Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:18][C:19]([CH3:34])([CH3:33])[CH2:20][CH2:21][O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:16]=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl>O1CCCC1>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:18][C:19]([CH3:33])([CH3:34])[CH2:20][CH2:21][O:22][Si:23]([CH:24]([CH3:25])[CH3:26])([CH:27]([CH3:28])[CH3:29])[CH:30]([CH3:32])[CH3:31])[C@@H:16]([OH:17])[CH2:5][CH2:4][CH:3]=[CH2:2])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)[Si](OCCC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: C=CCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCC[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C

Procedure:
The Grignard reagent is prepared from 3.70 ml of 4-bromo-1-butene and 880 mg of magnesium powder in 50 ml of tetrahydrofuran at 55° C. This solution is then added dropwise to a solution of 3.0 g of 2(S)-tert-butoxycarbonylamino-6-triisopropylsilyloxy-4,4-dimethyl-hexanal (Example 1g)) in 25 ml of tetrahydrofuran at 5°-10° C. 1 h after the end of the addition, the mixture is poured onto a 0.1N hydrochloric acid solution, extracted with methylene chloride and concentrated. The crude product contains the two 5(S):5(R) diastereomers in a ratio of about 5:1. The title compound (non-polar diastereomer) is obtained by purification over 250 g of silica gel (mobile phase E): Rf (E)=0.30.
Reaction SMILES: [Na][Na].[C:3]([NH:5][C:6](=[O:15])[CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]#[N:14])=[O:11])#[N:4].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C)C=O>[C:13]([N:12]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:3]#[N:4])=[O:15])#[N:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: N#CNC(=O)CCCC(=O)NC#N
Agent: [Na][Na]
Solvent: CN(C)C=O
Product: N#CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCC(=O)N(C#N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
22.4 g (0.1 mol) of the disodium salt of glutaric acid bis-(N-cyanamide) and 51.85 g (0.2 mol+20% excess) of 4-nitrobenzyl bromide are reacted in 120 ml of dimethylformamide at 36°-40° C. for 1 hour and the mixture is worked up in a manner similar to that in Example 2. 44.3 g (98.4% of theory) of a yellowish crystalline crude product are obtained, and are recrystallised from 440 ml of ethyl acetate. 31.5 g (70.0% of theory) of a colourless, crystalline product of a melting point 146.2°-148.2° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:21][NH:22][CH3:23].O1CCCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:16])[N:22]([CH3:23])[CH3:21])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a suspension of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (prepared as described in example 15) (183 mg, 0.75 mmol) in toluene (7 mL) was added thionyl chloride (2.2 mL, 30 mmol) and the mixture heated to reflux under argon for 2.5 hours. The mixture was then concentrated in vacuo, the residue suspended in dichloromethane (7 mL), a 2 M solution of dimethylamine in tetrahydrofuran (0.5 mL, 1 mmol) added and the mixture stirred at ambient temperature under argon overnight. The reaction mixture was concentrated in vacuo, the residue suspended in ethyl acetate and the solid removed by filtration. The filtrate was concentrated in vacuo and the residue purified by chromatography over silica gel eluted with 1% v/v methanol in ethyl acetate to give (4-dimethylcarbamoyl-thiazol-2-yl)-carbamic acid tert-butyl ester as a colorless solid (152 mg, 75%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:36]#[N:37].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C.N.CO>[C:36]([C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:37]
Reactant: [C-]#N
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a (70 mg, 0.14 mmol), KCN (Aldrich, 46 mg, 0.70 mmol) and 18-crown-6 (Aldrich, 190 mg, 0.70 mmol) in DMF (1 mL) were heated to 150° C. in a sealed tube overnight. The reaction solution was loaded on a silica gel column with a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][NH2:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.FC(F)(F)CS(Cl)(=O)=O>>[F:5][C:4]([F:7])([F:6])[C:2]([NH:27][CH2:26][CH2:25][CH:24]([C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:12]1[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=1)[N:16]=[CH:17]2)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:1]
Reactant: O=C(O)C(F)(F)F
Reactant: NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=S(=O)(Cl)CC(F)(F)F
Product: O=C(NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Yield: 99.7 %

Procedure:
Prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropan-1-amine TFA salt (25 mg, 0.05 mmol) by adding 2,2,2-trifluoroethanesulfonyl chloride under the General Coupling Method B conditions. Obtained 22 mg (82%) of 2,2,2-trifluoro-N-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropyl)acetamide. MS found: (M+H)+=442.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][C:15]=1[F:16].[Cl:20][C:21]1[CH:22]=[C:23]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1.Cl>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH2:18][C:28]([C:23]2[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=2)([OH:33])[C:29]([F:32])([F:31])[F:30])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(F)c(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ethylbenzene 10.18 mL, 20.36 mmol) was added to tetrahydrofuran (8 mL) at −78° C. A solution of 1-(3-bromo-4-fluorophenyl)ethanone (4.01 g, 18.47 mmol) in tetrahydrofuran (8 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred at −78° C. for 30 min. Then a solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (4.50 g, 18.52 mmol) in tetrahydrofuran (8 mL) was added dropwise to the mixture so the temperature of the reaction mixture did not exceed −60° C. After the addition was complete the mixture was stirred at −78° C. for 60 min. The mixture was allowed to warm to 0° C. and then poured into 1N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (2×100 mL), and the combined extracts were dried and evaporated. Chromatography of the residue on silica gel (eluted with 1:4 ethyl acetate/hexanes) gave the title product as a white solid (3.32 g, 39% yield) melting at 134-135° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[H-].[Na+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:20][CH:19]([N:10]1[C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[CH:8]=[CH:9]1)[CH3:21]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(OC)c2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a cooled (ice/water bath) solution of methyl 7-(methyloxy)-1H-indole-4-carboxylate (350 mg, 1.706 mmol) in DMF (20 mL) was added sodium hydride (56.0 mg, 2.217 mmol). After 10 minutes added 2-iodopropane (0.188 mL, 1.876 mmol). The reaction was stirred at RT for 1 h, followed by heating at 50° C. for 2 h. The reaction was then cooled in an ice water bath and more sodium hydride (56.0 mg, 2.217 mmol) and 2-iodopropane (0.188 mL, 1.876 mmol) were added. The reaction was heated at 50° C. for 3 h, at which time it was concentrated. The residue was dissolved in DCM and washed with water and brine, dried over MgSO4, filtered and concentrated to give 400 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (d, 6H), 3.95 (s, 3H), 4.01 (s, 3H), 5.46 (dt, J=13.39, 6.69 Hz, 1H), 6.66 (d, J=8.34 Hz, 1H), 7.15 (d, J=3.03 Hz, 1H), 7.34 (d, J=3.28 Hz, 1H), 7.87 (d, J=8.34 Hz, 1H). MS(ES) [M+H]+248.2.
Reaction SMILES: [OH-:1].[Na+].[OH-].[CH3:4][C:5]1[C:11](=[O:12])[C:10]2[N:13]3[C@@:17]([O:24][CH3:25])([C@H:18]([CH2:19][O:20][C:21]([NH2:23])=[O:22])[C:9]=2[C:7](=[O:8])[C:6]=1N)[C@H:16]1[NH:26][C@H:15]1[CH2:14]3.[H][H]>CO>[CH3:4][C:5]1[C:6](=[O:1])[C:7](=[O:8])[C:9]2[C@@H:18]([CH2:19][O:20][C:21]([NH2:23])=[O:22])[C@@:17]3([O:24][CH3:25])[C@H:16]4[NH:26][C@H:15]4[CH2:14][N:13]3[C:10]=2[C:11]=1[OH:12]
Reactant: [H][H]
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12

Procedure:
Turning now to preferred conditions for the wet route, the aqueous solution of 7-salt oxide-9a-methoxymitosane (7-Na+O- -9a-methoxymitosane when aqueous sodium hydroxide is the hydroxide solution reacted with mitomycin C) is reacted directly with acid. While aqueous acid solutions or strong acid cation exchange resin in the hydrogen form can be used as the acidifying agent, in this case, unlike in the dry route, aqueous acid solution is preferred over cation exchange resin since use of cation exchange resin requires a resin separation step whereas the water introduced with aqueous acid does not need to be removed for reaction of diazodiphenylmethane with 7-hydroxy-9a-methoxymitosane. The reaction is readily carried out, for example, by combining diphenyldiazomethane solution with the 7-salt oxide-9a-methoxymitosane solution, adjusting the pH into the desired range of about 4 to 7 with acid solution, preferably 5-15% phosphoric acid, maintaining the pH in said desired range by the periodic addition of acid solution while maintaining the temperature in the range of 0° C. to 30° C. and adding additional diphenyldiazomethane solution if needed. As previously indicated methanol is preferably used in combination with methylene chloride reaction solvent. The methanol aids in extracting formed 7-hydroxy-9a-methoxymitosane from aqueous phase for reaction in the organic phase with diazodiphenylmethane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.OO.FC(F)(F)C(O)=[O:37].[OH-:41].[Na+]>C(OCC)(=O)C.O>[ClH:31].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:24]([C:21]2[CH:22]=[C:23]3[C:18]([CH:17]=[CH:16][N:15]=[C:14]3[N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][CH:20]=2)(=[O:37])=[O:41])=[CH:26][CH:27]=1
Reactant: [OH-]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccc(Cl)cc4)cc23)CC1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc2ccnc(N3CCNCC3)c2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[7-(p-chloro-phenylsulfanyl)-isoquinolin-1-yl]-piperazine-1-carboxylic acid tert-butyl ester (297 mg, 0.65 mmol), H2O2 (30% in water, 0.5 mL), trifluoroacetic acid (3 mL) was heated at 50° C., 2 h. The reaction was continued overnight at 35° C. A water solution of NaOH (1N) was added (pH=14), ethyl acetate was added and the organic phase was separated, dried (MgSO4), filtered. The filtrated was concentrated and the residue was purified by flash column chromatography (SiO2, dichloromethane:methanol 9.5:0.5→9.0:1.0) The free base was converted into hydrochloride by treatment with HCl in diethyl ether to obtained 70 mg of the title compound. 1H NMR (CH3OH-d4) δ 8.75-8.85 (m, 2H), 8.10-8.25 (m, 3H), 8.00-8.08 (m, 2H), 7.60-7.68 (m, 3H), 3.85-3.95 (m, 4H), 3.55-3.65 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]1[O:19][CH2:18][C@@H:16]([OH:17])[C@H:14]1[OH:15]>C(Cl)Cl>[CH3:8][S:9]([O:15][C@H:14]1[C@@H:16]([O:17][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:18][O:19][CH2:13]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1COC[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1COC[C@H]1OS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
Triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) were successively added dropwise to a solution of 1,4-anhydroerythritol (5.0 g) in methylene chloride (50 ml) under ice cooling, and the mixture was stirred for 10 minutes under ice cooling. The reaction mixture was diluted with methylene chloride and washed with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (9.2 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:27])[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:22]([NH:27][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCCCCN
Product: CCCCCNC(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and n-pentylamine were used in the procedure described in Example 1, to obtain N-n-pentyl-3,4-dihydroxyphenylpropionamide as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1C
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)Cl)c1C
Yield: 86.2 %

Procedure:
To 3-methoxy-2-methylbenzoic acid (454 g, 2.73 tool) in 1300 mL chloroform containing 20 g dimethyl formamide at 65° C., thionyl chloride (390 g) was added dropwise over 6 hours, whereupon the solvent was removed by evaporation at a reduced pressure. The residue (512 g) was distilled at 110° C. at 1-2 mm Hg to give 3-methoxy-2-methylbenzoyl chloride (435 g. 85%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:26]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:34](=[O:42])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:43])[N:27]=1)[NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:26]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:34](=[O:42])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:43])[N:27]=1)[NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][NH:21]2
Reactant: Cc1cccc2nc(C(CCCCNC(=O)OCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2nc(C(CCCCN)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12

Procedure:
A mixture of compound 49 (28.5 mg) and palladium on carbon (10 mg, 10% Pd) in ethanol (2 mL) was shaken with hydrogen (40 psi) for 48 h. The mixture was filtered through CELITE® and the filtrate was concentrated to afford the product 54. ESI-MS m/z 455 (MH+). Compound 54 is shown below.
Reaction SMILES: [Cl:1][C:2]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:3]=1[CH2:4][NH:5][C:6](=[O:42])[N:7]([C@H:9]([CH2:27][O:28][C:29](=[O:41])[NH:30][C:31]1[N:32]=[CH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:13])[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[C:31]([NH:30][C:29](=[O:41])[O:28][CH2:27][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:2]=2[Cl:1])=[O:42])[CH2:10][CH2:11][C:12](=[O:13])[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[N:32]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1cc2ccccc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentanoyl)piperazine-1-carboxylate (22 g, 32.8 mmol) in DCM (200 mL) was added TFA (100 mL). The reaction mixture was stirred at RT for 3 h and concentrated. The residue was purified on silica gel column using a mixture of MeOH and DCM. The fractions were concentrated, dissolved in water (200 mL), neutralized to pH 8-9 with 1N NaOH, and extracted with EtOAc (300 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl isoquinolin-3-ylcarbamate (14 g, 75%). LRMS (M+H) m/z 571.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][OH:12]
Reactant: O=Cc1ccccc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a suspension of 2-fluorobenzaldehyde (63.3 g, 495 mmol) and hydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) and water (69 mL) was added ice (205 g). Then an aqueous solution of sodium hydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 1 h stirring at room temperature the resulting mixture was then acidified with HCl (5 N). The mixture was then extracted with dichloromethane to afford the title compound (66.8 g, 97%) which was obtained as a light yellow solid. MS m/e (EI): 139.0 [M].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]1[OH:23].[C:24]([O:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36]#[CH:37])[CH2:31][CH2:30]1)(=[O:26])[CH3:25]>CN(C=O)C.[Cu]I.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:24]([O:27][CH2:28][CH:29]1[CH2:30][CH2:31][CH:32]([CH2:35][C:36]#[C:37][C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[C@H:12]3[C@H:13]([OH:23])[C@H:14]([OH:22])[C@@H:15]([C:17](=[O:18])[NH:19][CH2:20][CH3:21])[O:16]3)=[C:2]([NH2:1])[N:10]=2)[CH2:33][CH2:34]1)(=[O:26])[CH3:25]
Reactant: C#CCC1CCC(COC(C)=O)CC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)[C@H](O)[C@@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(COC(C)=O)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a degassed solution of 125 mg (0.29 mmol) of [(2S,3S,4R,5R)-5-(6amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]-N-ethylcarboxamide (6.9), 150 mg (0.77 mmol) (5.6), and 1.0 mg CuI in 1.3 mL of TEA and 4 mL DMF was added 25 mg of Pd(PPh3)4. The solution was stirred for 72 h at 60° C. after which time the solution was filtered through celite and chromatographed on silica gel with MeOH-CHCl3 (5:95) to give JMR193 (10%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.C(O)C.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:29])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)nc12
Yield: 95.6 %

Procedure:
To a mixture of methyl 4-{[(5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}benzoate (1.31 g) synthesized above, ethanol (20 mL) and tetrahydrofuran (20 mL) was added 1N lithium hydroxide aqueous solution (20 mL), and the mixture was stirred with heating under reflux for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration and the obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (1.21 g, 96%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1>>[F:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:31]([C:26]3[C:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[CH:29][N:28]([CH3:30])[N:27]=3)=[O:32])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2oc(CC3CCCCN3)cc12
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2cc3c(F)cccc3o2)n1

Procedure:
The title compound (45 mg) was prepared from (RS)-2-(4-fluoro-benzofuran-2-ylmethyl)-piperidine, D76 (157 mg) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (160 mg) according to a procedure similar to that described for Example 4.