Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)c2cccnc2n1
Reactant: Nc1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccccc1-c1cc(Nc2ccncc2)c2cccnc2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 259 mg (1.00 mmol) 4-chloro-2-(2-fluorophenyl)-[1,8]naphthyridine and 104 mg (1.10 mmol) 4-aminopyridine in 5 ml dioxane 236 mg (2.10 mmol) potassium tert.-butylate were added, the mixture heated to 80° C. and kept at this temperature for 1 hr. After cooling to ambient temperature water was added to the reaction mixture. The precipitate formed was filtered off, washed with water and dried in vacuum. This yielded [2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-4-yl-amine as beige crystals; HPLC-MS: [M+H] 317. 1H-NMR (d6-DMSO): δ [ppm]=7.34 (d, J=5.9 Hz, 2H), 7.38 (dd, J1=11.8 Hz, J2=8.2 Hz, 1H), 7.41 (t, J=7.4 Hz, 1H), 7.57 (m, 1H), 7.66 (dd, J1=8.3 Hz, J2=4.1 Hz, 1H), 7.83 (s, 1H), 8.12 (t, J=7.8 Hz, 1H), 8.46 (d, J=5.9 Hz, 2H), 8.81 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 9.1 (dd, J1=4.3 Hz, J2=1.8 Hz, 1H), 9.67 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:11].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5]([NH:11][C:21](=[O:22])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: COC(=O)c1c(N)cccc1F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(F)cccc1NC(=O)Cc1ccc(F)cc1
Yield: 66.5 %

Procedure:
First, 2-amino-6-fluoro-benzoic acid methyl ester (1.00 g, 5.91 mmol) was dissolved in purified CH2Cl2, and after adding DMAP (0.04 g, 0.30 mmol) and (4-fluoro-phenyl)-acetyl chloride (1.22 g, 6.50 mmol) at 0° C., reacted together at normal temperature for 10 hours. After adding cold sodium bicarbonate solution containing ice, the reaction mixture was extracted with CH2Cl2, washed with distilled water, dried with MgSO4, and then concentrated under reduced pressure to obtain crude 2-fluoro-6-[2-(4-fluoro-phenyl)-acetylamino]-benzoic acid methyl ester (1.20 g, 61%) as the solid.
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=3[N:14](COCC[Si](C)(C)C)[CH:13]=2)[CH:3]=1.C(OCC)(=O)C>C(O)C>[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=3[NH:14][CH:13]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ncnc2[nH]cc(-c3cnc4ccccc4c3)c12
Reaction time: 0.42 h

Procedure:
Concentrated hydrochloric acid (20 ml) was added at 90° C. to a solution of 5-(quinolin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.0 g) obtained in Step 3 in ethanol (200 ml), and the mixture was stirred at the same temperature for 25 minutes. Subsequently, concentrated hydrochloric acid (30 ml) was added thereto, and the mixture was stirred at the same temperature for 75 minutes. After the reaction mixture was cooled, ethanol (100 ml) was added thereto, and stirred at 95° C. for 90 minutes. Subsequently, ethanol (100 ml) and concentrated hydrochloric acid (25 ml) were added, and the mixture was stirred at the same temperature for 4 days. After the reaction mixture was cooled, ethyl acetate was added thereto. The resulting precipitate was then collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (4.4 g) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH4+].[Cl-]>CCOCC>[C:2]1([C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2ccccc2)CCCCC1
Yield: 71 %

Procedure:
The Grignard reagent resulting from the action of 48.9 g (0.3M) of bromobenzene on 8.75 g (0.35M) of magnesium in the form of turnings is prepared in 300 ml of anhydrous ether. To it is added 19.6 g (0.2M) of cyclohexanone dissolved in 300 ml of anhydrous ether. Stirring takes place for 3 h on the reflux condenser and the complex is decomposed by a cold, saturated NH4Cl solution and then, after settling, the liquids are extracted with ether (3×200 ml). The ethers are dried (Na2SO4) and evaporated in vacuo to give a yellowish solid which, after two crystallizations in petroleum ether, give 25 g of white 1-phenyl-cyclohexanol melting at 60° to 61° C. (IR).
Reaction SMILES: [ClH:1].ClC1C=CC([CH:9]([NH:20][NH2:21])[C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=CC=1.[OH-].[Na+]>ClCCl.O>[Cl:1][C:10]1[CH:11]=[CH:12][C:13]([NH:21][NH:20][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[N:16][N:15]([CH3:18])[C:14]=3[CH:19]=2)=[CH:14][CH:19]=1
Reactant: Cn1nnc2ccc(C(NN)c3ccc(Cl)cc3)cc21
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Reaction time: 0.25 h

Procedure:
To a suspension of 8.1 g of intermediate 2-b in 60 ml of dichloromethane was added a solution of 1 g sodium hydroxide in 15 ml of water. The whole was stirred for 15 min., then the organic layer was separated and evaporated. The residue and 1.4 g of potassium hydroxide were refluxed in 50 ml ethanol for 3 hours, yielding (-)-6-[(4-chlorophenyl)hydrazinomethyl]-1-methyl-1H-benzotriazole (interm. 2-c); enantiomeric excess: 20%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].F[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:17]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
To 3-hydroxy-4-methoxyphenylacetic acid (5.0 g, 27.4 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical tlc, the solution was concentrated and dried under high vacuum to give (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester. A solution of (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (1 equivalent), 2-fluoro-5-nitrobenzaldehyde (1 equivalent), and potassium carbonate (2 equivalents) in 1,4-dioxane was heated overnight at 70° C. The mixture was partitioned between EtOAc and H2O and acidified with 1N aqueous HCl to pH 1, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (EtOAc in hexane gradient) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[Cu](C#N)[C:17]#[N:18]>CN(C)C=O>[C:17]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[CH:4][N:3]=1)#[N:18]
Reactant: N#Cc1cccc(-c2cc(Cl)ncn2)c1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2cc(C#N)ncn2)c1

Procedure:
4-chloro-6-(3-cyanophenyl)-pyrimidine is reacted with copper cyanide in boiling N,N-dimethylformamide to give the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([C:14]([CH:16]([C:18]2[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=2)O)=O)[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[S:32])=[CH:29][CH:28]=1>O1CCOCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]2[S:32][C:16]([C:18]3[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[CH:20][CH:19]=3)=[C:14]([C:6]3[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=3)[N:33]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: NC(=S)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccc(F)cc3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
Three ml. of concentrated sulfuric acid, 250 ml. of dioxane, 27.2 g. (0.10 mole) of anisoin, and 15.5 g. (0.10 mole) of 4-fluorothiobenzamide were placed in a round bottom flask. The mixture was stirred at reflux for 3 days, then cooled to room temperature, and poured onto ice. Then the mixture was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. After the ethyl acetate was evaporated, a crude solid of 35 g. remained. The solid was then recrystallized from ethyl acetate and weighed 27.5 g. (70% yield). It had a melting point of about 140°-141.5° C. and the mass spectrum showed the expected molecular ion at m/e=391.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([C@@H:13]1[CH2:15][C@H:14]1[C:16]([OH:18])=O)=[O:12].C(C1NC=CN=1)([C:21]1[NH:22][CH:23]=CN=1)=O.CNC>O1CCCC1>[CH3:21][N:22]([CH3:23])[C:16]([C@@H:14]1[CH2:15][C@H:13]1[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:12])=[O:18]
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Reaction time: 3 h

Procedure:
A solution of trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid (1.5 g, 6 mmol) and carbonyl diimidazole in tetrahydrofuran was stirred for 0.5 hr. A solution of dimethylamine in tetrahydrofuran (3 ml, 2 M solution, 6 mmol) was added and the solution stirred for 3 hr. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with 1 N HCl and saturated sodium bicarbonate solution. The solution was dried over sodium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give 1.5 g of trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid dimethylamide, mp 239-241° C. LC/MS mw=274; retention time 1.23 min. Mol wt calc1d for C15H15FN2O2: 274.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O:11][C:12](=O)[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[C:19]=1[F:25])[C:14](=O)[CH3:15])C>O>[F:25][C:19]1[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:13]1[C:12](=[O:11])[O:1][C:2]2[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][C:7]=2[C:14]=1[CH3:15]
Reactant: Oc1cccc(S)c1
Reactant: CCOC(=O)C(Cc1cccc(N)c1F)C(C)=O
Solvent: O
Product: Cc1c(Cc2cccc(N)c2F)c(=O)oc2cc(S)ccc12
Temperature: 70 °C
Yield: 6.3 %

Procedure:
152 mg (1.21 mmol) of 3-hydroxy-benzenethiol and 153 mg (0.60 mmol) of 2-(2-fluoro-3-aminobenzyl)-3-oxobutanoic acid ethyl ester were added to polyphosphoric acid (6 g), and the mixture was stirred and heated at 70° C. for 2.5 hours. Water was then added to the reaction mixture, and the precipitated solid was filtered out. The obtained solid was purified by silica gel column chromatography (dichloromethane:methanol=50:1 to 20:1) to yield 12 mg (1%) of compound 5d-0-4S1 as a pale yellow powder.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:33]1[CH:32]=[CH:31][C:30]([C@H:28]([CH3:29])[CH2:27][N:19]([CH3:18])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:35][CH:34]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Yield: 48.4 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.6 g, 8.2 mmol) was reacted with (S)-tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate (4.6 g, 12 mmol) to afford the desired product (1.9 g, 50%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH:11]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:13])[CH3:12]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[CH:21][CH:20]=1)=[O:7]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=C(O)c1cccc(I)c1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(I)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-iodobenzoic acid and 4-isopropoxyaniline as the starting materials.
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([OH:26])=[C:23]([C:27]#[N:28])[C:22](=[O:29])[NH:21][C:20]=3[S:19][CH:18]=2)=[CH:13][CH:12]=1>C(O)(=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:24]([OH:26])=[C:23]([C:27]#[N:28])[C:22](=[O:29])[NH:21][C:20]=3[S:19][C:18]=2[Cl:1])=[CH:15][CH:16]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: N#Cc1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3ccc(Br)cc3)c(Cl)sc2[nH]c1=O
Temperature: 90 °C

Procedure:
N-chlorosuccinamide (1.56 mmol, 0.2 g) was added to a solution of 3-(4-bromophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (1 mmol, 0.350 g) in acetic acid (5 mL) at room temperature. The reaction was heated at 90° C. for 5 h, cooled and quenched with water (30 mL). The aqueous mixture was extracted with ethyl acetate (3×30 mL), dried (Na2SO4), concentrated and purified on RP-HPLC to afford the title compound. MS (ESI) m/e 381 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 11.93 (br s, 1H), 7.59 (d, J=10, 2H), 7.28 (d, J=10, 2H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:37])([F:36])[F:38])[CH:22]=2)=[O:19])=[CH:39][C:40]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Product: CC(C)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)ccc2Cl)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 133-134° C.; 1H NMR (300 MHz, CDCl3) δ: 9.62 (1H, s), 8.11 (1H, s), 8.05 (1H, s), 8.01-8.03 (1H, d, J=9.0 Hz), 7.86-7.88 (1H, d, J=6.0 Hz), 7.60-7.63 (1H, d, J=6.0 Hz), 7.44-7.47 (1H, d, J=9.0 Hz), 7.33-7.36 (1H, d, J=9.0 Hz), 6.63-6.66 (1H, d, J=9.0 Hz), 3.99-4.07 (1H, m), 3.67 (2H, s), 2.84 (8H, brs), 2.56 (3H, s), 1.25-1.30 (6H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H30ClF3N6O: 571.2194. found: 571.2209.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C@H:7]([NH:29][C:30]([C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:31])[C:8]([O:10][C@@H:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:12][C:13]([NH2:15])=[O:14])=[O:9])([OH:3])=[O:2].[CH3:42][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:42][O:2][C:1]([CH2:4][CH2:5][CH2:6][C@H:7]([NH:29][C:30]([C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:31])[C:8]([O:10][C@@H:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:12][C:13]([NH2:15])=[O:14])=[O:9])=[O:3]
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)O)NC(=O)c1cnc2ccccc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OC)NC(=O)c1cnc2ccccc2c1
Reaction time: 48 h

Procedure:
To a solution of (3S)-3-[(2S)-5-carboxy-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (100 mg) in methanol (10 ml) was added 2M solution of trimethylsilyldiazomethane in hexane (2 ml) at room temperature. After being stirred at the same temperature for 2 days, the solvent was removed under reduced pressure and the resulting solid was triturated with ethyl ether to give (3S)-3-[(2S)-5-methoxycarbonyl-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (68.4 mg).
Reaction SMILES: [C:1](=[O:11])([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[O:2][CH2:3]Cl.[I-:12].[Na+]>CC(C)=O>[C:1](=[O:11])([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[O:2][CH2:3][I:12]
Reactant: [I-]
Reactant: CC(C)CCOC(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)CCOC(=O)OCI
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Chloromethyl isopentyl carbonate (4.2 g) was dissolved in dry acetone (25 ml) and anhydrous sodium iodide (6.0 g) was added to it. The reaction mixture was stirred at room temperature protected from light for 6 hours. The acetone was evaporated off. The residue was taken in water (50 ml) and extracted with ether. The ether extract was washed successively with aqueous sodium bisulfite, water and brine and dried over sodium sulfate. Evaporation of ether gave a light-yellow oil of product weighing 6.1 g NMR (CDCl3)δ 0.96 (6H, d, J=5 Hz, (CH3)2), 1.63 (3H, m, CH2CH), 4.26 (2H, t, J=7 Hz, OCH2) and 5.96 (2H, s, CH2I).
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=3)[CH:5]=[CH:4][CH:3]=[N:2]1.ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:78][S:79]([CH:82]5[CH2:84][CH2:83]5)(=[O:81])=[O:80])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[N:1]1([C:6]2[N:7]=[C:8]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:78][S:79]([CH:82]6[CH2:84][CH2:83]6)(=[O:81])=[O:80])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=3)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-n3cccn3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title product 68 was prepared from 17-(3-pyrazol-1-yl-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (67) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=678 (M+H)+; 1H-NMR (CDCl3): 10.5 (br s, 1H), 8.4 (dd, J=2.5 Hz, 0.5, 1H), 8 (d, J=9.8 Hz, 1H), 7.75 (s, 2H), 7.00-7.10 (m, 2H), 6.55 (s, 1H), 6.45 (dd, J=2.5 Hz, 0.5, 1H), 5.95 (br s, 1H), 5.75 (dd, J=18.1 Hz, 8 Hz, 1H), 5.1 (t, J=10.3 Hz, 1H), 4.75 (t, J=7.0 Hz, 1H), 4.1 (dd, J=11.0 Hz, 4.3, 1H), 3.90 (s, 3H), 3.70 (d, J=11.0 Hz, 1H), 3.10-3.20 (m, 1H), 2.90-3.01 (m, 1H), 2.85 (s, 3H), 2.50-2.62 (m, 3H), 2.20-2.30 (m, 1H), 1.90-2.00 (m, 2H), 1.55-1.60 (m, 4H), 1.30-1.50 (m, 6H).
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:25]=[C:24]([O:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:23]=2[O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>O>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[N:27]=[C:26]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:25]=[C:24]([O:34][CH2:35][CH2:36][C:37]([O:39][CH3:1])=[O:38])[C:23]=2[O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])(=[O:20])=[O:19])=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCOc1nc(N2CCOCC2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Methanol (0.5 ml) and concentrated sulfuric acid (two droplets) were added to 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid (50 mg), and the mixture was stirred for 4 hours at room temperature, then poured into water, and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (chloroform-methanol (30:1)), to thereby obtain 46 mg (yield: 90%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.C1COCC1>[Pd].CO>[O:15]1[C:14]2([CH2:19][CH2:20][N:11]([C:3]3[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:12][CH2:13]2)[O:18][CH2:17][CH2:16]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N)cc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 123 %

Procedure:
To a solution of 8-(2-Methyl-5-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (100 mg, 0.278 mmol) in the mixed solvent of THF (3 ml) and methanol (3 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture is filtered and the filtrate was concentrated under vacuum to give 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-phenylamine [29] (Yield: 84.9 mg, 95.2%) as a off white solid.
Reaction SMILES: N[C:2]([C:4]1([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].C([OH:30])C>[Pd]>[CH2:21]([O:20][C:18]([NH:17][C:4]1([C:2]([OH:30])=[O:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Reaction time: 18 h

Procedure:
Palladium (10% on carbon; 210 mg) was added to a solution of tert-butyl 4-(aminocarbonyl)-4-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate (0.43 g, 1.14 mmol) in ethanol (20 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated to give the title compound (290 mg).