Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=O)[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:36][N:37]=[C:38]=[S:39].Cl>C([O-])([O-])=O.[K+].[K+]>[CH3:36][N:37]1[C:38](=[S:39])[NH:25][N:24]=[C:22]1[C:20]1[N:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[CH:21]=1
Reactant: CN=C=S
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(-c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3)c(-c3ccccc3C(F)(F)F)n2)n[nH]c1=S
Temperature: 25 °C
Yield: 11.3 %

Procedure:
To a suspension of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (215 mg, 0.430 mmol) in 8 mL 10% K2CO3 solution was added methyl isothiocyanate (0.06 mL, 0.877 mmol) via syringe. The reaction was refluxed 12 h and cooled to room temperature. The reaction was neutralized at 0° C. with 1M HCl and then extracted 3×10 mL with ethyl acetate. The combined organic layers were dried with MgSO4 and the solvent removed in vacuo. The crude residue was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 4-methyl-3-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazole-5(4H)-thione (27 mgs, II %) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 13.89 (s, 1H), 8.37 (s, 1H), 8.15-8.14 (m, 1H), 8.05-8.02 (m, 1H), 7.93-7.89 (m, 2H), 7.85 (d, J=8.58 Hz, 2H), 7.75-7.73 (m, 1H), 7.72-7.68 (m, 2H), 7.62-7.59, (m, 1H), 7.41 (d, J=8.58 Hz, 2H), 3.78 (s, 3H), 3.28 (s, 3H); MS (ES): 556.0 [M+H]+ and 578.3 [M+Na]+.
Reaction SMILES: [C:1](OCC(C)C)(=O)[C:2](C)=[CH2:3].[C:11]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[C:12]([CH3:14])=[CH2:13].C(OCCCC)(=O)C=C.[C:30](O)(=O)[CH:31]=[CH2:32].C1C(C(OOC(C)(C)C)=O)=CC=CC=1>CCCCOCCO.C(O)(C)C>[CH3:13][C:12]([C:11]([O:16][CH:17]1[C@@:31]2([CH3:32])[C:2]([CH3:3])([CH3:1])[C@H:19]([CH2:20][CH2:30]2)[CH2:18]1)=[O:15])=[CH2:14]
Reactant: C=C(C)C(=O)OCC(C)C
Reactant: C=CC(=O)O
Reactant: C=C(C)C(=O)OCCCC
Agent: C=CC(=O)OCCCC
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CCCCOCCO
Product: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
One hundred twenty-five parts of butyl Cellosolve is heated to 150° C. and a monomer mix consisting of 200 parts of isobutyl methacrylate, 137.5 parts of n-butyl methacrylate, 50 parts of n-butyl acrylate, 62.5 parts of acrylic acid and 50 parts of methacryloxyethyl esters of linseed oil fatty acids and an initiator solution consisting of 1.5 parts of t-butyl perbenzoate dissolved in 10 parts of butyl Cellosolve are added to the 150° C. solvent over three hours at a constant rate. Reaction temperature is held at 150±2° C. throughout the gradual additions and for 15 minutes after the addition of an initiator chaser solution consisting of 3 parts of t-butyl perbenzoate dissolved in 10 parts of butyl Cellosolve. The polymer solution is then cooled to 100° C. and diluted with 174 parts of isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:33])[N:21]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O.C(OCC)(=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:23]=[C:22]([NH2:33])[N:21]=[C:20]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([O:9][C:10]4[CH:15]=[CH:14][N:13]=[C:12]5[NH:16][CH:17]=[CH:18][C:11]=45)=[C:2]([F:1])[CH:3]=3)[CH:25]=2)=[CH:31][CH:30]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(-c2ccc(F)cc2)n1

Procedure:
36 mg (0.15 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XIX) and 38.5 mg (0.15 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine (from example LIX) are suspended in 1.5 ml of water, and 0.1 ml of 2 molar hydrochloric acid is added. The mixture is heated under reflux overnight. Ethyl acetate and a few drops of dimethylformamide are then added. The mixture is made alkaline using saturated sodium carbonate solution, the organic phase is separated off and the solvent is removed under reduced pressure. The product is purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([NH:28][CH:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1)[CH3:27].C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]([CH2:26][CH3:27])[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl)C1CCNCC1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, tert-butyl 4-ethylaminopiperidin-1-ylcarboxylate, PFTU, and diisopropylethylamine in DMSO at ambient temperature and subsequent reaction with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 3.87 minutes; C24H27Cl2N5O2 (488.42); mass spectrum: (M−H)−=487/489/491 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 39.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (100 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (94 mg) and triphenylphosphine (182 mg) in THF (3.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (315 μL) at room temperature, and the mixture was stirred for 14 hr. Triphenylphosphine (182 mg) and a 40% solution of diethyl azodicarboxylate in toluene (315 μL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (71 mg) as a pink oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[O:17]([CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[NH2:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCOc1ccccc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cnc2ccccc2c1NCCOc1ccccc1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
3—Nitro-N-(2-phenoxyethyl)quinolin-4-amine (6.0 g, 19 mmol), 5% platinum on carbon (1.5 g) and ethyl acetate (300 ml) were placed in a hydrogenation flask. The mixture was shaken overnight under a hydrogen pressure of 40 psi (2.8 Kg/cm2). The reaction mixture was filtered and the catalyst was washed with ethyl acetate. The filtrate was dried (MgSO4), filtered, and concentrated under vacuum to near dryness. Hexane was added and the resulting precipitate was collected by vacuum filtration to provide 4.9 g of N4-(2-phenoxyethyl)quinoline-3,4-diamine as a pale yellow solid.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1.[CH2:16]([CH2:18][NH2:19])[OH:17].CCN(C(C)C)C(C)C>CCCCO>[C:10]1([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:19][CH2:18][CH2:16][OH:17])[CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc(Nc2ccccc2)ncn1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2ccccc2)ncn1
Temperature: 200 °C
Yield: 97 %

Procedure:
50 mg of 6-chloro-N-phenylpyrimidin-4-amine hydrochloride, 14 mg of ethanolamine and 69 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 10:1. 2-(6-(Phenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=2)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:21]#[N:22].C([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C.[F-].[K+].Cl[CH:33](Cl)[CH3:34]>>[N:25]1([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][N:8]=3)[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]=2[C:21]#[N:22])[CH2:26][CH2:27][CH2:34][CH2:33][CH2:29][CH2:28]1
Reactant: CCN(CC)CC
Reactant: CC(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Agent: [F-]
Agent: [K+]
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2N2CCCCCC2)nc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
5-Chloro-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile (70 mg, 0.2 mmol) and triethylamine (40 mg, 0.4 mmol) were dissolved in dry dichloroethane (1.5 ml) and potassium fluoride (0.35 mg, 0.6 mmol) was added to the solution. The mixture was stirred at 20° C. for a period of 48 hours. Analytical HPLC indicated the reaction completion. The mixture was purified directly by preparative TLC to provide the desired product as white solid. MS: 414 (M+H); r.t.: 2.6 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]1(C)[C:40](O)=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:39]=[CH:40][CH:35]=[CH:36][C:37]=2[CH3:38])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4C)cc3)c2cc1OC
Yield: 79.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, o-cresol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (116 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 432 (M++1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:9]([Br:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16]([O-])(=O)[CH3:17].[Na+]>O>[Br:15][CH2:9][CH2:10][CH2:11][CH2:12][CH2:16][CH2:17][N:1]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(Br)Br
Reactant: CC(=O)[O-]
Reactant: Nc1ccccc1
Agent: [Na+]
Solvent: O
Product: BrCCCCCCN(CCCCCCBr)c1ccccc1
Temperature: 97.5 °C
Reaction time: 10 h

Procedure:
0.45 ml of aniline (5 mmol), 2.5 ml of dibromohexane (14.6 mmol), and sodium acetate (14.5. mmol) were charged in a reaction container and slowly heated to about 95 to 100° C. while generating bubbles under a nitrogen atmosphere. The reactant mixture was agitated for about 10 hours at about 95 to 100° C. The mixture was cooled down to room temperature, mixed with 30 ml of distilled water, and agitated for 10 minutes. The mixture was then treated to extract organic layers using ethylacetate, and then was distillated through reduced pressure distillation, thereby obtaining a sticky liquid. The sticky liquid was separated using preparative TLC (eluent: CH2Cl2:Hexane=1:2.5). The obtained compound was confirmed to be the compounds 221 of FIG. 3 using a 1H-NMR spectometry and mass spectometry. The results are shown in FIG. 5.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[CH:4]1[CH:17]([OH:23])[C:18]([O:20]CC)=[O:19])=[O:2].O[Li:25].O.[OH-].[Na+]>>[Li+:25].[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[C:5](=[O:16])[CH:4]1[CH:17]([OH:23])[C:18]([O-:20])=[O:19])=[O:2]
Reactant: [Li]O
Reactant: CCOC(=O)C(O)C1C(=O)N(c2ccc(C)cc2)CCN1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(N2CCN(C=O)C(C(O)C(=O)[O-])C2=O)cc1
Product: [Li+]
Yield: 93.8 %

Procedure:
According to the Step 1-2 in synthetic method for EXAMPLE 1, compound 110-1 (0.14 g) and LiOH—H2O (18 mg) were used instead of 1-1 (LP) and NaOH to obtain compound 110-2 (0.12 g) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].[Co:13]>[Pt]>[CH3:10][CH2:9][CH2:8][CH2:7][CH:3]([C:4]([O-:6])=[O:5])[CH2:1][CH3:2].[CH3:10][CH2:9][CH2:8][CH2:7][CH:3]([C:4]([O-:6])=[O:5])[CH2:1][CH3:2].[Co+2:13]
Reactant: CCCCC(CC)C(=O)O
Reactant: [Co]
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(CC)C(=O)[O-]
Product: [Co+2]

Procedure:
The electrochemical reaction was carried out in a reaction cell containing 20.0 g (0.138 mole) of 2-ethylhexanoic acid, 10.0 g mineral spirits and 40.0 g of 0.1N sodium hydroxide. A cobalt rod was used as the anode and platinum foil as the cathode. The connections were made and direct current was passed through the cell. After passing 14,645 coulombs of electricity, the electrosynthesis process was terminated and the weight of the cobalt consumed in the reaction was determined. 3.68 g (0.062 mole) cobalt was consumed. The organics were separated from the aqueous phase and were dried under reduced pressure resulting in a violet solution of cobalt octoate in mineral spirits that contained 10.1% cobalt.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([C@@:32]1([CH2:47]CO)[CH:36]([CH3:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([C@@:32]1([CH2:47][CH2:1][Br:5])[CH:36]([CH3:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: BrC(Br)(Br)Br
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCO)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
Carbon tetrabromide (1.64 g, 4.95 mmol) and triphenylphosphine (1.30 g, 4.95 mmol) were sequentially added to a solution of (3S)-3-(2-hydroxyethyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (1.56 g, 4.50 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere at 0° C. After heating to room temperature, the reaction solution was stirred for 10 minutes and concentrated to about 5 mL. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=4:1→2:1→1.5:1) to give 1.30 g (70%) of the diastereomer mixture title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[S:41]([CH2:45][C:46](O)=[O:47])([OH:44])(=[O:43])=[O:42].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:46]([CH2:45][S:41]([OH:44])(=[O:43])=[O:42])=[O:47])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)CS(=O)(=O)O
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CS(=O)(=O)O)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (17), and 48 μl of diisopropylethylamine in 1 ml of dimethylformamide was added to a solution of 40 mg of sulfoacetic acid, 110 μl of diisopropylcarbodiimide, and 76 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20->10/90). This gave the product of molecular weight 544.58 (C27H26F2N2O6S1); MS (ESI) 527.10 (M+H+—H2O)
Reaction SMILES: Br[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3cccs3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 3-[3-(2-bromoimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (22 mg, 0.0431 mmol; see example 11 (b)) in toluene (5 mL) and ethanol (0.5 mL) was added 2-thienyl boronic acid (27.6 mg, 0.216 mmol), Pd(PPh3)4 (3.0 mg, 2.59 μmol) and NaOH (0.17 mL, 0.26 mmol, 1.5 M aq), and the reaction mixture stirred for 4 h at 90° C. Another portion of 2-thienyl boronic acid (27.6 mg, 0.216 mmol) and Pd(PPh3)4 (3.0 mg, 2.6 mmol) was added and the reaction was stirred overnight at 90° C. The reaction mixture was diluted with EtOAc (30 mL) and washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:hexane (7:3) as eluent to give the sub-title compound in 90% yield (20 mg, 0.039 mmol).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[F:5][C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=[O:15])[CH2:12][CH2:11]2.CO>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[F:5][C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=[O:15])[NH:1][CH2:12][CH2:11]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2ccc(C(F)(F)F)c(F)c21
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2ccc(C(F)(F)F)c(F)c21
Yield: 56.1 %

Procedure:
Sodium azide (492 mg, 7.5688 mmol) was added portion wise to a stirred solution of 7-fluoro-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (I-77c: 500 mg, 2.2935 mmol) in TFA (15 mL) over a period of 5 hours at 80° C. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was concentrated under reduced pressure, followed by the addition of ice. The precipitated solid was filtered, washed with water (20 mL) and dried under reduced pressure to yield the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 300 mg of the product (56.1% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(Cl)Cl>O>[CH2:28]([O:27][C:25](=[O:26])[N:10]([CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCC(NCCCc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(N(CCCc2ccccc2)C(=O)OCc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
A mixture of 4-(3-phenyl-propylamino)-cyclohexanone (1.9 g, 8.21 mmol), K2CO3 (1.15 g, 8.3 mmol), benzyl chloroformate (1.42 g, 8.3 mmol) and CH2Cl2 (20 ml) was stirred at r.t for 1.5 h. H2O (50 ml) was added, and the mixture was extracted with CH2Cl2. The organic layer was dried (Na2SO4), evaporated and the residue was purified by chromatography (SiO2, CH2Cl2—MeOH 95:5) to give (4-Oxo-cyclohexyl)-(3-phenyl-propyl)-carbamic acid benzyl ester as a yellow oil (2.7 g, 90%, MS: m/e=365(M+)).