Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:8]2[NH:7][C:6]=1[CH3:24])=[O:4].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:8]2[N:7]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)[C:6]=1[CH3:24])=[O:4]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)C1=C(C)Nc2nn(C)c(=O)n2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 3.6 %

Procedure:
Intermediate 8 (900 mg, 2.77 mmol), 3-trifluoromethylphenylboronic acid (1.05 g, 5.54 mmol), Et3N (925 μl, 6.6 mmol), and copper (II) acetate (1.0 g, 5.54 mmol) were dissolved in DCE (25 mL), and the reaction mixture was stirred at 80° C. for 18 hours. After cooling to RT the reaction mixture was partitioned between DCM and water. The organic layer was separated, washed with water, followed by brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 3-10% MeOH in DCM and then using HPLC system 1 to yield the title compound as an orange solid (47 mg).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C([O-])(O)=O.[Na+].[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26](F)=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1)([CH3:19])([CH3:18])[CH3:17]>CS(C)=O>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]([O:20][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:33])=[CH:24][C:25]=1[N+:30]([O-:32])=[O:31])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
Glycine tert-butyl ester hydrochloride (4.1 g, 29.4 mmol) and NaHCO3 (5.1 g, 61.0 mmol) were added to a solution of (4-fluoro-3-nitro-phenyl)-carbamic acid tert-butyl ester (5.2 g, 20.3 mmol) in DMSO (16 mL). The reaction was heated to 65° C. for 5 hours, cooled to room temperature, and partitioned between H2O and EtOAc. The organic layer was washed several times with H2O and concentrated to afford the sub-title compound. MS calculated for C17H25N3O6+H: 368, observed: 368.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br[CH2:11][CH2:12][CH3:13].[NH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)[N:17]=1>CN(C)C=O>[CH2:11]([NH:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)[N:17]=1)[CH2:12][CH3:13]
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Reactant: CCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Reaction time: 12 h
Yield: 57.5 %

Procedure:
0.87 ml of N-ethyldiisopropylamine and 0.28 ml (3 mmol) of 1-bromopropane were added to a solution of 0.500 g (1.52 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 15 ml of dimethylformamide, whereupon the mixture was stirred at 70° for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was extracted twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20:1) yielded 0.324 g (57%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.24 (silica gel, ethyl acetate/methanol 20:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)=[O:4].I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(I)cc1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(cnn2-c2ccc(C)cc2)c1
Temperature: 120 °C
Reaction time: 14 h
Yield: 72.4 %

Procedure:
5-(1H)indazole carboxylic acid methyl ester (302.1 mg, 1.715 mmol), 4-iodotoluene (457.2 mg, 2.097 mmol), copper iodide (17.4 mg, 0.091 mmol), trans-1,2-bis(methylamino)cyclohexane (275 μl, 0.348 mmol), and tribasic potassium phosphate (771.4 mg, 3.63 mmol) were dissolved in toluene (1700 μl) at 25° C. under Ar. The reaction mixture was warmed to 120° C. and allowed to stir for 14 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×10 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 40 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-65%). The title compound (330.5 mg, 1.241 mmol, 72.4% yield) was recovered as a light yellow/white solid. LC-MS: [M+1]=267.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10].C(O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)CCCCCCC>C(Cl)(Cl)Cl.CCCCCC>[CH2:4]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:18][C:4]3[CH:5]=[CH:6][C:7]([C:8](=[O:17])[CH:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH3:10])=[C:2]([OH:1])[CH:3]=3)=[O:39])=[CH:41][CH:42]=2)=[CH:32][CH:33]=1)[CH2:3][CH2:2][CH2:7][CH2:8][CH2:9][CH2:11][CH3:12]
Reactant: CC(C(=O)c1ccc(O)cc1O)c1ccccc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)C(C)c4ccccc4)c(O)c3)cc2)cc1

Procedure:
600 mg (2.5 millimols) of the thus obtained 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenol was reacted with 830 mg (2.4 millimols) of 4-(4'-octyloxyphenyl)benzoic acid chloride, similar to the procedure as described in Preparation Example 2, to obtain 960 mg of a crude product. The crude product was refined through silica gel column chromatography while using a mixed solvent of chloroform/hexane (50/50) as the eluent. The refined product was recrystallized from a mixed solvent of chloroform/ethanol (20/80) to obtain 153 mg of 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenyl 4-(4'-octylphenyl)benzoate.
Reaction SMILES: [CH3:1][C:2]([S:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([CH3:8])[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:8][C:2]([S:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)SC[C@@H]1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(SC[C@@H]1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 153.4 %

Procedure:
To a solution of 2.17 g (6.18 mmol) of ethyl 2-methyl-2-{[(2S)-oxan-2-ylmethyl]sulfanyl}propanoate (70%) in THF/water (1/1, 40 mL) are added 1.39 g (18.52 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 2 d, then concentrated under reduced pressure to remove the organic solvent. The aqueous residue is washed with diethyl ether (200 mL), then acidified with 6N aqueous HCl solution and extracted with ethyl acetate (3×20 mL). The combined organic extracts are dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to give 2.07 g of 2-methyl-2-{[(2S)-oxan-2-ylmethyl]sulfanyl}propanoic acid (58 wt % by NMR, residual solvent). Yield: 89%, ES-MS: m/z 219 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29-1.42 (1H, m), 1.45-1.61 (9H, m), 1.65-1.73 (1H, m), 1.80-1.90 (1H, m), 2.71-2.75 (1H, m), 2.78-2.84 (1H, m), 3.37-3.49 (2H, m), 4.00 (1H, dt, J=11.41, 2.16 Hz).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17](C)C(=O)C.N#CCl>ClCCCl>[C:16]([N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)#[N:17]
Reactant: CC(=O)N(C)C
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: N#CCl
Solvent: ClCCCl
Product: N#CN1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
By a procedure analogous to that described in Example 1, 97.0 g of 5H-dibenz[b,f]azepine are suspended in 320 ml of 1,2-dichloroethane, and 2 ml of N,N-dimethylacetamide are added. The temperature is raised to 60°, and 50 g of cyanogen chloride are introduced in the course of 2 hours, the reflux condenser being cooled to -17° in order to avoid loss of cyanogen chloride. The mixture is kept at 60° for 16 hours; a descending condenser is then fitted, and at normal pressure 200 ml of a mixture of cyanogen chloride and 1,2-dichloroethane are distilled off into a cooled receiver. During distillation, the 1,2-dichloroethane passing over is continuously replaced by fresh solvent in order to remove residual cyanogen chloride. The contents of the flask are cooled to room temperature; 200 ml of water are added, and the mixture is rendered permanently alkaline by the addition of 30% sodium hydroxide solution. Further processing, analogous to that in Example 2, yields 96.3 g of 5-cyano-5H-dibenz[b,f]azepine, which, according to the IR spectrum, is identical to authentic material; m.p. 108°-109°. A further 4 g of final product can be obtained from the mother liquor, and the total yield is 100.3 g (92% of theory).
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Zn].C(O)(=O)C>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:13]([C:15]4[O:16][C:17]([CH3:20])=[CH:18][CH:19]=4)=[O:14])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8]([NH:9][CH3:10])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1)C1CCCCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(NC(=O)c3ccc(C)o3)cc2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(4-Nitro-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (760 mg, 1.96 mmol), acetic acid 15 mL and zinc (1.2 g, 19 mmol) are combined and stirred at room temperature for 30 minutes. The crude reaction mixture is filtered through celite, washed with acetonitrile and the combined washings concentrated in vacuo. The crude material is taken up in 10% methanol in DCM and washed with saturated aqueous sodium bicarbonate. The organic layer is dried, filtered and evaporated in vacuo to yield the title compound that is used without further purification, 660 mg, 94%, LC/MS ESI m/z (M+H)+=356.2.
Reaction SMILES: O.O.C([O-])(=O)C.[Zn+2:7].C([O-])(=O)C.[CH2:12]([CH:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][O:18][P:19](=[O:22])([OH:21])[OH:20])[CH2:13][CH2:14][CH3:15]>CO>[CH2:12]([CH:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][O:18][P:19]([O-:22])([O-:21])=[O:20])[CH2:13][CH2:14][CH3:15].[Zn+2:7]
Reactant: CCCCCCC(CCCC)COP(=O)(O)O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: CCCCCCC(CCCC)COP(=O)([O-])[O-]

Procedure:
A solution of 1 mole of zinc acetate dihydrate in 750 ml of methanol at 55°C was added to a solution of 0.7 mole of mono(2-butyloctyl)phosphoric acid in 500 ml of methanol.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:18]3[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[O:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:18]3[NH:26][C:25]4[CH:24]=[CH:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=3)[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccccc5)nc34)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1[nH]ccc2[nH]c(-c3cccc4ccc(Oc5ccccc5)nc34)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.8 %

Procedure:
To a solution of 2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 37; 0.07 g, 0.197 mmol) in 1,4-dioxane (20 mL) was added DDQ (0.134 g, 0.591 mmol), and the reaction was stirred at RT for 2.5 h. The mixture was diluted with ice water (50 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried, filtered and concentrated. The residue was purified with preparative HPLC (Phenomenex Gemini C18 column (100×50 mm, 10 μm), 90 mL/min, 30-90% ACN in water with 0.1% TFA) to give 2-(2-phenoxyquinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.034 g, 49%) as a pale brown solid. MS (ESI, pos. ion) m/z: 354.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H), 10.73 (d, 1H, J=5.2 Hz), 8.54 (d, 1H, J=8.9 Hz), 8.31 (d, 1H, J=7.1 Hz), 7.89 (d, 1H, J=7.6 Hz), 7.67 (t, J=7.8 Hz, 2H), 7.54 (t, J=7.6 Hz, 2H), 7.44-7.47 (m, 3H), 7.24 (d, 1H, J=1.3 Hz), 6.90-7.03 (m, 1H), 5.87 (d, 1H, J=7.0 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].CCN(C(C)C)C(C)C.[CH2:23]([O:26][C:27](Cl)=[O:28])[CH:24]=[CH2:25].Cl>C(Cl)Cl.O>[CH:7]1([NH:6][C:4](=[O:5])[CH:3]([OH:10])[CH:2]([NH:1][C:27](=[O:28])[O:26][CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9]1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)NC(CCC)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (10 g, 53.7 mmol), DIEA (28 mL, 161 mmol, 3 eq.) in methylene chloride (250 mL) was added dropwise at 0° C. to a solution of allylchloroformate (6.8 mL, 64.4 mmol, 1.2 eq.) in DCM (50 mL). The reaction solution was warmed to room temperature and stirred for 4 hours. Water (300 mL) was then slowly added followed by aqueous HCl (1.0 N, 300 mL). The phases were separated and the organics washed with saturated aqueous NaHCO3 (300 mL), brine (300 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting off-white solid was recrystallized from 30% hexanes in EtOAc (120 mL) to yield the title compound M1A as a white solid. The mother liquor was concentrated, in vacuo, and recrystallized from 50% hexanes in EtOAc to yield another 4.04 g of MIA. The mother liquor from the second recrystallization was concentrated in vacuo on Celite®, and the resulting Celite® plug was purified by flash chromatography (Isco Companion®, SiO2, DCM to 70% EtOAc in DCM) to give 1.46 g of MIA. The total amount of compound MIA was 13.4 g (yield 93%). (Rf˜0.40 in 1:1 DCM:EtOAc, CAM detection).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1C=CN[N:12]=1.[C:17]1([C:23]2[N:24]=CN[CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[NH:12][CH:27]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Product: O=C(Cc1nc(-c2ccccc2)c[nH]1)c1ccc(Cl)cc1Cl

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that 4-phenylimidazole (6.5 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (50% EtOAc/hexanes) to yield a light yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][O:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=2)=[O:32])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:15][CH3:16])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:16][O:15][CH:5]([O:4][CH3:3])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:10][CH:9]=1
Reactant: COC(CNc1ccc(O)cc1)OC
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(CNc1ccc(OCCN(C)C)cc1)OC
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.57 g) was added to a solution of 4-(2,2-dimethoxyethyl-amino)phenol (4.3 g) in dimethylformamide (25 mL). After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 3.14 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated. The residue was purified by MPLC (eluent: dichloromethane/methanol/ammonia solution 95:4.9:0.1). The product with the molecular weight of 268.36 (C14H24N2O3); MS (ESI): 269 ([M+H]+), was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1.[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH:15]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:17]
Reactant: CCON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 87.7 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 100 g.), formic acid (85.5 g.) and acetic anhydride (190.1 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer, 99.1 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36]N)=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@@H:46]([CH2:60][CH:61]([CH3:63])[CH3:62])[C@@H:47]([OH:59])[CH2:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:46]([CH2:60][CH:61]([CH3:63])[CH3:62])[C@@H:47]([OH:59])[CH2:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)OCc1ccccc1
Yield: 26.8 %

Procedure:
The procedure described in Example 1(c) was repeated, but using 300 mg (0.6 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidine hydrazide and 180 mg of benzyl 4(S)-t-butoxycarbonylamino-3(S)-hydroxy-6-methylheptanoate. The resulting syrup was purified by silica gel column chromatography eluted with mixtures of chloroform and methanol ranging from 20:1 to 5:1. The solvent was removed by distillation under reduced pressure from the active fractions, and diethyl ether was added to the residue, to solidify it. This solid was finely pulverized and separated by filtration, giving 97 mg of the title compound as a white powdery solid, melting at 102°-109° C., [α]24 -31.0° (C=0.5 methanol).
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[O:32]([C:39]1[N:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([S:45]([C:42]6[CH:43]=[N:44][C:39]([O:32][C:33]7[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=7)=[CH:40][CH:41]=6)(=[O:46])=[O:47])[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)nc1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(S(=O)(=O)c3ccc(Oc5ccccc5)nc3)C4)n[nH]c2c1
Yield: 17.2 %

Procedure:
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) and 6-phenoxy-pyridine-3-sulfonyl chloride (22 mg, 80 μmol) using the method of Example 6. The crude material was purified by HPLC Method A to afford 8.4 mg of the title compound.
Reaction SMILES: [C@H:1]1(C(O)=O)[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.C([N:14](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O1CCCC1.O>[C@H:1]1([NH2:14])[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: O=C(O)[C@@H]1CC12CCOCC2
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CC12CCOCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.528 g of (R)-6-oxaspiro[2.5]-octane-1-carboxylic acid in 5 ml of tetrahydrofuran is mixed with 1.20 ml of triethylamine, and the solution is then cooled to 0° C. The solution is mixed with 0.657 ml of ethyl chloroformate, and the reaction mixture is stirred at 0° C. for 1 hour. A solution of 4.44 g of sodium azide in 5 ml of water is added and the reaction mixture is stirred at 0° C. for a further hour. The reaction mixture is diluted with water and extracted with tert-butyl methyl ether. The combined extracts are washed with brine, dried with sodium sulphate and evaporated. The residue is taken up in 5 ml of benzene, and the solution is heated to reflux for 2 hours and then evaporated. The residue is dissolved in 5 ml of tetrahydrofuran, and 5 ml of water and 0.347 g of lithium hydroxide are added. The reaction mixture is stirred at room temperature for 3 hours and then adjusted to pH 2 with 4M HCl. The tetrahydrofuran is distilled off, and the aqueous residue is adjusted to pH 12 with 2M NaOH. The aqueous phase is extracted with dichloromethane, and the combined organic extracts are dried over sodium sulphate and evaporated. The title compound is obtained as a yellow oil which is employed without further purification in the next stage. Rf=0.26 (dichloro-methane-methanol-conc. ammonia 25% 200:20:1).