Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:29]=[O:30])[CH:8]=2)[S:3]1
Reactant: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C=O)cc32)cc1
Temperature: -10 °C
Reaction time: 5 h

Procedure:
To a cold (-78° C.) solution of 2,2-dimethyl-4(tol-4-yl)-6-bromo-thiochrom-3-ene (Compound N, 280 mg, 0.81 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M solution, 0.66 mL). The mixture was gradually warmed to -10° C. over 25 min. and recooled to -78° C. To this solution was added DMF (80 mg, 1.1 mmol) and stirred at ambient temperature for 5 hours. The reaction was quenched by adding water (10 mL), ethyl acetate (100 mL), and the organic layer was washed with brine (10 mL), dried and the solvent removed by distillation. The crude material was used in the next reaction without further purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[C:6]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:26][CH3:27])=[CH:5]1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:26][CH3:27])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc(N)cc12
Reaction time: 24 h
Yield: 96.4 %

Procedure:
Palladium-on-carbon (10% w/w, 0.1 g.) was added to a solution of 4-(1-acetyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.35 g.) in a mixture of 1: 1 v/v methanol: tetrahydrofuran (50 ml.), which solution had been deoxygenated by passing a stream of nitrogen gas through it, and the mixture hydrogenated at an initial pressure of 50 psi. After 24 hours, the catalyst was removed by filtration through diatomaceous earth, and the filtrate evaporated to give 4-(1-acetyl-5-aminoindol-3-ylmethyl)-3-methoxybenzoic acid (Z) (0.31 g., 91%); partial NMR (250 MHz, CD3OD): 2.53(s,3H, NCOCH3); 3.94(s,3H, OMe); 4.00(s,2H, ArCH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].I[CH3:38]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:20]1[CH:21]=[CH:22][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])=[CH:24][CH:25]=1)[N:5]([S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:38]
Reactant: CI
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.06 g (0.014 mmol) of [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid methyl ester dissolved in 50 mL of DMF was added 0.618 g (0.015 mmol) of a 60% oil dispersion of sodium hydride. The reaction was stirred for 30 min at room temperature and then 2.62 mL of iodomethane was added. After 5 h the reaction was diluted with water and extracted with ether. The combined organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic acid methyl ester as a white waxy solid. Electrospray Mass Spec 518.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:31][C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=1)=[O:9]
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 3-fluorobenzenamine (72.4 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1). The product was then purified by preparative HPLC (A: 0.05% trifluoroacetic acid/water B: dichloromethane) to yield the title compound. 73 mg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:29])([F:28])[F:19])[CH:26]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: Oc1cccc(C(F)(F)F)c1
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin Example 94, Step D) via Mitsunobu coupling with 3-trifluoromethylphenol and cleavage from the resin (Standard Procedure CG) gave an oily solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](I)=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(I)n3n2)CC1
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ncc(-c4ccccc4)n3n2)CC1

Procedure:
4-(3-Phenyl-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared using the approach described in example 5.6.112 from 4-(3-iodo-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (513.4 mg, 1.2 mmol) and phenyl boronic acid [98-80-6] (178.3 mg, 1.5 mmol) to obtain 220.2 mg of white powder, mp. 101-103° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 9H) 3.52 (br. s., 8H) 7.22 (d, J=9.85 Hz, 1H) 7.31-7.37 (m, 1H) 7.46-7.54 (m, 2H) 7.95 (d, J=10.11 Hz, 1H) 8.00 (s, 1H) 8.11-8.18 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.03, 42.73, 45.56, 79.08, 110.13, 125.75, 126.24, 126.93, 127.14, 128.61, 129.03, 131.07, 137.15, 153.85, 154.63. LRMS (ESI) m/z 411.3 [(M+H)]+, calc'd for C21H25N5O2: 379.47.
Reaction SMILES: C(C1N(C)C=C([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16](OCC[Si](C)(C)C)[C:17](C)=[CH:18][C:11]=23)N=1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].CO.[NH4+].[OH-]>>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[NH:16]1[C:12]2=[N:13][CH:14]=[CH:15][CH:10]=[C:11]2[CH:18]=[CH:17]1
Reactant: Cc1cc2c(-c3cn(C)c(C(C)(C)C)n3)ccnc2n1OCC[Si](C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2[nH]ccc2c1
Yield: 149.1 %

Procedure:
A solution of 4-(2-tert-butyl-1-methyl-1H-imidazol-4-yl)-1-[2-(trimethylsilyl)-ethoxy]-methyl-1H-pyrrolo[2,3-b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours. Then the excess TFA was evaporated and the residue was stirred in methanol (3 mL, 0.07 mol) and NH4OH (1 mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 442-tut-butyl-1-methyl-1H-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, trifluoroacetate salt (9 mg, 90%). 1H NMR (400 MHz, d6-DMSO): δ 12.24 (s, 1H), 8.38 (br s, 1H), 8.24 (s, 1H), 7.70-7.63 (m, 2H), 7.08 (br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS(ES):255(M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][C:15]([F:17])([F:16])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3.[F:18][C:19]1[C:20]([N:25]2[CH:29]=[C:28]([CH:30]=O)[C:27]([CH2:32][O:33][CH:34]([CH3:36])[CH3:35])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:13][CH2:14][C:15]([F:16])([F:17])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][N:10]([CH2:30][C:28]1[C:27]([CH2:32][O:33][CH:34]([CH3:36])[CH3:35])=[N:26][N:25]([C:20]2[C:19]([F:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:29]=1)[CH2:11][CH2:12]3
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Reactant: CC(C)OCc1nn(-c2ncccc2F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OCc1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
To a solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (170 mg, 0.61 mmol) in dichloromethane (2.4 mL), 1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazole-4-carbaldehyde (192 mg) is added. The mixture is stirred 10 min at room temperature. Then, sodium triacetoxyborohydride (268.3 mg) is added, and the reaction is stirred at room temperature overnight. The mixture is diluted with dichloromethane and quenched slowly with sodium bicarbonate (saturated solution). The organic phase is then extracted with more dichloromethane, decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. The residue is purified by reverse phase HPLC to give 67.9 mg of 2-chloro-4,4-difluoro-1′-[[1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. MS (m/z): 527 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24]CC)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:18]#[N:19])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(COc2ccc(CC#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred DMF (10 mL) solution of 2-[4-[(4-Methoxyphenyl)methoxy]phenyl]-acetonitrile (500 mg, 1.97 mmol) was added ethyl bromoacetate (330 μL, 2.96 mmol), followed by K2CO3 (820 mg, 5.9 mmol). The reaction mixture was stirred at room temperature for 2 h, poured into ice water (100 mL), filtered, and dried to a white solid. 20 mg of this white solid in 1:1 THF/1N NaOH in MeOH (4 mL) was stirred for 5 h. The reaction mixture was concentrated, diluted with water (10 mL), washed with EtOAc (5 mL×2). The aqueous layer was acidified with 3N HCl to pH ˜2, extracted with EtOAc (10 mL×2), dried over MgSO4, filtered, and concentrated to a white solid. MS ESI (neg.) m/e: 310.0 (M−1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2ccc(F)nc2)c1
Yield: 55 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 6-fluoro-3-pyridineboronic acid, the expected product is obtained in the form of a white powder with a yield of 55%.
Reaction SMILES: Br[C:2]1([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>N1C=CC=CC=1>[C:10]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: O=C(c1ccccc1)C1(Br)CCCCC1
Solvent: c1ccncc1
Product: O=C(C1=CCCCC1)c1ccccc1
Temperature: 25 °C

Procedure:
(1-Bromocyclohexyl)phenyl ketone (14.1 g) was dissolved in pyridine (60 ml) and the mixture was refluxed for 1 hour. After cooling to the ambient temperature the mixture was filtered and evaporated. The residue was dissolved in CH2Cl2 (50 ml) and extracted with 1 M HCl (2×30 ml) and water (30 ml). The organic layer was dried over Na2SO4 and evaporated. Yield was 9.7 g.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Reactant: Oc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1ccc(Cl)cc1)c1ccccc1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.) p-chlorophenol (3.9 g.), sodium hydride (50% oil dispersion, 1.5 g.) 18-crown-6 (0.9 g.), and acetonitrile (250 ml.) as described in Example 12. The product melted at 148°-150°, and amounted to 2.7 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:4]=1[CH:10]1[C:16](=[O:17])[CH:15]2[CH2:18][CH:12]([CH2:13][CH2:14]2)[C:11]1=[O:19])[CH3:2].[Cl-].[Li+].C([Mg]Cl)(C)C.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1.ClCCl>[O:17]=[C:16]1[CH:10]([C:4]2[CH:5]=[C:6]([B:27]([OH:30])[OH:28])[CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:11](=[O:19])[CH:12]2[CH2:18][CH:15]1[CH2:14][CH2:13]2
Reactant: COB(OC)OC
Reactant: CCc1ccc(I)cc1C1C(=O)C2CCC(C2)C1=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccc(B(O)O)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
To a solution of 3-(2-ethyl-5-iodophenyl)bicyclo[3.2.1]octane-2,4-dione (0.65 g, 1.77 mmol) in anhydrous tetrahydrofuran (15 ml) at −10° C. is added iso-propyl magnesium chloride lithium chloride complex (10.6 ml, 10.6 mmol, 1M in tetrahydrofuran) dropwise over 10 minutes. The reaction mixture is stirred at this temperature for 1.5 hours, then cooled to −78° C., at which point trimethyl borate (1.39 ml, 12.4 mmol) is added dropwise to maintain a temperature below −60° C. After re-cooling to −78° C. the mixture is further stirred for 5 minutes, then additionally at room temperature for 1 hour. The solution is quenched with 2M hydrochloric acid and extracted with ethyl acetate (×3). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give an orange-coloured gum. This crude product is dissolved in a minimum amount of dichloromethane then precipitated with iso-hexane to afford 3-(2,4-dioxo-bicyclo[3.2.1]oct-3-yl)-4-ethylphenylboronic acid (0.46 g, 90%) as a cream-coloured solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:9])[C:6]([OH:8])=[O:7].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>S(=O)(=O)(O)O>[OH:9][CH:5]([CH2:4][CH2:3][CH2:2][CH3:1])[C:6]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7]
Reactant: CCCCCCCCCCO
Reactant: CCCCC(O)C(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCOC(=O)C(O)CCCC
Temperature: 140 °C
Yield: 41.9 %

Procedure:
A 50 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and a nitrogen inlet/outlet was charged with 5.0 g (0.038 moles) DL-2-hydroxycaproic acid, 23.95 g (0.151 moles) decyl alcohol, and 0.019 g sulfuric acid. The reactants were heated to 140° C. for 8 hours and water collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. Approximately 50 ml ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Excess decyl alcohol was removed by high vacuum distillation to yield 4.34 g (49% yield) of clear colorless liquid. According to GC the product is 95.74% pure.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:3]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCOC(OCC)N(C)C
Product: COc1cc(C(=O)C=CN(C)C)cc(OC)c1OC

Procedure:
0.5 g (2.38 mmol) of 3,4,5-trimethoxyacetophenone is stirred in 2.7 ml of dimethylformamide diethylacetal for 96 h at 110°. After cooling to 0°, filtering and drying, 3-dimethylamino-1-(3,4,5-trimethoxy-phenyl)-2-propen-1-one is obtained; 1H-NMR (DMSO): 2.9 (3H,s), 3.1 (3H,s), 3.7 (3H,s), 3.85 (6H,s), 5.83 (1H,d), 7.19 (2H,s), 7.7 (1H,d).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)C1C=CC=CC=1>CCO>[NH2:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Solvent: CCO
Product: CCOC(=O)C1CC(N)CC1CC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
To a vessel containing a slurry of 20% Pd(OH)2—C (12.9 g, 92.0 mmol) in EtOH (1.0 L) was added ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol, Preparation #EE.1). The reaction was shaken for about 90 min at about 50° C. under about 30 psi of H2. After removal of the H2 source, the resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to give ethyl 4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup: 1H NMR (CDCl3) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].O[CH2:16][NH:17][C:18](=[O:21])[CH2:19][Cl:20]>C(O)(=O)C.S(=O)(=O)(O)O>[C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([CH2:16][NH:17][C:18](=[O:21])[CH2:19][Cl:20])[C:5]=1[OH:14])(=[O:3])[CH3:2]
Reactant: O=C(CCl)NCO
Reactant: CC(=O)c1cc(C(C)(C)C)ccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1cc(C(C)(C)C)cc(CNC(=O)CCl)c1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To 2.88 g of 2-acetyl-4-tert-butylphenol (prepared in Reference Example 2) dissolved in 20 ml of a mixed solution of glacial acetic acid and conc. sulfuric acid (10:1) were added 2.78 g of N-hydroxymethylchloroacetamide at room temperature and stirred at 60° C. for 2 hours. The reaction mixture was poured into 100 ml of ice-water, extracted with diethyl ether and the extract was washed with water and saturated brine successively, dried over magnesium sulfate anhydride and concentrated at reduced pressure. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride and ethyl acetate (50:1) as an eluting agent to give 3.83 g of the title compound having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: COc1ccc(Br)cn1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(OC)nc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-methoxypyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8])[CH3:2].IC.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([C:7](=[O:9])[CH3:8])([CH3:16])[C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)CC(C)(C(C)=O)C(C)=O
Yield: 67.8 %

Procedure:
48.3 g of 3-acetyl-4-oxo-pentanoic acid ethyl ester, 41 g of iodo-methane, 34 g of potassium carbonate, and 90 ml of acetone were mixed and refluxed for 9 hours. After cooling, 100 ml of petroleum ether was added, and the solid was filtered off and washed with acetone and petroleum ether. Fractional distillation yielded 33.4 g of 3-acetyl-3-methyl-4-oxo-pentanoic acid ethyl ester (boiling point: 69° C./0.02 mbar; purity: 97%; colorless).
Reaction SMILES: [C:1]([O:8][CH:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:11]([O:13]C(C)(C)C)=O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:31]([OH:33])=[O:32])[CH2:29][OH:30])=[O:26]>>[C:1]([O:8][CH:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:11]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:31]([OH:33])=[O:32])[CH2:29][OH:30])=[O:26])=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCC(=O)N[C@@H](CO)C(=O)O
Reactant: CCCCCC(=O)OC(CCCCC)CC(=O)OC(C)(C)C
Product: CCCCCC(=O)OC(CCCCC)CC(=O)NCC(=O)N[C@@H](CO)C(=O)O
Yield: 52.3 %

Procedure:
Starting from tert-butyl 3-hexanoyloxyoctanoate (157 mg) prepared by the method described in Preparation 5 and N-glycyl-L-serine (243 mg), N-[N-(3-hexanoyloxyoctanoyl)glycyl]-L-serine (105 mg) was obtained as an oil according to similar manner to that of Example 1.