Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([CH2:14][C:15](OCC)=[O:16])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[BH4-].[Na+]>C(O)C.[Cl-].[Na+].O>[C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:14][CH2:15][OH:16])[CH2:4][OH:3])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A stirred solution of (S)-N-BOC diethyl Laspartate 3 (47.41 g, 0.16 mol) in absolute ethanol (770 ml) was cooled in ice, then sodium borohydride (60.8 g, 1.6 mol) was added in 10 g portions. The cooling bath was removed when the reaction subsided, and the reaction mixture was heated slowly to reflux for 1 h; after this time TLC (EtOAc-EtOH 3:1) analysis indicated complete consumption of the starting material. The reaction mixture was cooled to 25° C., and the lumps formed were broken-up to give a slurry that was poured into brine (450 ml). The mixture was filtered, the filtrate concentrated in vacuum to ca. 100 ml, and was extracted with ether (6×300 ml). The insoluble solid material was extracted by stirring in ether (4×1 L) for 2 h. The combined ether extracts were dried over MgSO4, filtered and concentrated to give 4 as a colourless oil (24 g, 73%), which crystallised on standing. Spectral data for this sample were consistent with those given in the literature2. 1H NMR (200 MHz, d6-DMSO) 6.45 (d, J=8.4 Hz, 1H), 4.57 (t,J=5.6 Hz, 1H), 4.35 (t,J=5.1 Hz, 1H), 3.40 (m, 4H), 3.23 (m, 1H), 1.62 (m, 1H), 1.40 (m, 1H), 1.36 (s, 9H); 13C NMR (50 MHz, d6-DMSO) 155.5, 77.4, 63.5, 58.0, 49.6, 34.4, 2.83.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:18])=[N:4][N:3]=1.[CH3:19][C:20]1([CH3:40])[O:24][CH:23]([C:25]2[CH:26]=[N:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:22][O:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(NS(C1C=NC=C(C2C3C(=C(C4C=CC=CC=4)C=CC=3)C(Cl)=NN=2)C=1)(=O)=O)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[Cl:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([C:29]2[CH:28]=[N:27][CH:26]=[C:25]([CH:23]3[CH2:22][O:21][C:20]([CH3:40])([CH3:19])[O:24]3)[CH:30]=2)=[N:3][N:4]=1
Reactant: CC1(C)OCC(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)O1
Reactant: Clc1nnc(Cl)c2c(-c3ccccc3)cccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Product: CC1(C)OCC(c2cncc(-c3nnc(Cl)c4c(-c5ccccc5)cccc34)c2)O1
Yield: 82.2 %

Procedure:
4-Chloro-1-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5phenylphthalazine (1.00 g, 82.0% yield) was prepared from 1,4-dichloro-5-phenylphthalazine (0.800 g, 2.91 mmol), 3-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.887 g, 2.91 mmol), K3PO4 (0.617 g, 2.91 mmol), tricyclohexylphosphine (0.0160 g, 0.0580 mmol) and Pd2(dba)3 (0.0270 g, 0.0290 mmol) by the methods described for N-(tert-butyl)-5-(4-chloro-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide in Example 1. The crude product was taken to next step without purification. LCMS (Condition 11): retention time 1.05 min, [M+1]=418.1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:16](=[O:19])[CH2:17][CH3:18])[C:7]=2[CH:20]=1.B(Br)(Br)Br.C(O)C>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:16](=[O:19])[CH2:17][CH3:18])[C:7]=2[CH:20]=1
Reactant: CCC(=O)N1CCC[C@H]2c3cc(OC)ccc3CC[C@@H]21
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCC(=O)N1CCC[C@H]2c3cc(O)ccc3CC[C@@H]21

Procedure:
A solution of 6.8 g of the compound obtained in Step D in 72 ml of chloroform is cooled to 0° C., then 5.3 ml of boron tribromide are added dropwise thereto. The whole is stirred for 18 hours at room temperature before the addition of 20 ml of ethanol. The resulting precipitate is filtered and washed with water, and 5.1 g of the expected compound are thereby isolated.
Reaction SMILES: C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[Cl:78][C:79]1[CH:84]=[C:83]([Cl:85])[CH:82]=[CH:81][C:80]=1[C:86](=O)[CH2:87][C:88]#[N:89].C1C(=O)N(Br)C(=O)C1.[NH2:99][C:100]([NH2:102])=[S:101]>O.CC(C)=O>[NH2:102][C:100]1[S:101][C:87]([C:88]#[N:89])=[C:86]([C:80]2[CH:81]=[CH:82][C:83]([Cl:85])=[CH:84][C:79]=2[Cl:78])[N:99]=1
Reactant: NC(N)=S
Reactant: N#CCC(=O)c1ccc(Cl)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1sc(N)nc1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Yield: 41.9 %

Procedure:
beta-Cyclodextrin (4.29 g, 3.78 mmol) was dissolved in water (75 mL) at 50° C. and a solution of 3-(2,4-dichlorophenyl)-3-oxopropanenitrile (810 mg, 3.8 mmol) in Acetone (3.80 mL) was added dropwise, followed by NBS (0.808 g, 4.54 mmol) and thiourea (0.346 g, 4.54 mmol). Reaction mixture was stirred at 50° C. 1 hr. LCMS indicated complete conversion. Reaction mixture was cooled to rt, extracted with ethyl acetate (3×50 mL), dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO with 5-30% ethyl acetate in hexanes to give 0.43 g of the title compound (42%). LCMS: (FA) ES+, 270, 272. 1H NMR (400 MHz, d1-chloroform) δ 7.49 (d, J=1.84 Hz, 1H), 7.41 (d, J=8.30 Hz, 1H), 7.31 (dd, J=8.16, 1.74 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[OH-:11].[Na+]>>[C:3]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: O=C1Cc2ccccc2N1
Agent: [Na+]
Product: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1

Procedure:
The hydrolysis of an indolin-2-one (II) is carried out in dilute aqueous base as, for example, 3 N sodium hydroxide solution, for a period of from about 0.5 hour to about 1.0 hour. The hydrolysis may be run in an inert atmosphere using nitrogen. The hydrolysis mixture may be filtered to remove base-insoluble materials and the pH of the basic solution is adjusted to pH 6-pH 7 by the addition of a weak organic acid such as glacial acetic acid or a dilute mineral acid such as hydrochloric acid. When (I) is a 2-amino-5-benzoylphenylacetic acid or a 2-amino-6-benzoylphenylacetic acid the product can be readily recrystallized from a suitable solvent. When (I) is a 2-amino-3-benzoylphenylacetic acid, recrystallization may result in partial cyclization to the precursor 7-benzoylindolin-2-one (II). Therefore, in the preparation of a 2-amino-3-benzoylphenylacetic acid (I) the product is preferably not recrystallized and is isolated by careful acidification of the filtered basic hydrolysis mixture.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:4]=2[N:3]=1.[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2cccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2cccnc12
Temperature: 45 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A mixture of methyl 2-methyl-6-(4-morpholinyl)-1-(8-quinolinylmethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 34 (300 mg, 0.72 mmol) and 2 N LiOH (2.2 mL, 4.3 mmol) in THF (10 mL), was stirred at 45° C. for 16 h. It was filtered and the filter cake was dissolved in water (20 mL) and then added into formic acid to adjust the pH of the solution to 3-4. Then a filtration was performed to give the product (200 mg, 69%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.61 (s, 3H), 3.06 (t, 4H, J=4.8 Hz), 3.71 (t, 4H, J=4.8 Hz), 6.13 (s, 2H), 7.03 (d, 1H, J=7.5 Hz), 7.41 (s, 2H), 7.51 (t, 1H, J=7.5 Hz), 7.66 (dd, 1H, J=4.2, 8.4 Hz), 7.95 (d, 1H, J=7.5 Hz), 8.45 (dd, 1H, J=1.8, 8.4 Hz), 9.05 (dd, 1H, J=1.8, 4.2 Hz); LC-MS: m/e=403 [M+1]+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:3]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc(I)c(CCN(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2)c(CCN(C)C)c1
Reaction time: 8 h

Procedure:
To a solution of 1 g (3.3 mmoles) of 2-iodo-5-methoxy-N,N-dimethylbenzeneethanamine and 0.33 g (3.3 mmoles) phenylacetylene in 18 ml dry triethylamine were added, under nitrogen, 23.1 mg bis(triphenylphosphine) palladium (II) chloride and 11.4 mg Copper (I) iodide. The reaction mixture was stirred overnight. The yield by glc using internal standard of 5-methoxy-N,N-dimethyl-2-(phenylethynyl)benzeneethanamine was 91%.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([NH2:9])=[O:8])[C:5]1([CH3:11])[CH3:10].ClC(Cl)=CC1C(C(O)=O)C1(C)C.C(Cl)(=O)C(Cl)=O.N.[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7](=[NH:9])[O:8][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:40]=2)[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(N)=O
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Product: CC1(C)C(C=C(Cl)Cl)C1C(=N)OCc1cccc(Oc2ccccc2)c1

Procedure:
Following the method of Example 1, 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropaneamide, from 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, oxalyl chloride and ammonia, is reacted with 3-phenoxybenzyl bromide to give 3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanimidate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:31](=[O:32])[CH2:30][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Product: CN1CCN(CC(=O)Nc2ccc3nc(NC4CCc5cccc(F)c54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.4 (M+H+).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19]([NH2:21])=[O:20])=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[NH:12]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].O>O1CCCC1>[NH2:18][C:16]([NH:15][C:11]1[NH:12][C:13]2[C:9]([C:10]=1[C:19]([NH2:21])=[O:20])=[CH:8][CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:14]=2)=[O:17]
Reactant: CC(=O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
Sodium borohydride (10 mg, 0.26 mmol) was added to a solution of 6-acetyl-2-aminocarbonylaminoindole-3-carboxamide (Compound 14-1,14 mg, 0.054 mmol) in anhydrous tetrahydrofuran (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (5 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (2 mL) and dried under reduced pressure to give the title compound (3 mg) as a colorless solid (yield 22%).
Reaction SMILES: [CH3:1][C:2]#[C:3][CH3:4].CN1C(=O)N(C)CCC1.N#N.C([Li])CCC.I[CH2:22][CH2:23][C@@H:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1.CC1(C)O[C@H](CCO)CO1>C1COCC1>[CH2:23]([C@@H:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:22][C:1]#[C:2][CH2:3][CH3:4]
Reactant: CC1(C)OC[C@@H](CCI)O1
Reactant: CC#CC
Agent: CC1(C)OC[C@@H](CCO)O1
Agent: N#N
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCC#CCC[C@@H]1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a flask cooled to −78° C. under N2 was added 2-butyne gas via syringe needle until approximately ˜3 mL of liquid had condensed in the flask. THF (120 mL) was then added followed by DMPU (18.9 ml, 156 mmol). The flask was purged with N2 and n-butyllithium (2.5M hexanes, 18.7 ml, 46.9 mmol) was added via syringe over 5 min and stirred for an additional 15 min at which time (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (10.0 g, 39.1 mmol) was added as a solution in THF (30 mL) [preparation of enantiopure (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane from commercially available (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol was performed using the procedure described by: Taber. D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem. Soc. 2002, 124, 13121]. The reaction was slowly warmed to rt and stirred a total of 3 h. The mixture was quenched with sat. NH4Cl, and extracted with Et2O (2×). The organics were washed with H2O, and brine, dried over MgSO4, filtered, and concentrated. The material was purified by silica gel chromatography (5% EtOAc in hexanes gradient to 15% EtOAc in hexanes) to give (R)-4-(hex-3-ynyl)-2,2-dimethyl-1,3-dioxolane as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.19 (1H, m), 4.08 (1H, dd, J=8.0, 6.0 Hz), 3.58 (1H, dd, J=7.6, 6.8 Hz), 2.26 (2H, m), 2.15 (2H, qt, J=5.2, 2.4 Hz), 1.81 (1H, m), 1.68 (1H, m), 1.40 (3H, s), 1.36 (3H,s), 1.11 (3H, t, J=7.6 Hz).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]([CH3:22])([CH2:19][CH2:20][CH3:21])[CH2:15][C:16]([OH:18])=O.[K+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.[Cl-].[Mg+2].[Cl-].[N-]1C=CN=C1.OP(O)(O)=O>C1COCC1>[CH3:22][C:14]([CH3:13])([CH2:19][CH2:20][CH3:21])[CH2:15][C:16](=[O:18])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCCC(C)(C)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=P(O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCC(C)(C)CC(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
Under N2, 1,1′-Carbonyldiimidazole (294 g, 1.82 mol) and THF (1000 mL) was slowly added to 3,3-dimethylhexanoic acid (238 g, 1.65 mol in 200 mL of THF), to a 2 L 3-necked flask. After the addition was completed, the solution was stirred at ambient temperature for 3 hours. Ethyl malonate potassium salt (281 g, 1.65 mol), THF (1500 mL) and magnesium chloride (157 g, 1.65 mol) were added under N2 to a flask equipped with an over-head stirrer. The mixture was stirred at 50° C. for 3 hours. It was then cooled down to room temperature and above acid imidazolide solution was added. The resultant slurry was stirred for 18 hours. H3PO4 (30%, 1.5 L) was added and the mixture was stirred for 1 hour. The aqueous layer was separated and extracted with MTBE (3×700 mL). The combined organic layer was washed with K2CO3 (25%, 2×500 mL) and brine (1000 mL) and dried over magnesium sulfate (˜40 g). The drying reagent was filtered and solvent was removed to give 250 g of ethyl 5,5-dimethyl-3-oxo-octanoate (yield 71%).
Reaction SMILES: [CH:1]([O-:3])=[O:2].[NH4+:4].C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38]CC3C=CC=CC=3)=[C:34]([C@@H:46]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH2:47][CH2:48][N:49]([CH:53]([CH3:55])[CH3:54])[CH:50]([CH3:52])[CH3:51])[CH:33]=2)=[CH:15][C:14]=1[NH:70][S:71]([CH3:74])(=[O:73])=[O:72])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[Si:63]([O:62][C@H:19]([C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[C:14]([NH:70][S:71]([CH3:74])(=[O:72])=[O:73])[CH:15]=1)[CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C@@H:46]([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:47][CH2:48][N:49]([CH:50]([CH3:51])[CH3:52])[CH:53]([CH3:55])[CH3:54])[CH:33]=1)([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64].[CH:1]([O-:3])=[O:2].[NH4+:4]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Temperature: 25 °C

Procedure:
Palladium hydroxide (10% on carbon, 20 mg) was added to a stirred solution of ammonium formate (344 mg, 5.46 mmol) and N-{2-(benzyloxy)-5-[(1R)-2-{[10-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}dec-9-en-1-yl]amino}-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanesulfonamide (Preparation 4, 90 mg, 0.091 mmol) in methanol (10 ml) at room temperature. The reaction was heated under reflux for 1 hour, cooled to room temperature and filtered through Arbocel™. The filtrate was collected and the solvent removed in vacuo to yield N-(5-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[(10-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}decyl)amino]ethyl}-2-hydroxyphenyl)methanesulfonamide as a mixture with residual ammonium formate. LRMS: m/z 811 [M+H]+. This mixture was dissolved in tetrahydrofuran (4 ml) and methanol (2 ml) and triethylaminetrihydrofluoride (88 ul, 0.54 mmol) was added in one portion at room temperature. The reaction was stirred for 12 hours and the solvent removed under reduced pressure, the residue was dissolved in methanol (10 ml) and 880 ammonia (1 ml) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (80/20/2.0 by volume) to furnish the title compound as a glass, 35 mg.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COCOc1cc(OC)ccc1B(O)O
Reactant: CCCCn1cnc(C(=O)OCC)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCn1cnc(C(=O)OCC)c1-c1ccc(OC)cc1OCOC
Yield: 44.7 %

Procedure:
A mixture of ethyl 5-bromo-1-n-butyl-1H-imidazole-4-carboxylate (0.10 g, 0.37 mmol), 2-methoxymethoxy-4-methoxyphenylboronic acid (0.16 g, 0.73 mmol), sodium carbonate (0.08 g, 0.73 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.04 g) in 12 mL of toluene/ethanol/water (10/1/1) was stirred at reflux for 24 h. After an aqueous work up, extracting with ethyl acetate (3×20 mL), the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.06 g, 46%). 1H NMR (250 MHz, CDCl3)δ 7.53 (s, 1H), 7.09 (d, 1H), 6.75 (d, 1H), 6.60 (dd, 1H), 5.05 (q, 2H), 4.21 (q, 2H), 3.85 (s, 3H) 3.80 (t, 2H), 3.30 (s, 3H) 1.60 (quintet, 2H), 1.30 (m, 5H), 0.80 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]N.C(Cl)(Cl)Cl.CO>CO>[C:11]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:6]2[C:5](=[O:19])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Reactant: CN(C)CCN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Reaction time: 14 h

Procedure:
To a suspension of 1.542 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 10 ml of methanol is added 4.408 g of N,N-dimethylethylenediamine, and the mixture is stirred for 14 hours. The reaction mixture is condensed under reduced pressure, and subjected to flash column chromatography on 50 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (10:1) to perform separation and purification. The title compound is obtained as colorless crystal in a yield of 1.174 g.
Reaction SMILES: O[C@@H:2]([CH3:20])[C@@H:3]([NH:7][C:8]([O:10][C@@H:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:19][C@H:11]([O:10][C:8](=[O:9])[NH:7][C@H:3]1[C:4](=[O:6])[O:5][C@H:2]1[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCC[C@H](C)OC(=O)N[C@@H](C(=O)O)[C@H](C)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC[C@H](C)OC(=O)N[C@H]1C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 53.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-3-hydroxy-2-[[(1S)-1-methyloctoxy]-carbonylamino]-butanoic acid (0.2 g, 0.69 mmol) in dry CH2Cl2 (20 mL), Et3N (0.29 mL, 2.07 mmol) and subsequently TBTU (0.27 g, 0.83 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 40:60) to give the title compound (0.1 g, 53%) as a white solid. MS (ESI) m/z: 272 [M−H]+; (ESI) m/z: 270 [M−H]−. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.8 Hz, 3H), 1.15 (d, J=6.3 Hz, 3H), 1.20-1.31 (m, 10H), 1.34 (d, J=6.4 Hz, 3H), 1.41-1.56 (m, 2H), 4.63-4.74 (m, 1H), 4.83 (dq, J=6.3 Hz, 1H), 5.39 (dd, J=6.3, 9.3 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.S(=O)(=O)(O)O>O>[CH:17]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][N:11]3[C:19]=2[C:18]=1[C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=13
Reactant: O=C1CCCCCCC1
Reactant: NN1CCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: c1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 30.7 %

Procedure:
Following the procedure of Example 1, Step 1, cyclooctanone (6.9 mL, 52 mmol), 1-aminoindoline (7.0 g, 52 mmol) and concentrated sulfuric acid (10 mL) in water (90 mL) provided 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indole (3.6 g). MS (ES) m/z 226.2.