Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10]>CO>[C:9]([NH2:10])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: N#Cc1cccnc1
Agent: [K+]
Solvent: CO
Product: NC(=O)c1cccnc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution comprising nitrile hydratase solution 25 (0.697 μmol/min; 0.025 ml) and potassium phosphate buffer (0.1 M; pH 7.0; 0.475 ml) was incubated at different temperatures in the range from 20 to 70° C. for 60 min. The solution was then cooled to 20° C. using an ice bath and 3-cyanopyridine (0.5 M; 0.500 ml) was 30 added. The reaction mixture was incubated at 20° C. for 10 min. The reaction was stopped by adding MeOH. The amount of nicotinamide produced was determined by means of HPLC according to Example 1. After 60 minutes of incubation at temperatures above 40° C., nitrile hydratase activity decreased markedly and, after 60 min of incubation at 50° C., nitrile hydratase activity was only about 25% of the original activity (FIG. 15).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:29](Cl)=[O:30])[CH3:25].CC[O-].[Na+]>C1C=CC=CC=1.O>[CH2:24]([O:26][C:27]([C:28]1[C:29](=[O:30])[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:5]2[C:6]([C:7]=1[OH:8])=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:32])[CH3:25]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(=O)N(C)OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 80 °C
Yield: 42749.8 %

Procedure:
A solution of 9 (0.13 g, 0.38 mmol) in 3 mL of anhydrous benzene was treated with ethyl-3-chloro-3-oxopropionate (54 μL, 63.0 mg, 0.421 mmol). The reaction mixture was heated to 80° C. for 1 h. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was dissolved in 3 mL of ethanol, treated with NaOEt (40.0 mg, 0.59 mmol). The suspension was heated to 80° C. for 10 min, allowed to cool to room temperature, and diluted with H2O. The resulting precipitate was filtered to give 10 (63.0 g, 43%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[S:10]([O:13]S(C(F)(F)F)(=O)=O)(=[O:12])=[O:11].O[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[N:28]([CH3:34])[C:27]2([CH3:36])[CH3:35].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:8][C:9]([F:22])([F:21])[S:10]([O:13][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[N:28]([CH3:34])[C:27]2([CH3:36])[CH3:35])(=[O:12])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN1C(=O)c2ccc(O)cc2C1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1C(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2C1(C)C
Reaction time: 1 h

Procedure:
With cooling with ice, 0.192 mL of triethylamine and 0.174 mL of trifluoromethanesulfonic acid anhydride were added to 4.3 mL of a chloroform solution of 165 mg of 5-hydroxy-2,3,3-trimethylisoindolin-1-one obtained in Production Example 49-2, and stirred for 1 hour with cooling with ice. 2 mL of aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (chloroform) to obtain 257 mg of the entitled compound as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([CH3:21])(=[O:20])=[O:19])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([CH2:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@H:30]([C:31]([N:15]2[CH2:16][CH2:17][N:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:13][CH2:14]2)=[O:32])[CH2:29][C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of (cyclopropylmethyl)(methylsulfonyl)-(2-piperazinyl-phenyl)amine (HCl salt, 2.3 g, 6.0 mmol), (2S)-3-[(tert-butyl)oxycarbonyl]-2-[(4-chlorophenyl)-methyl]propanoic acid (1.8 g, 6.02 mmol, Step 4), HOBt (0.81 g, 6.0 mmol, Novabiochem), and TEA (1.67 mL, 12.0 mmol) in 20 mL of CH2Cl2 at 0° C. was added EDC (1.73 g, 9.03 mmol, Advanced Chemtech). The reaction was warmed to RT and stirred for 12 h. The reaction was quenched with satd NaHCO3, extracted with 80 mL of EtOAc and the organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The compound was further purified by silica gel column chromatography (50% EtOAc in hexane) to provide 2.3 g of tert-butyl (3S)-3-[(4-chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)-amino]phenyl}-piperazinyl)-4-oxobutanoate as a white foam. MS (ESI, pos. ion) m/z: 590.6 (M+1). Calc'd for C30H40ClN3O5S: 589.24. Anal. Calcd for C30H40ClN3O5S: C, 61.05; H, 6.83; N, 7.12; Cl, 6.01. Found: C, 60.91; H, 6.69; N, 7.09; Cl, 6.16.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:20]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=3)=[O:30])[C:19]([C:39]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=3[O:49][CH2:50][CH3:51])=[N:18]2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[N:20]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)=[CH:33][CH:32]=3)=[O:30])[C:19]([C:39]3[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:42]=[CH:41][C:40]=3[O:49][CH2:50][CH3:51])=[N:18]2)=[CH:13][CH:12]=1
Reactant: OCCN1CCNCC1
Reactant: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CCl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CN2CCN(CCO)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(2-Hydroxyethyl)-piperazine (10 uL, 0.08 mmol) was added to a solution of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl)-methanone (20 mg, 0.03 mmol) and diisopropylethylamine (7 uL, 0.04 mmol) in anhydrous dimethylformamide (1.0 mL). The mixture was stirred overnight at 80° C. Evaporation of the solvent and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-{(4-(2-hydroxyethyl)piperazine-1-yl)methyl}phenyl]methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-{(4-(2-hydroxyethyl)piperazine-1-yl)methyl}phenyl]methanone hydrochloride as a off-white powder (21 mg, 98%). LR-MS (APCI): 726.1 [(M+H)+].
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[C:49](O)(=[O:53])[CH:50]([CH3:52])[CH3:51]>>[C:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:44][CH2:45]1)(=[O:53])[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)C(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (0.4 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using isobutyric acid as the acylating agent. LCMS: m/e 712.8 (M+H)+, 4.46 min (method 15). 1H NMR (500 MHz, METHANOL-d4) δ 7.88 (d, J=8.2 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.77-3.54 (m, 4H), 2.97 (dt, J=13.4, 6.6 Hz, 2H), 2.86-2.71 (m, 3H), 2.70-2.51 (m, 4H), 2.46 (br. s., 1H), 2.15 (dd, J=17.1, 6.4 Hz, 1H), 2.08-1.82 (m, 5H), 1.75 (s, 3H), 1.73-1.18 (m, 16H), 1.22 (s, 3H), 1.11 (d, J=6.7 Hz, 6H), 1.10 (s, 3H), 1.05 (s, 3H), 0.97 (s., 3H), 0.97 (s., 3H),
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[O:17][CH2:18][O:19][CH3:20].[CH:21]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=2)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH:21]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][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]([O:17][CH2:18][O:19][CH3:20])[CH:12]=3)[CH:32]=2)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COCOc1cc(O)ccc1-c1cc(OC)ccc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OCOC)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 78 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-(methoxymethoxy)biphenyl-4-ol (1.29 g), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (1.26 g) and tributylphosphine (2.3 mL) in toluene (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.32 g), and the mixture was stirred at room temperature for 50 hr. To the reaction mixture was added hexane, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.84 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@H:33]([CH3:37])[C@H:34]([OH:36])[CH3:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:36][C@H:34]([CH3:35])[C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH3:37]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](N)[C@@H](C)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)[C@@H](C)O)[nH]2)c1
Reaction time: 72 h
Yield: 57.4 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (2.00 g, 4.48 mmol) synthesized in Example (78k) and (2R,3R)-3-aminobutan-2-ol (0.94 g, 8.96 mmol) synthesized in Example (88a) were dissolved in methanol (30 mL), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.84 g, 8.96 mmol) was added at room temperature, followed by stirring for 3 days under nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (30 mL) was added, and the solution was separated with ethyl acetate (70 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (1.33 g, 57%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:19][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[Cl:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=Cc1ccncc1Cl
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NCc2ccncc2Cl)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To 6-amino-nicotinic acid methyl ester (553, 2.15 g, 0.014 mol) in acetonitrile (60.0 mL) were added 3-chloro-pyridine-4-carbaldehyde (554, 2.00 g, 0.014 mol), triethylsilane (11.00 mL, 0.069 mol) and trifluoroacetic acid (5.00 mL, 0.065 mol). The reaction was stirred at 80° C. overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (555, 1.5 g, 38.2%). MS (ESI) [M+H+]+=278.9.
Reaction SMILES: [C:1]1([CH:7]([O:10][Si](C)(C)C)[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].BrC[C:27]1[CH:28]=[C:29]([F:36])[C:30]([S:34][CH3:35])=[C:31]([F:33])[CH:32]=1.Cl>C1COCC1>[F:36][C:29]1[CH:28]=[C:27]([CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH:32]=[C:31]([F:33])[C:30]=1[S:34][CH3:35]
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1
Reactant: CSc1c(F)cc(CBr)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(F)cc(CC(=O)c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of phenyl[(trimethylsilyl)-oxy]aceto-nitrile (13.7 g, 60.7 mmol) in anhydrous THF (140 mL) cooled in a dry ice/acetone bath, was added a ThF solution of lithium bis(trimethylsilyl)amide(62 mL 1.0 M) slowly over 15 minutes. The reaction mixture was stirred for 45 minutes cooling at −78° C., then a solution of 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene (14.7 g, 58 mmol) in anhydrous THF (20 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. To this mixture was added 5% HCl (300 mL) and the mixture stirred for one hour. The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL). To the combined extracts was added 5% sodium hydroxide (200 mL), and the mixture stirred for one hour. Additional water (200 mL) was added, the organic phase was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30% gave 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone as light yelow solid (11.0 g, 68%). MP 71.8-71.9° C. 1H NMR (CDCl3/400 MHz) 7.96-7.99 (m, 2H), 7.57-7.61 (m, 1H), 7.24-7.50 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 2.42 (s, 3H). HRMS m/z 279.0667 (M+H+, calcd 279.0655). Anal. Calcd for C15H12F2OS: C, 64.73; H, 4.35; Found: C, 64.70; H, 4.38.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.C1C(=O)N([I:18])C(=O)C1>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]([I:18])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1csc(N)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N)sc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of methyl 2-aminothiazole-4-carboxylate (5.6 g, 35.4 mmol) in DCM (60 mL) was added NIS (9.56 g, 42.5 mmol). The mixture was stirred at rt for 24 hours and then diluted with EtOAc (200 mL) and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to provide 9.5 g (94%) of the desired product methyl 2-amino-5-iodothiazole-4-carboxylate (8A): LC/MS(APCI): m/z 284.9 (M+H).
Reaction SMILES: [C:1]([CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)[CH3:16])=[CH:10][CH:9]=1)[CH3:7])([O:3][CH3:4])=[O:2].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=O>>[C:1]([CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([N:17]2[CH2:18][CH:19]([C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)[O:26][CH:28]2[C:27]([O:31][CH3:32])=[O:30])[CH3:16])=[CH:12][CH:13]=1)[CH3:7])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C)n2)cc1
Reactant: COC(=O)C=O
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CC(c3csc(C)n3)OC2C(=O)OC)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column using petroleum ether/ethyl acetate =7:3 as eluant.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([CH3:19])([O-:18])=[O:17].N12CCCN=C1CCCCC2>ClCCl>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]([OH:9])[CH2:19][N+:16]([O-:18])=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[N+](=O)[O-]
Reactant: O=CC(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=[N+]([O-])CC(O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Fifty grams (254.78 mmol) of diphenylacetaldehyde (Aldrich) and 18.66 g (305.73 mmol) of nitromethane was dissolved in 635 mL of dichloromethane. The stirred solution was treated with 35 g of 3Å molecular sieves followed by 11.64 g (76.43 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Aldrich) and stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was treated with 700 mL of 2N aqueous HCl. The organic layer was separated and washed with saturated brine solution, dried with sodium sulfate and evaporated in vacuo. The residue was treated with 600 mL of hexane and stirred overnight whereupon crystallization occurred. After isolation there was obtained 38.22 g (58%) of 3,3-diphenyl-2-hydroxy-l-nitropropane as a pale yellow solid which was used directly in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NC[CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])C>CN(C)C1C=CN=CC=1.ClCCl.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)OCCN(C)C)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 7 h
Yield: 86.2 %

Procedure:
To a mixture of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-carboxypent-1-yl]oxy-4-methylphenyl]benzamide (250 mg), 2-dimethylaminoethyl (99 mg) and 4-dimethylaminopyridine (36 mg) in dichloromethane (10 ml) was added N-ethyl-N'-(3-dimethylaminoprop-1-yl)carbodiimide hydrochloride (71 mg) at 0° C. and stirred at the same temperature for 7 hours. The mixture was diluted with chloroform (20 ml) and the solution was washed with water (20 ml×2) and brine. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. This residue was purified by silica gel column chromatography (SiO2 30 g, 1-10% methanol in chloroform) to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(2-dimethylaminoeth-1-yl)oxycarbonylpent-1-yl]oxy-4-methylphenyl]benzamide (238 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][OH:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][OH:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: O=C(O)c1ccc(S(=O)(=O)CCO)cc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCO)cc1Cl

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 2-chloro-4-(2-hydroxyethylthio)benzonitrile. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxyethylthio)benzoic acid. 1 g of 2-chloro-4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 451.0 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11]([O:13][C:14](=O)[CH3:15])=[CH2:12]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:12]=[CH:11][O:13][CH:14]=[CH:15][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=COC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(C=COC=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
104 g (0.75 Mol) of 4-nitrophenol are dissolved in 420 ml (4.5 Mol) acetic acid vinyl ester. After washing with nitrogen, successively 3.0 g mercury acetate and 0.2 ml BF3 -etherate are added. The reaction mixture is stirred for 4 hours at 50° C. After cooling, 2 g sodium acetate are added, evaporated, and the residue then dissolved in ether. There follows washing three times with 2 n-caustic soda, three times with water, drying and evaporation. The residue is recrystallized from ether. 65 g (52% of theoretical amount) of 4-nitrophenylvinylether are obtained, with a melting point of 59°-61° C.