 (MH+, 100%);
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCN)C1=O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCNC(C)=O)C1=O
Reaction time: 8 h
Yield: 92.9 %

Procedure:
Acetic anhydride (0.2 g) was added dropwise to a solution of 3-(2-aminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.50 g, 1.43 mmol) in pyridine (2 ml) with stirring under cooling with ice. The mixture was left standing overnight at room temperature. To this solution was added saturated aqueous NaHCO3 (30 ml), and the mixture was extracted with benzene. After drying of the extract, the solvent was removed therefrom by evaporation under reduced pressure, giving the intended 3-(2-acetylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.52 g, 92% yield) as an oily form.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17](C#N)=[CH:16][C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][N:13]=1.[ClH:25].[C:26](=[O:29])([O-])[O-:27].[Na+].[Na+]>O>[ClH:25].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:26]([OH:27])=[O:29])=[CH:16][C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][N:13]=1.[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:26]([OH:27])=[O:29])=[CH:16][C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][N:13]=1
Reactant: CCCCCc1cnc(NCCSCc2nc[nH]c2C)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCCc1cnc(NCCSCc2nc[nH]c2C)c(C(=O)O)c1

Procedure:
The 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-cyano-5-n-pentylpyridine obtained above (2.53 g; 0.0074 moles) was treated with conc. hydrochloric acid (20 ml) and heated to reflux for 36 hours. After stripping the mixture to dryness, the residue was dissolved in a little water and basified to about pH6 with sodium carbonate solution giving a precipitate. The mixture was azeotroped to dryness and chromatographed on silica-gel using chloroform/ethanol (20:1) to collect the desired band. The 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-5-n-pentylpyridine-3-carboxylic acid hemihydrochloride obtained (1.25 g) could not be crystallised and it was a straw-coloured glass. NMR data (DMSO-d6): --CH3CH2 at 0.88; (CH2)3 at 1.1-1.7; Im-CH3 at 2.24; pyr-CH2 at 2.47; CH2CH2S at 2.70; NCH2CH2 at 3.64; ImCH2S at 3.82; pyr-4H at 7,93; pyr-6H at 8.12 and Im-2H at 8.40.