Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[CH:3]=1.BrC1C=CC2C(=CC=C(O)C=2)C=1.[H-].[K+].C([Li])(C)(C)C.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.S(=O)(=O)(O)O>C1COCC1.CCCCC.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:32]([OH:37])[OH:33])[CH:6]=[CH:5]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Nc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Agent: Oc1ccc2cc(Br)ccc2c1
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: Nc1ccc2cc(B(O)O)ccc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
According to a known method described in a publication (Anderson, L. C. et al., J. Am. Chem. Soc, 1943, vol. 65, p. 241), a solution of 2-amino-6-bromonaphthalene (223 mg) obtainable from commercially available 2-bromo-6-hydroxynaphthalene (TCI) in anhydrous THF (10 ml) was added with 30% potassium hydride (191 mg, Ald) under ice cooling, and stirred for 1 hour. The reaction mixture was cooled to −78° C. under argon gas atmosphere, added dropwise with a 1.7 M solution of t-butyllithium in pentane (1.88 ml) over 10 minutes, and stirred for 30 minutes. This reaction mixture was added dropwise with (iPrO)3B (0.92 ml) over 10 minutes, stirred for 30 minutes, then warmed to room temperature, and further stirred for 3 hours. The reaction mixture was added with water (3 ml) and 0.5 M aqueous sulfuric acid (4 ml), and extracted with diethyl ether (100 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 6-amino-2-naphthaleneboronic acid (402 mg). A solution of this substance in ethanol (0.5 ml), Compound No. A-1 (119 mg), 2 M aqueous sodium carbonate (1.5 ml) and (Ph3P)4Pd (61 mg) were reacted and treated according to the procedure described in the synthesis method of Compound No. V-3 with the modifications that the reaction was carried out for 13 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate 4:1) to obtain the title compound (Compound No. V-13, 129 mg).
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.FC1C=CC(OCC2C3C=NC(C(OCC)=O)=CC=3N(CC)C=2)=CC=1.[F:57][C:58]1[CH:59]=[CH:60][C:61]([OH:81])=[C:62]([CH:80]=1)[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([O:75]CC)=O)=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1>>[F:57][C:58]1[CH:59]=[CH:60][C:61]([OH:81])=[C:62]([CH:80]=1)[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([NH:21][OH:22])=[O:75])=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)ccc1O)cn2CC
Agent: CCOC(=O)c1cc2c(cn1)c(COc1ccc(F)cc1)cn2CC
Product: CCn1cc(Cc2cc(F)ccc2O)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(5-fluoro-2-hydroxybenzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 4-fluorophenol using methods similar to that set forth in Example 55. (b) 3-(5-Fluoro-2-hydroxybenzyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from the mixture of ethyl 3-(4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: C(OC([C:6]1[C:7](=[O:25])[N:8](CC)[C:9]([CH3:22])=[C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[OH:12])=O)C.[OH-].[Na+].Cl>O>[OH:12][C:11]1[C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([CH3:22])[NH:8][C:7](=[O:25])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c(CCCc2ccccc2)c(C)n(CC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]c(=O)cc(O)c1CCCc1ccccc1

Procedure:
A mixture of intermediate 24 (0.1 g; 0.003 mol) and sodium hydroxide (0.038 g; 0.0009 mol) in H2O (1.5 ml) was stirred and refluxed for 15 hours, then cooled to 5° C. with HCl 3N. The precipitate was filtered, washed with H2O, then with isopropanol and dried to yield 0.07 g (91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.O.[OH-].[Li+].O1CCCC1.C(O)C.O.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnc2cc(Br)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
Added ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (15 g, 56 mmol) and lithium hydroxide monohydrate (3 g, 71.4 mmol) into tetrahydrofuran/ethanol/water (1:2:1, 560 mL total) solution. After stirring at ambient temperature overnight, the solvent was removed under vacuum to give a yellow gum. Water (300 mL) and dichloromethane was added, and the phases were separated. The aqueous layer was cooled in an ice-water bath before adjusting the pH to 3 using 2N sulfuric acid. The product precipitated out and was collected by filtration and washed with a small amount of water (50 mL) before drying under vacuum to give 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid as an off-white solid (8.3 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5].C(N(CC)CC)C.[CH:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=[O:28]>CN(C)C=O.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[C:33]([C:32]1[CH:37]=[CH:38][C:29]([C:27](=[O:28])[CH2:2][CH2:3][C:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=3[CH:7]=2)=[O:5])=[CH:30][CH:31]=1)([O:35][CH3:36])=[O:34]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 1 h
Yield: 45.5 %

Procedure:
5.6 g (0.02 mole) of 6-(3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnapthalene and 3.3 ml (0.024 mole) of triethylamine in 30 ml of dimethylformamide were stirred for 1 hour at room temperature. Thereafter, a solution of 3.6 g (0.025 mole) of methyl 4-formylbenzoate and 1 g of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride in 10 ml of dimethylformamide was added dropwise. Stirring was continued for 1 hour, after which the mixture was poured onto ice/water and extracted twice with ethyl acetate, and the combined organic extracts were washed several times with water, dried over magnesium sulfate and evaporated down. 3.7 g of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione of melting point 139°-141° C. were obtained from the residue (6.4 g) after recrystallization from ethanol.
Reaction SMILES: [ClH:1].C[O:3][C:4](=[O:35])[C@H:5]([CH2:31][CH2:32][S:33][CH3:34])[NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[C@H:15]([CH2:17][C:18]2[N:22]=[CH:21][NH:20][CH:19]=2)[NH2:16])=[CH:10][C:9]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O[Li].O.Cl>C1COCC1.O>[ClH:1].[NH2:16][C@H:15]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:35])=[O:3])[CH2:31][CH2:32][S:33][CH3:34])=[O:30])=[C:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:10]=1)=[O:23])[CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)[C@@H](N)Cc2c[nH]cn2)cc1-c1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(C(=O)[C@@H](N)Cc2c[nH]cn2)cc1-c1ccccc1)C(=O)O
Reaction time: 6 h
Yield: 30.8 %

Procedure:
To a solution of [4-(L-histidyl)-2-phenylbenzoyl methionine methyl ester hydrochloride (98.9 mg, 0.200 mmol), prepared as in Example 184B, in THF/H2O (4:1, 20 mL) was added LiOH.H2O (68.5 mg, 1.60 mmol). The solution was stirred for 6 hours and then was treated with 1 M aqueous HCl (20 mL). The mixture was lyopholized to provide a white solid. Recrystallization from methanol afforded [4-(L-histidyl)-2-phenylbenzoyl]methionine hydrochloride (31 mg, 32%) as a white solid. 1H NMR (D2O) δ 1.68-1.82 (m, 1H), 1.88-1.99 (comp, 2H), 2.02 (s, 3H), 2.00-2.12 (m, 1H), 3.28-3.32 (m, 2H), 3.49 (d, 2H), 4.28-4.34 (m, 1H), 4.44 (t, 1H), 7.36-7.53 (comp, 8H), 7.57 (m, 1H), 8.67 (m, 1H); LRMS (CI): 482 (M+1)+, 701.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:29][CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: NCCc1ccccn1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NCCc2ccccn2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-pyridin-2-yl-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H22N2O5 [M+H]+: 359.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Br[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]#[CH:6]
Reactant: CCOC(=O)CCBr
Reactant: C#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCCOCCC(=O)OCC
Yield: 90.9 %

Procedure:
Sodium hydride (4.6 g of 60% dispersion in mineral oil) was added to a stirred solution of but-3-yn-1-ol (16.2 g, 0.23 mol, Lancaster) in dry toluene (200 ml). After stirring for 2 hours at 25° C. a solution of ethyl 3-bromopropionate (20.8 g, 0.115 mol, Lancaster) was added. The reaction mixture was stirred and refluxed for 7 hours. Ethyl 3-(but-3-ynyloxy)propionate (17.8 g) was obtained by quenching the cooled reaction mixture in water, extracting with ether, washing with brine, drying over anhydrous magnesium sulphate followed by evaporation.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:40]1(B(O)O)[CH2:42][CH2:41]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([CH:40]3[CH2:42][CH2:41]3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: OB(O)C1CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C3CC3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and cyclopropylboronic acid replacing phenylboronic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.19 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.76 g), anhydrous potassium carbonate (0.44 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.35 g, 82%) of ethyl 3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 64-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH3:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C([O:20]/[C:21](/[CH3:28])=[CH:22]/C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[C:15](/[CH3:16])=[CH:22]/[C:21](=[O:20])[CH3:28])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: CC(=O)c1ccc(C2CCCCCC2)c(Cl)c1
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCCC2)c(Cl)c1
Yield: 51 %

Procedure:
(E)-4-(3-chloro-4-cycloheptyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 3'-chloro-4'-cycloheptyl-acetophenone (b.p. 136°-139°C at 0.1 mm Hg; nD23 = 1.5572) and ethyl (E)-3-ethoxy-crotonate with a yield of 51% of theory. B.p. 160°-165°C at 0.1 mm Hg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15]Br>>[CH3:12][CH:13]([CH3:17])[CH2:14][CH2:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCCCCCCCCBr
Reactant: CC(C)CCBr
Product: CC(C)CCCCCCCCCCCO
Yield: 51 %

Procedure:
12-methyltridecan-1-ol was prepared from 9-bromononan-1-ol and 3-methylbutylbromide in 51% yield. The 1H NMR and MS-ESI data matched those reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour and Fragrance Journal 19:199-204).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.O.ClCCl.N>Cl.CO>[NH:19]1[CH2:20][CH2:21][CH:16]([CH2:15][O:14][C:11]2[C:10]3[C:5]([O:4][CH2:3][C:2]([F:1])([F:29])[F:30])=[CH:6][CH:7]=[CH:8][C:9]=3[O:13][N:12]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC(F)(F)F)c23)CC1
Agent: Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)COc1cccc2onc(OCC3CCNCC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of tert-butyl 4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)-piperidine-1-carboxylate (3.0 g, 6.96 mmol, EXAMPLE 2, Step 1) in 10% hydrogen chloride in methanol (100 mL) was added hydrochloric acid (3.0 mL) at ambient temperature. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo to give a solid. The residual solid was dissolved with water and dichloromethane. Sat. aq. ammonia was added to the mixture and extracted with dichloromethane (100 mL×3). The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give 2.31 g (quant.) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[NH2:12][C:13]1[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][C:14]=1[C:15](N(OC)C)=[O:16].Cl>COC.CCCCCC.O1CCCC1>[NH2:12][C:13]1[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])=[CH:21][C:14]=1[C:15]([C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: Brc1cccs1
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Agent: COC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)c2cccs2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of 2-bromothiophene (2.7 g, 16 mmol) in dimethyl ether (30 ml) was added dropwise 1.6 M solution (8.9 ml) of n-butyllithium in n-hexane at −78° C. The reaction mixture was stirred at −78° C. for 30 min. and a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (2.0 g, 6.4 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min. and 0.1N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(thien-2-yl)methanone (0.98 g, yield 46%) as a yellow oil.
Reaction SMILES: [C:1]1([C@@H](N)C)[CH:6]=CC=[CH:3][CH:2]=1.[CH:10]1([CH2:16][NH:17][CH2:18][C:19]([N:21]2[CH2:26]COC[CH2:22]2)=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:26][N:21]([CH3:22])[C:19](=[O:20])[CH2:18][NH:17][CH2:16][C:10]1[C:11]2[C:12](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CNCC1CCCCC1)N1CCOCC1
Reactant: C[C@H](N)c1ccccc1
Product: CN(C)C(=O)CNCc1cccc2ccccc12

Procedure:
By following the procedure of section (a) of this example but replacing (S)-1-phenylethylamine with twice the equivalent amount of 1-(naphthylmethyl)amine and omitting the triethylamine, N,N-dimethyl-2-[(1-naphthylmethyl)amino]acetamide [1H NMR(CDCl3) δ8.25 (dd, J=1.2 Hz,8.0 Hz,1H), 7.86 (dd, J=1.8 Hz,7.6 Hz,1H), 7.79 (broad d, J=8.1 Hz,1H), 7.60-7.39 (m,4H), 4.30 (s,2H), 3.52 (s,2H), 2.97 (s,3H), 2.90 (s,3H)] was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:13][CH2:12]1)[CH3:23]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of trans (4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (1.03 g, 4.80 mmol) in dry toluene (38 mL) under an nitrogen atmosphere was treated with rhodium acetate (110 mg, 200 μmol) and heated at reflux. A solution of ethyl diazoacetate (600 μL, 5.70 mmol) in dry toluene (9 mL) was added dropwise over 1.5 hours. The mixture was then stirred at reflux for a further 30 minutes and allowed to cool to ambient temperature overnight. The reaction was treated with a further portion of rhodium acetate (50 mg) and re-heated to reflux. Further ethyl diazoacetate (300 μL) in dry toluene (5 mL) was added dropwise over 1 hour. Heating was continued for 30 minutes and then the cooled mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (gradient: 0-35% ethyl acetate in cyclohexane) to afford 720 mg (50%) of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid ethyl ester as a white solid. LCMS (Method Q, ESI): RT=3.63 min, m+H=324.0; 1H NMR (400 MHz, CDCl3) δ: 4.35 (br s, 1H), 4.21 (q, 2H), 4.09 (s, 2H), 3.44 (br s, 1H), 3.32 (m, 1H), 2.04 (m, 4H), 1.44 (m, 11H), 1.28 (t, 3H), 1.13 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:16][C:17]3[CH:39]=[CH:38][C:20]([CH2:21][O:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[CH:28]([CH2:32][C:33]([O:35]CC)=[O:34])[CH2:27][CH2:26]5)=[CH:19][CH:18]=3)[CH2:13][CH2:14][CH3:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:16][C:17]3[CH:39]=[CH:38][C:20]([CH2:21][O:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[CH:28]([CH2:32][C:33]([OH:35])=[O:34])[CH2:27][CH2:26]5)=[CH:19][CH:18]=3)[CH2:13][CH2:14][CH3:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(Cc1ccc(COc2ccc3c(c2)CCC3CC(=O)OCC)cc1)c1nc(-c2ccccc2)cs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCN(Cc1ccc(COc2ccc3c(c2)CCC3CC(=O)O)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.5 %

Procedure:
To a solution of ethyl {5-[(4-{[(4-phenyl-1,3-thiazol-2-yl)(propyl)amino]methyl}benzyl)oxy]-2,3-dihydro-1H-inden-1-yl}acetate (0.684 g, 1.17 mmol) in a mixed solvent of ethanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-80% ethyl acetate/hexane) and recrystallized from ethyl acetate-hexane to give the title compound (0.393 g, yield 66%) as colorless prism crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3([N+:21]([O-])=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]3[OH:20])[CH:5]=[CH:4][C:3]1=2.Cl>O.C(O)C.[Fe]>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]3[OH:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C3([N+](=O)[O-])C=CC=CC3O)ccc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C3(N)C=CC=CC3O)ccc21
Yield: 85 %

Procedure:
Compound 27 was suspended in water (2 ml) and ethanol (6 ml), and the suspension was added with concentrated hydrochloric acid (0.5 ml). The mixture was added with iron powder (220 mg) and then heated under reflux for 30 minutes. The reaction mixture was filtered to remove solid materials and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was then evaporated under reduced pressure to give o-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtalenyl)-2-aminophenol (Compound 28, 80.5 mg, 85%).