Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].C1N(CCS(O)(=O)=O)CCN(CCS(O)(=O)=O)C1.C1N(CCCS(O)(=O)=O)CCN(CCO)C1.C([O-])(=O)C.[O:44]=[CH:45][C@@H:46]([C@H:48]([C@@H:50]([C@@H:52]([CH2:54][OH:55])[OH:53])[OH:51])[OH:49])[OH:47]>C1N(CCCS(O)(=O)=O)CCOC1.C1(C=CC=C(O)C=1)O.[NH4+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[Fe+3].Cl.O>[OH:44][CH2:45][C:46]([C@H:48]([C@@H:50]([C@@H:52]([CH2:54][OH:55])[OH:53])[OH:51])[OH:49])=[O:47]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Fe+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Glucose isomerase assays: TNXI and its mutants were assayed routinely with glucose as the substrate. The enzyme (1–1.5 mg/ml) was incubated in 100 mM MOPS (pH 7.0) [or 100 mM sodium acetate (pH 5.5)] containing 1 mM CoCl2 and 0.4 M glucose at 80° C. for 10 min. The reaction was stopped by transferring the tube to an ice bath. The amount of fructose produced was determined by the resorcinol-ferric ammonium sulfate-hydrochloric acid method (Schenk and Bisswanger, 1998). To determine the effect of temperature on activity, the enzymes were incubated in the reaction mixture at the temperatures of interest in a heated water (45–95° C.) or oil bath (95–110° C.) for 10 min. The effect of pH on activity was determined using the routine assay described above except that the MOPS buffer was substituted with 100 mM sodium acetate (pH 4.3–5.8), 100 mM PIPES (pH 6.1–7.0), or 100 mM EPPS (pH 7.2–8.1). All pHs were adjusted at room temperature, and the ΔpKa/Δt's for acetate, PIPES, and EPPS (0,–0.0085, and −0.011, respectively) (USB, Cleveland, Ohio) were taken into account for the results. To determine the kinetic parameters, assays were performed in 50 mM MOPS (pH 7.0) containing 10–1,500 mM glucose and 1 mM CoCl2. One unit of glucose isomerase activity is defined as the amount of enzyme that produces 1 μmol of fructose per minute under the assay conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:30]1([CH2:36][CH2:37][NH:38][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:29])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: NCCN1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCN2CCNCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 42.3 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-ethylamine (38.7 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide (45.9 mg, 58.0%). HRMS (ES+) m/z Calcd for C29H37Cl2N5O+H [(M+H)+]: 542.2448. found: 542.2445.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH:20]([N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)=[O:21]>>[CH:20]([N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][CH:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:28])=[CH:25][CH:24]=1)=[O:21]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: CN(C=O)c1ccc(C(=O)O)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(N(C)C=O)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(formyl-methyl-amino)-benzoic acid. MS: 421.3 (M+H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([N:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1>[CH2:18]([N:25]1[C:29]([CH:30]([OH:31])[CH2:3][CH2:4][CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: O=Cc1cncn1Cc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
Magnesium turnings (0.5 g) were covered with dry tetrahydrofuran (4 ml). 1-Bromo-3,3-diphenylpropane (5.6 g) in 20 ml of dry tetrahydrofuran was added dropwise. The mixture was stirred at reflux for one hour. After being cooled to room temperature, 3-benzyl-3H-imidazole-4-carbaldehyde (3.8 g) in 20 ml of dry tetrahydrofuran was added dropwise to the Grignard reagent and the mixture was refluxed for two hours. The cooled reaction mixture was poured into a cold diluted hydrochloric acid solution. Work-up of the mixture gave the crude product, which was converted to its hydrochloride salt in ethyl acetate using dry hydrochloric acid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([OH:18])([CH3:17])[C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[OH:18][C:5]([CH3:17])([C:6]([NH:8][CH2:9][C:10]([F:15])([F:16])[C:11]([F:12])([F:14])[F:13])=[O:7])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of 2.91 g (9.93 mmol) 2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid ethyl ester in 50 ml of tetrahydrofurane were added 0.42 g (9,92 mmol) of lithium hydroxide in 20 ml of water and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was acidified to pH 1. Extraction with ethylacetate gave 2.46 g (94%) of the title compound as a solid, MS m/e (%): 263.9 (M−H, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])/[C:7](/[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=[N:8]\[OH:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[C:1]([O:5][C:6](=[O:16])[C:7]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=[N:8][O:9][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C(=N\O)c1csc(N)n1
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(=NOCC(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75.2 %

Procedure:
6.1 g (25 mmol) of 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetic acid t-butyl ester are dispersed in 250 ml of dry acetonitrile. There are now added thereto at room temperature while stirring 13.7 g (50 mmol) of 4-nitrobenzyl bromoacetate and 12.9 ml (75 mmol) of N-ethyldiisopropylamine. 5 minutes later 7.5 g (50 mmol) of sodium iodide are added thereto. The mixture is stirred at room temperature for 3.5 hours in an argon atmosphere. The solvent is subsequently removed by evaporation and the residue is diluted with 500 ml of ethyl acetate. The resulting solution is washed four times with a total of 2 l of water. The water is extracted with 300 ml of ethyl acetate and the combined ethyl acetate solutions are dried over sodium sulphate and evaporated to dryness. After crystallization from ethyl acetate/hexane, there are obtained 8.2 g (75%) of 2-(2-amino-4-thiazolyl)-2-[[(p-nitrobenzyloxycarbonyl)methoxy]imino]-acetic acid t-butyl ester of melting point 146.8° (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:26]=1[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)(C)NC(=O)c1cc(F)ccc1Br
Product: CC(C)(C)NC(=O)c1cc(F)ccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromo-N-(tert-butyl)-5-fluorobenzamide. MS (ESI): mass calcd. for C21H20F2N4O, 382.16; m/z found, 383.2 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])=[C:8]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cc(C)ccc1C(=O)NC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CBr)ccc1C(=O)NC(C)(C)C
Temperature: 25 °C

Procedure:
An amount of 160 mg (0.72 mmol) of the compound from Example 22A was heated under reflux with 129 mg (0.72 mmol) of N-bromosuccinimide and also 12 mg (0.07 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride for 16 h. After cooling to RT, the mixture was diluted with 10 ml of dichloromethane and washed with 10 ml of water. It was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was subsequently purified by chromatography [Method 8]. This gave 103 mg (47% of theory) of the target compound.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:20])[NH:12][CH:11]([CH3:13])[CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9]1.[Cl:21][CH:22]([Cl:26])[C:23](Cl)=[O:24]>C(N(CC)CC)C>[CH3:20][C:8]1([CH3:7])[N:12]([C:23](=[O:24])[CH:22]([Cl:26])[Cl:21])[CH:11]([CH3:13])[CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1NC(C)(C)OC1c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1C(c2ccccc2)OC(C)(C)N1C(=O)C(Cl)Cl
Reaction time: 0.5 h

Procedure:
Twenty-three (23) ml. of a benzene solution containing 5.7 g. of 2,2,4-trimethyl-5-phenyl oxazolidine was mixed with 25 ml. of benzene and 3.1 g. of triethylamine and stripped at room temperature, while 4.4 g. of dichloroacetyl chloride was added dropwise. After standing for about 30 minutes, the mixture was washed with water, separated, dried over magnesium sulfate and stripped under vacuum. The product which crystallized was extracted with ether and precipitated with pentane. There was obtained 3.9 g. of a solid, the title compound, m.p. 126° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][CH2:15][C@:16]1([CH3:29])[C@H:20]([CH:21]=[CH2:22])[O:19][C@H:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17]1)[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:49][O:50][C:51]1[CH:68]=[CH:67][C:54]([CH2:55][O:56][CH2:57]/[CH:58]=[C:59](\[CH3:66])/[C@@H:60](O)[C@@H:61]([CH3:64])[CH:62]=[CH2:63])=[CH:53][CH:52]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C1COCC1>[Si:1]([O:8][CH:9]([CH2:14][CH2:15][C@:16]1([CH3:29])[C@H:20]([CH:21]=[CH2:22])[O:19][C@H:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:17]1)[CH2:10][C:11]([O:13][C@@H:60]([C@@H:61]([CH3:64])[CH:62]=[CH2:63])/[C:59](/[CH3:66])=[CH:58]/[CH2:57][O:56][CH2:55][C:54]1[CH:67]=[CH:68][C:51]([O:50][CH3:49])=[CH:52][CH:53]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C[C@H](C)[C@H](O)/C(C)=C/COCc1ccc(OC)cc1
Reactant: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CCC(CC(=O)O[C@H](/C(C)=C/COCc1ccc(OC)cc1)[C@@H](C)C=C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
To an anhydrous THF (130 ml) solution of (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(2S,4R,5S)-4-methyl-2-phenyl-5-vinyl-1,3-dioxolan-4-yl] pentanoic acid (6.50 g, 15.5 mmol) was added triethylamine (2.80 ml, 20.2 mmol) under nitrogen atmosphere and cooled to 0° C. 2,4,6-Trichlorobenzoyl chloride (2.65 ml, 17.0 mmol) was added to the reaction solution. After the reaction solution was stirred at 0° C. for 10 minutes, it was stirred at room temperature for two hours. After the reaction solution was filtered with celite, the organic layer was concentrated under reduced pressure. To the obtained residue, an anhydrous toluene (130 ml) solution of (3S,4S,5E)-7-[(4-methoxybenzyl)oxy]-3,5-dimethylhepta-1,5-dien-4-ol (4.71 g, 17.0 mmol) and 4-dimethylaminopyridine (2.46 g, 20.2 mmol) were added under nitrogen atmosphere. After the reaction solution was stirred at room temperature for two hours, it was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution, water and brine sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=10:1→5:1) to obtain the title compound (9.81 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28]([C@@H:30]([NH:42]C(=O)OCC2C=CC=CC=2)[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:29])[CH:4]=[N:3]1>CO.[Pd]>[NH2:42][C@H:30]([C:28]([NH:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:29])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 42.5 %

Procedure:
A solution of 1-benzyl 4-tert-butyl ((1S)-1-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamoyl}tetramethylene)biscarbamate (6.4 g) in methanol (100 ml) was treated with 10% palladium on carbon (1.0 g) under a hydrogen atmosphere at room temperature for 6 days. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was triturated with ether and dried in vacuo to give tert-butyl (4S)-4-amino-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (2.2 g) as a solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[C:22](C(C)(C)C)[C:21](O)=[C:20](C(C)(C)C)[CH:19]=2)=[O:16])[CH:6]=[C:5]([CH3:33])[CH:4]=1.[CH3:34][N:35](C)[C:36]1C=CC(N)=CC=1.C(C1C=C(N)C=C(C(C)(C)C)C=1O)(C)(C)C>>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:35]([CH3:36])[CH3:34])=[CH:22][CH:23]=2)=[O:16])[CH:6]=[C:5]([CH3:33])[CH:4]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: Cc1cc(N)nc(CCCCCCC(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Agent: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: Cl
Product: Cc1cc(N)nc(CCCCCCC(=O)Nc2ccc(N(C)C)cc2)c1

Procedure:
The experimental protocol used is the same as that described for compound 16, N,N-dimethyl-p-phenylenediamine replacing the 2,6-di-t-butyl-4-aminophenol. Hygroscopic yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([OH:24])=O)=[CH:14][C:12]=2[N:13]=1.[CH3:26][C:27]([CH3:32])([CH3:31])[CH:28]([NH2:30])[CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([NH:30][CH:28]([C:27]([CH3:32])([CH3:31])[CH3:26])[CH3:29])=[O:24])=[CH:14][C:12]=2[N:13]=1
Reactant: CC(N)C(C)(C)C
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Solvent: CN(C)C=O
Product: Cc1cc2c(o1)c(C(=O)NC(C)C(C)(C)C)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Yield: 24.7 %

Procedure:
The title compound was prepared following the procedure described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-8, 0.050 g, 0.132 mmol), propyl phosphonic anhydride (0.084 g, 0.265 mmol), TEA (0.027 g, 0.265 mmol), DMF (3.0 mL) and 3,3-dimethyl-2-butyl amine (0.027 g, 0.318 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 0.96 (s, 6H), 1.11 (d, J=6.9 Hz, 3H), 2.50 (m, 3H), 3.95-3.97 (m, 1H), 6.65 (s, 1H), 7.35 (s, 1H), 7.63 (d, J=9.0 Hz, 1H), 8.45 (s, 2H), 11.20 (s, 1H), 11.80 (s, 1H); MS [M+H]+: 460.34.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[S:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>C1C=CC=CC=1>[CH3:12][C:9]([C:7]1[CH:6]=[C:5]([I:13])[C:4]2[O:14][C:18]3([CH2:19][CH2:20][S:15][CH2:16][CH2:17]3)[NH:1][CH2:2][C:3]=2[CH:8]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Reactant: O=C1CCSCC1
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(I)c2c(c1)CNC1(CCSCC1)O2
Yield: 62 %

Procedure:
A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (3.0 g., 0.01 mole), tetrahydrothiopyran-4-one (1.18 g., 0.01 mole), and benzene (100 ml.), is refluxed under a Dean-Stark trap for 4 hr. The solvent is evaporated, and the residue is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodospiro[2H-1,3-benzoxazine-2,4'-tetrahydrothiopyran], (2.5 g.), m.p. 123°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:13][CH3:14])=[CH:5][NH:6][C:7]2=O.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)[C:4]([O:13][CH3:14])=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c[nH]c(=O)c2cccc(Cl)c12
Product: COc1cnc(Cl)c2cccc(Cl)c12
Yield: 57.4 %

Procedure:
A solution of 5-chloro-4-methoxyisoquinolin-1-(2H)-one (6.4 g, 30.5 mmol) in POCl3 (45 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (4 g, 57.4%) as a light brown colored solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.28-8.25 (d, J=12 Hz, 1H), 7.87 (s, 1H), 7.79-7.76 (d, J=12 Hz, 1H), 7.58-7.54 (m, 1H), 4.03 (s, 3H); MS: MS m/z 228.0 (M++1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])(O)=[O:2].[CH2:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[CH2:24]([S:28]([NH:31][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:2])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCCS(N)(=O)=O
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NC(=O)c1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
According to the method of Example 59, 5-carboxy-3-(2,4-dichlorobenzoyl)-2-methylindole (0.500 g) is suspended in N,N-dimethylformamide (10 ml), to which is added N,N′-carbonyldiimidazole (0.350 g), and stirred at room temperature for 2 hours. Next, 1-butanesulfonamide (0.296 g) and diazabicycloundecene (0.328 g) are added thereto, and stirred under heat at 100° C. for 6 hours. The reaction mixture is concentrated under reduced pressure, and the residue is made acidic with water and 3 M HCl added thereto, and then extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting oily residue is purified through silica gel column chromatography (eluent: chloroform/methanol=10/1), and recrystallized from ethanol-hexane to obtain a colorless crystal of 5-(1-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzoyl)-2-methylindole (97) (0.420 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C:8]([O:10][CH3:11])=[O:9].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:29]1([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:29]1([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[C:8]([O:10][CH3:11])=[O:9])=[O:42])=[O:38])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H]1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H]1CCCCN1C(=O)CNC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of methyl (2R)-2-piperidinecarboxylate hydrochloride (1.0 g, 5.56 mmol) and HOBt (0.90 g, 6.67 mmol) in CH2Cl2 (20 mL) was added 4-methylmorpholine (2.44 mL, 22.24 mmol), N-{[(phenylmethyl)oxy]carbonyl}glycine (1.16 g, 5.56 mmol), and EDCI (1.28 g, 6.67 mmol). After stirring overnight, the solution was washed 6 N aq. HCl (100 mL) and water (100 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), and then dried over anhydrous MgSO4 and concentrated in vacuo to provide methyl (2R)-1-(N-{[(phenylmethyl)oxy]carbonyl}glycyl)-2-piperidinecarboxylate (2.029 g, 99%). LCMS: (M+H)+: 335.1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]1.OC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C=C1.[NH2:25][C:26]1[C:27]([Cl:33])=[N:28][CH:29]=[N:30][C:31]=1Cl.C(N(CC)CC)C.[OH-].[Na+]>C(O)CCC>[NH2:25][C:26]1[C:31]([NH:2][C@H:3]2[CH2:7][C@@H:6]([CH2:8][OH:9])[CH:5]=[CH:4]2)=[N:30][CH:29]=[N:28][C:27]=1[Cl:33]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N[C@H]1C=C[C@@H](CO)C1
Agent: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1N[C@@H]1C=C[C@H](CO)C1

Procedure:
A solution of (+)-(1S,4R)-4-amino-2-cyclopentene-1-methanol hydrochloride (from deblocking of 10.66 g, 50.0 mmoles of (+)-(1S,4R)-tert-butyl N-[4-(hydroxymethyl)-2-cyclopenten-1-yl]carbamate as described in part c of this example), 5-amino-4,6-dichloropyrimidine (Aldrich, 16.40 g, 0.100 mole), and triethylamine (15.2 g, 0.150 mole) in 1-butanol (25 mL) was refluxed under nitrogen for 18 hours. The solution was cooled and 1 N sodium hydroxide (100 mL) added. Volatiles were evaporated under reduced pressure and the residual solid was chromatographed on silica gel. Title compound eluted with 5% methanol-chloroform as a pale yellow glass (10.8 g). Crystallization of such a sample from ethyl acetate gave title compound as white needles, m.p. 151-154° C.; 1H-NMR (DMSO-d6) δ: 7.75 (s, 1H), 6.76 (d, J=6.8 Hz, 1H), 5.93 and 5.82 (two m, 2H), 5.11 (m, 3H), 4.66 (t, J=5.3 Hz, 1H), 3.40 (br t, J=6.1 Hz, 2H), 2.75 (m, 1H), 2.20 (m, 1H), 1.38 (m, 1H).