Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH:3]12[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH:4]2[C:18]([O:20]C)=[O:19].Cl>CO.O>[C:14]([O:13][C:11]([N:10]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]([C:18]([OH:20])=[O:19])[CH2:5][CH2:6]2)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CCC2CCC1N2C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC(C(=O)O)C1CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium hydroxide (0.44 g, 7.8 mmol) was added into a solution of 8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (840 mg, 3.12 mmol) in methanol (2 ml) and water (2 ml). The reaction solution was stirred at room temperature for 16 h, and 1.0 N HCl solution was added dropwise to adjust pH to 4. The resulting solution was extracted with EtOAc (50 ml, twice). The combined organic layers were washed with water (10 ml). The organic layer was separated, and dried over sodium sulfate. The solution was filtered, concentrated, and used in the next step without further purification.
Reaction SMILES: C(C1C=C([B:13]([OH:15])[OH:14])C=C(C(C)C)C=1)(C)C.[C:16]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](Br)[CH:28]=2)[C:23]([CH3:32])([CH3:31])[CH2:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([B:13]([OH:15])[OH:14])[CH:28]=2)[C:23]([CH3:32])([CH3:31])[CH2:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)c1cc(B(O)O)cc(C(C)C)c1
Reactant: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(B(O)O)cc21

Procedure:
Employing the procedure used for the preparation of 3,5-diisopropylphenylboronic acid (Compound 2), 1-tert-butyl-4,4-dimethyl-3,4-dihydro-7-bromonaphthalene (Compound 16) was converted to the title compound. The resulting crude product was used in the next step without further purification. 1-tert-butyl-4,4-dimethyl-3,4-dihydro-7-bromonaphthalene (Compound 16) can be obtained in accordance with the disclosure of U.S. Pat. No. 5,741,896, incorporated herein by reference.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1.Cl.CN(CCCN=C=NCC)C>C(#N)C>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:26])=[CH:20][CH:19]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: O=C(Cc1ccc(O)cc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Temperature: 23 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
1 g (4.8 mmol) 2-(2-Aminophenyl) indole was dissolved in 200 ml acetonitrile. 1.46 g (9.6 mmol, 2 eq) of 4-hydroxyphenylacetic acid were dissolved in 50 ml acetonitrile and added to the solution. To the mixture were added 1.84 g (9.6 mmol, 2 eq) of EDC (dimethylaminopropyl ethylcarbodiimide hydrochloride). The reaction mixture was stirred at 23° C. for 16 hours. The solvent was removed and the residue was dissolved in 100 ml ethylacetate:methanol (10:1). It was extracted twice with 100 ml of aqueous 1M HCl as well as 100 ml of aqueous, saturated sodium bicarbonate solution. The aqueous phases were re-extracted with EtOAc, respectively. The combined organic phases were dried over magnesium sulfate. The crude product was chromatographed on silica using a ethylacetate/hexane gradient (10%–50%) to obtain 1.23 g of the amide as a pink colored powder in an overall yield of 75%. 100% Purity by LC/MS (230 DAD) Mass-spec [M+H+]=343.9 1H NMR (MeOH-d4): 3.60 s (2H), 6.10 s (1H), 6.70 d, 8 Hz (2H), 7.03 t, 8 Hz (1H), 7.09–7.13 m (3H), 7.25 t, 7 Hz (1H), 7.34 m (2H), 7.49 d, 8 Hz (1H), 7.53 d, 8 Hz (1H), 7.95 d, 8 Hz (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[S:5].Cl[CH2:12][S:13][C:14]#[N:15]>>[S:13]([CH2:12][O:6][C:4](=[S:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:14]#[N:15]
Reactant: OC(=S)c1ccccc1Cl
Reactant: N#CSCCl
Product: N#CSCOC(=S)c1ccccc1Cl
Yield: 77 %

Procedure:
28.5 g (0.14 mol) of the K salt of 2-chloro-thiobenzoic acid and 15 g (0.14 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 26.3 g of a yellowish oil having a density of 1.36 (this corresponds to a yield of 77% of the theoretical conversion).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:31]=[CH:30][C:13]3/[C:14](=[CH:23]/[C:24]4[NH:28][C:27](=[O:29])[O:26][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH2:2][CH3:3].CO.[C:38]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:31]=[CH:30][C:13]3/[C:14](=[CH:23]/[C:24]4[N:28]([CH3:38])[C:27](=[O:29])[O:26][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=O)[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (69 mg, 0.15 mmol) obtained in Example 5 and methanol (30 μL, 0.75 mmol) were dissolved in THF (1 mL), polymer-supported triphenylphosphine (150 mg, 0.45 mmol) and di-tert-butyl azodicarboxylate (104 mg, 0.45 mmol) were added at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3 to 0/10) to give the title compound (compound 6) (65 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].CC(O)=O.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[CH:29]1([CH2:32][NH:1][C:2]2[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[NH:12][C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH3:15])[CH2:31][CH2:30]1
Reactant: O=CC1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(S(C)(=O)=O)c1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(S(C)(=O)=O)c1NCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of (S)-tert-butyl 1-(2-amino-3-(methylsulfonyl)phenylamino)-1-oxopropan-2-ylcarbamate (prepared in example 51) (440 mg, 1.23 mmol), glacial AcOH (0.43 mL, 7.4 mmol) and cyclopropanecarbaldehyde (0.18 mL, 2.5 mmol) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (780 mg, 3.7 mmol) and stirred at rt under N2 for 18 h. The reaction mixture was diluted with EtOAc, washed with water, sat. aq sodium bicarbonate solution, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel column using 10 to 20% gradient of EtOAC:DCM (1:1) in DCM as eluent to give (S)-tert-butyl 1-(2-(cyclopropylmethylamino)-3-(methylsulfonyl)phenylamino)-1-oxopropan-2-ylcarbamate: LC-MS (ESI) m/z 412.1 [M+H]+.
Reaction SMILES: [OH:1]C1C(C#N)=CC(F)=C(O)N=1.ClC1C(C#N)=CC(F)=C(Cl)N=1.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:34][C:35]1[N:43]=[C:42]([Cl:44])[C:41]([F:45])=[CH:40][C:36]=1[C:37](N)=[O:38].S(=O)(=O)(O)O.N([O-])=O.[Na+]>>[Cl:34][C:35]1[N:43]=[C:42]([Cl:44])[C:41]([F:45])=[CH:40][C:36]=1[C:37]([OH:1])=[O:38]
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: N#Cc1cc(F)c(O)nc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N#Cc1cc(F)c(Cl)nc1Cl
Agent: O=N[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cc(F)c(Cl)nc1Cl

Procedure:
A preferred embodiment for preparing the nicotinic acids is illustrated in Scheme II. The 2,6-dihydroxy-3-cyano-5-fluoropyridine (1) is prepared according to the method described in European Patent Application 333 020 (EP 020), incorporated herein by reference. This document describes the preparation of 2,6-dihydroxy-3-cyano-5-fluoropyridine starting with ethyl formate, ethyl fluoro acetate, and cyanoacetamide. The ethyl formate and ethyl fluoro acetate, are initially reacted in the presence of sodium methoxide, followed by addition of cyanoacetamide to provide the dihydroxy cyanopyridine (1). The 2,6-dihydroxy-3-cyano-5-fluoropyridine is converted to 2,6-dichloro-3-cyano-5-fluoropyridine (2) with phosphorus oxychloride (POCl3) and phosphorus pentachloride (PCl5). The 2,6-dichloro-5-fluoro-3-cyanopyridine is hydrolyzed to 2,6-dichloro-5-fluoronicotinamide (3) by heating the cyano compound in the presence of concentrated sulfuric acid. The 2,6-dichloro-5-fluoronicotinic acid (4) was prepared by reaction of the amide (3) with sodium nitrite under aqueous acidic conditions. ##STR8##
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(CO)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-hydroxymethyl-phenyl)-amide (502, 0.20 g, 0.81 mmol) in tetrahydrofuran (5.0 mL) was added Dess-Martin periodinane (0.377 g, 0.89 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water 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% ethyl acetate in hexane to give a white solid (503, 100 mg, 50.0%). MS (ESI) [M−H+]+=244.1.
Reaction SMILES: [C:1]1([CH:7]([K])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: [K]C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 5.01 g (24.3 mmol) of diphenylmethyl potassium in 25 mL of THF was added about 10 mL (about 8.6 g, 80 mmol) of chlorotrimethylsilane. The dark orange color instantly faded. The solvent was removed under reduced pressure. The residue was extracted with hexane and filtered and the solvent was removed under pressure to give the product as a pale yellowish liquid. The yield was 4.63 g, 79.3 percent. 1H NMR (C6D6) δ 7.08-7.23 (m, 8H), 6.98-7.06 (m, 2H), 3.41 (s, 1H), 0.00 (s, 9H). 13C NMR (C6D6) δ 143.2, 129.1, 128.6, 125.4, 46.5, -1.4.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:23][CH3:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl>C(OCC)(=O)C.CCOCC.C(O)C.[C].[Pd]>[C:1]([O:4][CH2:5][C:6]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])([CH2:23][CH3:24])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCC(CCc1ccc(OCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(CCc1ccc(O)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 2.67 h
Yield: 129.2 %

Procedure:
To a solution of 4-(4-benzyloxyphenyl)-2-tert-butoxycarbonylamino-2-ethylbutyl acetate (7 g) in ethyl acetate (80 ml) were added a 1 M solution of hydrochloric acid in ether (1 ml) and 10% palladium-carbon (0.4 g) and the suspension was subjected to catalytic reduction under an oridinary atmosphere at room temperature for 160 minutes. Catalyst was filtered off from the reaction mixture and the solvent was distilled away under reduced pressure. The residue obtained was dissolved in ethyl acetate (50 ml) and ethanol (50 ml). To the solution were added 10% palladium-carbon (0.4 g) and a 1 M solution of hydrochloric acid in ether (1 ml) and the suspension was subjected to catalytic reduction under an ordinary atmosphere at room temperature for 140 minutes. Catalyst was filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure to give the subject compound (7.2 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([N:15]1[CH2:56][CH2:55][CH2:54][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:51]([NH2:53])=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+]([O-])=O.Cl.N[C@H](C(O)=O)CCCNC(=N)N.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1>[Pd].O.C(O)(=O)C>[NH2:1][C@H:2]([C:13]([N:15]1[CH2:56][CH2:55][CH2:54][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:51]([NH2:53])=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1)=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:12]
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O

Procedure:
In 30 ml. of acetic acid was dissolved 500 mg. of Z-Arg(NO2)-Pro-Phe-Phe-Tyr-NH2, and catalytic reduction was carried out with Pd-black as a catalyst for 20 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml. of water and, after the small amounts of insolubles were filtered off, the filtrate was lyophilized. The product was dissolved in 5 ml. of water and the solution was applied on a column (1.8 × 9 cm) of carboxymethyl-sephadex. Gradient elution was carried out with 0.1M aqueous ammonium acetate (400 ml.) and 1M aqueous ammonium acetate (400 ml.). The fractions from 250 ml. to 370 ml. were pooled and lyophilized to yield 250 mg. (52.3 %) of a white fluffy product. [α]D24 -41.9° (c=0.47 %, water). Amino acid analysis (hydrolysis with HCl): Arg, 1.00;Pro, 1.05; Tyr, 0.91; Phe, 1.96;(peptide content 86.5 %).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:5])[C:3]4[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=4[F:1])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,5-difluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white powder (53% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 8.0, 7.17-7.11, 7.03, 4.02-3.92, 3.85-3.83, 3.59-3.5, 1.52, 0.74-0.69, 0.46-0.40, 0.09-0.04.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21](C(OC)=O)[C:22]([CH:24]1[CH2:28][S:27]C(C)(C)[N:25]1C=O)=[O:23])[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.[ClH:37]>>[ClH:37].[ClH:37].[NH2:8][C@@H:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:23])[CH:24]([NH2:25])[CH2:28][SH:27])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)C1CSC(C)(C)N1C=O
Agent: Cl
Product: NC(CS)C(=O)CCCCC[C@H](N)C(=O)O
Temperature: 25 °C

Procedure:
A solution of ketone 31 (401 mg, 0.76 mmol) in 4M HCl (6 mL) was refluxed for 2 hrs. The reaction mixture was cooled to room temperature and evaporated in vacuo to give the title compound 32 as a yellow oil that was used in subsequent biochemical studies without any further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:30]COC)=[CH:4][C:5]([O:26]COC)=[C:6]([C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[S:13])[NH:11][N:12]=2)[CH:7]=1.Cl.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10]([SH:13])=[N:11][N:12]=2)[C:5]([OH:26])=[CH:4][C:3]=1[OH:30]
Reactant: COCOc1cc(OCOC)c(-c2n[nH]c(=S)n2-c2ccc(N3CCOCC3)cc2)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(O)c(-c2nnc(S)n2-c2ccc(N3CCOCC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
The crude crystals of 5-(5-bromo-2,4-bis-methoxymethoxy-phenyl)-4-[4-(morpholin-4-yl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (IM6-S-d01) and a mixed solvent of 5.0 N aqueous hydrochloric acid (1 mL) and ethanol (1 mL) were placed in a test tube and stirred at room temperature for 24 hours. After completing the reaction, the reaction mixture was neutralized with 10 N aqueous sodium hydroxide, and then extracted with ethyl acetate and methylene chloride. The collected organic layer was dried over anhydrous sodium sulfate. After filtration and evaporation, the residue thus obtained was purified by HPLC fractionation to obtain the title compound (SH-d01: 8.6 mg, 34%).
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]1([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]2[CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[ClH:1].[ClH:1].[C:8]1([NH:14][C:15]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[CH2:30][O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 12 h
Yield: 98 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (114.5 mg, 0.278 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 105.2 mg (98%) of the desired product as a white solid. LC-MS: RT=5.284 min, [M+H]+=313.1
Reaction SMILES: C([C@@:5]12[N:12]([C:13]([OH:15])=[O:14])[C@@H:9]([CH2:10][CH2:11]1)[CH2:8][CH:7](C(=O)CCC=C)[CH2:6]2)(C)(C)C.C([O-])(=O)C.[NH4+].C([N+]#[C-])(C)(C)C>FC(F)(F)CO.O>[CH:9]12[N:12]([C:13]([OH:15])=[O:14])[CH:5]([CH2:11][CH2:10]1)[CH2:6][CH2:7][CH2:8]2
Reactant: C=CCCC(=O)C1C[C@@H]2CC[C@](C(C)(C)C)(C1)N2C(=O)O
Agent: CC(=O)[O-]
Agent: [C-]#[N+]C(C)(C)C
Agent: [NH4+]
Solvent: OCC(F)(F)F
Solvent: O
Product: O=C(O)N1C2CCCC1CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 248.6 %

Procedure:
A solution (1R,5S)-tert-butyl-3-pent-4-enoyl-8-azabicyclo[3.2.1]-octane-8-carboxylic acid (1.45 g, 4.95 mmol) and ammonium acetate (3.82 g, 49.5 mmol) in 2,2,2-trifluoroethanol (4 mL) was treated with tert-butyl isocyanide (2.06 g, 2.60 mL, 24.75 mmol). After stirring at room temperature for 3 days, the reaction mixture was added to a separatory funnel, diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 10-60% ethyl acetate in heptane) gave (1R,5S)-tert-Butyl-3(2-acetamido)-1-(tert-butylamino)-1-oxo-hex-5-en-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid as a colorless foam (1.91 g, 89%).; 1H NMR (CDCl3, 400 MHz) δ 6.90 (s, NH, 1H), 5.79 (m, 1H), 5.59 (s, NH, 1H), 4.98 (m, 2H), 4.15 (m, 2H), 2.93 (m, 2H), 2.07 (m, 1H), 2.00 (s, 3H), 1.74-1.96 (m, 3H), 1.50-1.72 (m, 6H), 1.45 (s, 9H), 1.38 (s, 9H), 1.20-1.36 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1>CN(C)C=O>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:31][CH:30]=1
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Reactant: ClCc1ccc(COc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cnn(Cc3ccc(COc4ccccn4)cc3)c2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2,6-diamine (25 mg, 0.14 mmol) described in Manufacturing Example 36-1-2 in N,N-dimethylformamide (3 mL) was added sodium hydride (8.6 mg, 0.22 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.). Following 30 minutes of stirring at room temperature, 2-(4-chloromethyl-benzyloxy)-pyridine (43.4 mg, 0.19 mmol) described in Manufacturing Example 30-1-1 was added and stirred for 30 minutes at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate only) to obtain the title compound (22.8 mg, 43%).
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13](O)[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][CH:12]=1)[O:9][CH2:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCC1
Reactant: Oc1cccc(Br)c1
Product: Brc1cccc(OCC2CCCCCC2)c1

Procedure:
Cycloheptylmethanol was coupled with 3-bromophenol following the method used in Example 10. After concentration under reduced pressure, hexanes was added. The mixture was stirred and sonicated then the precipitate was removed by filtration and the solids washed with hexanes. The combined filtrates were concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave ((3-bromophenoxy)methyl)cycloheptane. (Yield 1.0697 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.12 (t, J=8.4, 1H), 7.06-7.04 (m, 2H), 6.82 (dq, J=8.0, 1.2, 1H), 3.70 (d, J=6.4, 2H), 1.91-1.98 (m, 1H), 1.81-1.88 (m, 2H), 1.42-1.72 (m, 8H), 1.24-1.34 (m, 2H).