Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[F:39][C:40]1([F:46])[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>>[F:39][C:40]1([F:46])[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:41]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: FC1(F)CCCNC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCCC(F)(F)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3,3-difluoropiperidine were converted to the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:33]1C=C(S(Cl)(=O)=O)C=C[CH:38]=1>>[CH2:33]([O:28][C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:31][CH:30]=1)[CH3:38]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1

Procedure:
4-{[1-(3-Fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=439.3 (M−H), was prepared in analogy to example 30, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 4-{[1-(3-fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH:1]([C@H:4]1[O:9][CH2:8][C@H:7]([NH2:10])[CH2:6][O:5]1)([CH3:3])[CH3:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[CH:14][N:13]=1.C(N(CCCC)CCCC)CCC>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:1]([C@H:4]1[O:9][CH2:8][C@H:7]([NH:10][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[CH:14][N:13]=2)[CH2:6][O:5]1)([CH3:3])[CH3:2]
Reactant: Oc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Reactant: CC(C)[C@H]1OC[C@H](N)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)[C@H]1OC[C@H](Nc2ncc(Cc3ccc(O)nc3)c3ccccc23)CO1

Procedure:
In a sealed glass bottle under N2-atmosphere, 424 mg (2.92 mmol) of trans 2-isopropyl-[1,3]dioxan-5-ylamine, 396 mg (1.46 mmol) of 1-chloro-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline (contains 1-iodo derivative) and 2 ml of tributylamine are stirred at 150° C. for 48 h. The resulting mixture is diluted with EtOAc and NaHCO3-solution, the aqueous layer is separated and extracted twice with EtOAc. The organic phases are washed with brine, dried (Na2SO4) and concentrated in vaccuo. “Reversed Phase” medium-pressure chromatography (water/acetonitrile/TFA) yields trans 1-(2-isopropyl-[1,3]dioxan-5-ylamino)-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline; FAB-MS; (M+H)+=286; HPLC(gradient20-100) tRet=8.6.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: CCOC(=O)C1(N)CCCC1
Agent: Cl
Product: CCOC(=O)C1(NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)CCCC1
Yield: 77 %

Procedure:
Prepared as in Example 1b-JF from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and ethyl 1-aminocyclopentanecarboxylate hydrochloride. Yield 77%, a colorless liquid. MS 378 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[OH:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35]>C(OCC)C.C(O)C.C(OCC)(=O)C.O1CCOCC1.O>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35].[C:8]1([CH:6]([OH:7])[CH2:5][O:4][CH2:3][CH2:2][NH:1][C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: NCCOCC(O)c1cccc2ccccc12
Reactant: Clc1ncccn1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC(COCCNc1ncccn1)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
7 ml of water and 7 ml of dioxane were added to 0.7 g of 2-(2-aminoethoxy)-1-(1-naphthyl)ethanol to obtain a solution. To the solution was added 0.32 g of potassium carbonate. The resulting mixture was heated to 50° C. Thereto was added 0.35 g of 2-chloropyrimidine. The resulting mixture was refluxed for 3 hours. Thereto were added 0.32 g of potassium carbonate and 0.35 g of 2-chloropyrimidine. The resulting mixture was further refluxed for 2.5 hours. The reaction mixture was cooled and added to a mixture of 20 ml of ethyl acetate and 20 ml of ice water. The organic layer was separated. The aqueous layer was extracted with 10 ml of ethyl acetate. The extract was combined with the previously separated organic layer. To the combined organic layer was added 15 ml of water and the resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted with 10 ml of water. The extract was combined with the previously separated aqueous layer. To the combined aqueous layer was added 50 ml of methylene chloride and the resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=20/1) to obtain an oily product. To the oily product were added 4 ml of ethanol and 0.21 g of maleic acid. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2 ml of diethyl ether. The resulting mixture was stirred at the same temperature for 1 hour. The resulting crystals were collected by filtration and dried to obtain 0.53 g of 1-(1-naphthyl)-2-{2-[(pyrimidin-2-yl)amino]ethoxy}ethanol maleate (compound No. 268).
Reaction SMILES: CS(N)(=O)=O.[CH3:6][O:7][CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([O:52][CH2:53][C:54]2([C:64]#[N:65])[CH:61]3[CH2:62][CH:57]4[CH2:58][CH:59]([CH2:63][CH:55]2[CH2:56]4)[CH2:60]3)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[Cl:41][C:42]1[C:43]([O:52][CH2:53][C:54]2([C:64]#[N:65])[CH:55]3[CH2:56][CH:57]4[CH2:58][CH:59]([CH2:60][CH:61]2[CH2:62]4)[CH2:63]3)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47]([NH:13][S:10]([CH2:9][CH2:8][O:7][CH3:6])(=[O:12])=[O:11])=[O:48]
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2Cl)C2CC3CC(C2)CC1C3
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: COCCS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with 2-methoxyethanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following trituration with a 5:1 mixture of hexanes in diethyl ether (10 mL) as a colorless powder (0.094 g, 63%): 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.40 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 3.70 (s, 4H), 3.18 (s, 3H), 2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H), 1.70-1.60 (m, 4H); MS (ES−) m/z 483.2, 485.2 (M−1).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])[C:8]=1[CH2:40][CH2:41][CH3:42])C>CO.[OH-].[Na+]>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:43])=[O:3])=[C:8]([CH2:40][CH2:41][CH3:42])[C:9]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=1[CH2:37][CH2:38][CH3:39])(=[O:15])[CH3:14]
Reactant: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 81.4 %

Procedure:
A solution of 2.617 g (0.0044 mole) of [4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]acetic acid ethyl ester in 50 ml of methanol and 21.8 ml of 1.0N sodium hydroxide was stirred at reflux for 2 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to 2.0. The product was extracted with methylene chloride and the dried (magnesium sulfate) extract was concentrated in vacuo. The residue was crystallized from ether-hexane to give 2.05 g (82% yield) of [4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]acetic acid, melting point 68°-71°.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51](O)=[O:52]>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:51]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=3)=[O:52])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccn1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.174 g, 0.50 mmol), HOBt (0.068 g, 0.50 mmol), EDCI (0.115 g, 0.60 mmol) and picolinic acid (0.068 g, 0.55 mmol) were dissolved in 5 ml of dry DMF. The mixture allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure. Then residue was dissolved in EtOAc (30 ml) and the mixture was washed with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 0% to 10% MeOH in EtOAc to afford the title compound 7 (195 mg, 86%). The product was taken up in 2 ml of EtOAc. To the mixture, 2 ml of 4 N HCl in EtOAc was added. The solvent was removed and remaining material was the desired product 7 was obtained as a hydrochloride salt (pale yellow solid). LC: 100%. MS: m/z=453.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C1COCC1.CCO>[CH3:1][CH:2]([CH3:19])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(Cc1cccc(OC)c1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(CC(CC(=O)O)C(C)C)c1
Temperature: 60 °C
Yield: 100.1 %

Procedure:
Ethyl 4-methyl-3-{[3-(methyloxy)phenyl]methyl}pentanoate (66) (1.72 g, 6.51 mmol) was dissolved in THF (30 mL) and EtOH (30 mL). To this solution was added 1 N NaOH (35 mL). The reaction mixture was heated at 60° C. for 1.5 h. Cooled, the mixture was extracted with EtOAc. The combined extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give 1.54 g (100%) of the crude product 67 as a yellow oil. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3): δ 0.91 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H), 1.70-1.80 (m, 1H), 2.10-2.25 (m, 2H), 2.32 (dd, J1=15.3 Hz, J2=6.5 Hz, 1H), 2.46 (dd, J1=13.7 Hz, J2=8.2 Hz, 1H), 2.67 (dd, J1=13.7 Hz, J2=6.4 Hz, 1H), 3.79 (s, 3H), 6.70-6.80 (m, 3H), 7.15-7.25 (m, 1H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:20])[CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]=1[CH3:18])=[O:20])[CH3:10]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccccc2)c1C

Procedure:
Similar to Example 1, phenyl hydrazine (7.5 mmol, 0.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (7.5 mmol, 1.3 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum and the oil resuspended in chloroform. The resulting suspension was washed with 5% sodium bicarbonate, 5% hydrochloric acid, and then brine. The organic layer was dried over NaSO4, the solids filtered, and the solvents removed under vacuum. The crude material was purified over silica gel to yield the named product as an oil. 1H-NMR (CDCl3, ppm): 1.37 t (3H); 2.51 s (6H); 4.32 q (2H); 7.42 bs (5H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:36])[CH2:16]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13]>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9]/[CH:10]=[CH:16]/[C:15]([O:14][CH2:12][CH3:13])=[O:36])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
2-(Tert-butyldimethylsilyloxy)acetaldehyde (10.0 g, 57.3 mmol) was added to a solution of (2-ethoxy-2-oxoethyl)triphenylphosphorane (20.0 g, 57.4 mmol) in 150 mL toluene, the mixture was stirred at RT overnight and then heated to 50° C. for 5 hrs. Solvents were removed and the residue was suspended in 400 mL of hexane. The solution was filtered, the filtrate was concentrated to give the product 3A as a colorless liquid 13.7 g (98%). 1H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6H), 0.92 (s, 9H), 1.30 (t, 3H, 6 Hz), 4.21 (q, 2H, 6 Hz), 4.34 (dt, 2H), 6.09 (dt, 1H), 7.00 (dt, 1H); ESI-MS:m/z 245.3 (M+H)+, HPLC retention time: T=2.737 min (analytical-3).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)N(C)c3ccc(Cl)cc32)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)C(Cc2ccccc2Cl)N=C(c2ccc(O)cc2)c2cc(Cl)ccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
(Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (230 mg, 0.524 mmol) was dissolved in methylene chloride (5 mL) and cooled to −78° C. under nitrogen. Boron tribromide (54 μL 0.576 mmol) was added dropwise. The mixture turned orange. It was kept at −78° C. for 2 h then allowed to warm to RT. Tlc indicated no reaction after 6 hr. An additional equivalent of boron tribromide was added. The mixture was left stirring overnight at RT. Carefully added water (2 mL) then brine (2 mL). The aqueous layer was extracted twice with methylene chloride. The combined organic layers were dried over magnesium sulfate then filtered and the solvent evaporated. The residue was chromatographed on silica gel eluting with 30-50% ethyl acetate in hexanes to give (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-hydroxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one as a yellow solid (18 mg). 1H NMR (300 MHz, CDCl3) δ 3.4 (s, 3H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 1H), 6.8 (d, 2H), 7.1-7.6 (m, 9H); ESI m/z measured 425.0828 [M+H+], calculated 425.0824.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:29][CH:30]=[C:31]([C:33]([N:35]2[CH2:40][C:39]3([CH2:45][CH2:44][N:43]([CH2:46][CH2:47][C:48]4[CH:61]=[CH:60][C:51]([CH2:52][CH2:53][O:54][CH2:55][CH2:56][C:57](O)=[O:58])=[CH:50][CH:49]=4)[CH2:42][CH2:41]3)[O:38][CH2:37][CH2:36]2)=[O:34])[N:32]=1)([CH3:27])[CH3:26].[CH3:62][O:63][CH:64]([O:73][CH3:74])[CH2:65][NH:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1.C(N(CC)CC)C>CN(C=O)C>[CH:67]1([N:66]([CH2:65][CH:64]([O:73][CH3:74])[O:63][CH3:62])[C:57](=[O:58])[CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]2[CH:60]=[CH:61][C:48]([CH2:47][CH2:46][N:43]3[CH2:42][CH2:41][C:39]4([O:38][CH2:37][CH2:36][N:35]([C:33]([C:31]5[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][CH:30]=5)=[O:34])[CH2:40]4)[CH2:45][CH2:44]3)=[CH:49][CH:50]=2)[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)O)cc4)CC3)C2)cs1
Reactant: COC(CNC1CCCCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(CN(C(=O)CCOCCc1ccc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)cc1)C1CCCCC1)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.23 g) was added in one portion to an ice cold solution of 3-(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)phenethoxy)propanoic acid [Example 1, step e] (0.3 g) and N-(2,2-dimethoxyethyl)cyclohexanamine [WO 2008075025] (0.087 g) and triethylamine (0.26 mL) in DMF (10 mL). The mixture was stirred at 20° C. for 1 hour before being partitioned between ethyl acetate and brine. The organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.32 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccncc4)c3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccncc4)c3c2)cc1
Yield: 70.5 %

Procedure:
The title compound was prepared using methyl 4-[N-(3-(4-pyridyl)-1H-indazol-5-yl)carbamoyl]benzoate (0.129 g, 0.35 mmol) and lithium hydroxide mono hydrate (0.075 g, 1.8 mmol) in tetrahydrofuran (5 mL). The compound was isolated as a beige powder that was washed with small portions of diethyl ether (5 mL). (0.091 g, 70.5% yield) 1H NMR (DMSO-d6) 10.2 (s, 1H), 8.5 (m, 3H), 7.9–7.8 (m, 6H), 7.6 (s, 2H); ES-MS (m/z) 359 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23])=[CH:25][CH:26]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)c1ccc(NC(c2cc3ccccc3o2)C2CCCCC2)cc1
Reactant: CCOC(=O)CCNC
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cc3ccccc3o2)C2CCCCC2)cc1

Procedure:
Using 4-{[1-benzofuran-2-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized above and ethyl 3-(methylamino)propanoate (113 mg) and in the same manner as in Example A1(4), the title object compound (226 mg, 73%) was obtained as a pale-red solid.
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=O.[CH:15]([C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:19]=1[NH2:20])([CH3:17])[CH3:16]>C(O)(=O)C>[CH:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:18]([CH:15]([CH3:17])[CH3:16])[C:19]=1/[N:20]=[C:2]1/[C:1](=[N:20]/[C:19]2[C:21]([CH:25]([CH3:26])[CH3:27])=[CH:22][CH:23]=[CH:24][C:18]=2[CH:15]([CH3:17])[CH3:16])/[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[C:3]/1=[CH:4][CH:5]=[CH:6]3)([CH3:27])[CH3:26]
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1/N=C1C(=N/c2c(C(C)C)cccc2C(C)C)/c2cccc3cccc/1c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
A mixture of 1.82 g (10 mmol) of acenaphtoquinone, 3.54 g (20 mmol) of 2,6-diisopropylaniline, and 40 ml of glacial acetic acid was refluxed for 2 h and then stirred for 12 h at room temperature. The resulting precipitate was separated, washed with 20 ml of cold water, and dried under vacuum. 3.89 g of dark-yellow solid were obtained with a yield of 78%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: O=C1CCc2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCCCC3)c(F)cc21

Procedure:
5,6-difluoro-indan-1-one (2.49 g, 14.8 mmol) and piperidine (4.4 ml, 3.78 g, 44.4 mmol) were dissolved in pyridine (10 ml) and heated to reflux for 16 hours. The reaction was cooled, and the solvent removed under vacuum. The residue was taken in ethyl ether, washed with 1N aqueous sodium hydroxide and water, dried with magnesium sulfate, and the solvent removed under vacuum to give the desired product as 2.97 g of a black solid that was used without further purification. 1H NMR (300 MHz, CDCl3) 7.32 (d, 1H), 6.88 (d, 1H), 3.19 (m, 4H), 3.03 (m, 2H), 2.66 (m, 2H), 1.73 (m, 4H), 1.62 (m, 2H). MS (CSI) m/e 234 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][NH2:8])=[O:4].[Cl:32][CH2:33][CH2:34][CH2:35][S:36](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:38])=[O:37]>>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([NH:8][CH2:7][CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:38])=[O:37]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)NC(=O)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OC

Procedure:
2-Methoxycarbonylamino-3-octadecylcarbamoyloxypropylamine IVe1 is allowed to react and worked up by the same procedure as described in (4). m.p. 99°-101° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.