Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:14][C:15]1[C:19]2[N:20]=[CH:21][NH:22][C:23](=[O:24])[C:18]=2[NH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])C1C=CC=CC=1>C(O)(C)C.[Pd]>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:14][C:15]1[C:19]2[N:20]=[CH:21][NH:22][C:23](=[O:24])[C:18]=2[NH:17][CH:16]=1
Reactant: O=c1[nH]cnc2c(CN(CCCCO)Cc3ccccc3)c[nH]c12
Agent: [Pd]
Solvent: CC(C)O
Product: O=c1[nH]cnc2c(CNCCCCO)c[nH]c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 7-((benzyl(4-hydroxybutyl)amino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (230 mg, 0.70 mmol) in iso-propanol (3 ml) was added 10% Pd—C (50 mg). The mixture was stirred at 50° C. under an atmospheric pressure of H2 overnight. Then the solution was filtered on a pad of Celite and the pad washed with MeOH (10 ml). The filtrate was evaporated to dryness and the residue was chromatographed on silica (DCM-MeOH 8:2+1% cNH3) to give 7-(((4-hydroxybutyl)amino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (133 mg, 0.56 mmol, 80% yield) as a white solid. 1H NMR (300 MHz, CD3OD+DCl) 1.64 (2H, m), 1.87 (2H, m), 3.19 (2H, t, J 7.6 Hz), 3.63 (2H, t, J 5.9 Hz), 4.48 (2H, s), 7.87 (1H, s), 9.05 (1H, s); 13C NMR (75 MHz, CD3OD+DCl) 24.7, 30.7, 30.9, 42.1, 62.5, 105.6, 120.2, 133.4, 133.8, 146.8, 153.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:8]([CH:10]1[O:12]C1)[Cl:9].Cl>>[ClH:9].[CH3:1][O:2][C:3]([CH2:4][C:5](=[NH:6])[O:12][CH2:10][CH2:8][Cl:9])=[O:7]
Reactant: COC(=O)CC#N
Reactant: ClCC1CO1
Agent: Cl
Product: COC(=O)CC(=N)OCCCl
Yield: 92 %

Procedure:
A mixture of 9.9 parts of methylcyanoacetate and 8.05 parts of epichlorohydrin was saturated with dry hydrogen chloride gas under ice-cooling and further cooled with icewater for one hour, followed by keeping in a refrigerator overnight. The resulting solid was washed with ethylether and dried to give 19.9 parts of 2-chloroethyl methoxycarbonylacetimidate hydrochloride. Yield 92% Melting point: 103 to 107°C (decomposition).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[Cl:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(Cl)c1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 309 under basic conditions (aq. NaOH/EtOH). 1H NMR (DMSO-d6, 300 MHz) δ 1.10-1.40 (m, 3H), 1.45-1.60 (m, 2H), 2.25-2.45 (m, 2H), 2.55-2.80 (m, 1H), 4.30 (m, 4H), 4.50 (m, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.00 (m, 3H), 7.10 (m, 1H), 7.25 (d, J=16.0 Hz, 1H), 7.48 (d, J=8.0 15.5 Hz, 1H), 7.90 (d, J=15.5 Hz, 1H). MS (ESI) m/z 458 (M+H)+. Anal. calcd. for C23H21ClNO5SNa.1.3H2O: C, 54.69; H, 4.73; N, 2.45. Found: C, 54.67; H, 4.71; N, 2.77.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:20][O:19][C:18](=[O:21])[C:17]2[C:22]([CH3:36])=[C:23]([O:34][CH3:35])[CH:24]=[C:25]([O:26][Si](C(C)(C)C)(C)C)[C:16]=2[CH2:15][S:14][CH2:13][C@@H:12]([C:37]([OH:39])=O)[NH:11][C:10]1=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:42]=1.C([Mg]Br)C.[F-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CO.O>[OH:26][C:25]1[C:16]2[CH2:15][S:14][CH2:13][C@@H:12]([C:37](=[O:39])[CH2:41][CH3:42])[NH:11][C:10](=[O:40])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:20][O:19][C:18](=[O:21])[C:17]=2[C:22]([CH3:36])=[C:23]([O:34][CH3:35])[CH:24]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(c1C)C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)CSC2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC[Mg]Br
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To a solution of 90 mg of (4R,7S)-7-tert-butoxycarbonylamino-14-tert-butyldimethylsilyloxy-1,3,4,5,6,7,8,10-octahydro-12-methoxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylic acid in 1.5 ml of tetrahydrofuran were added 49 mg of dipyridyl-2,2-disulfide and 79 mg of triphenylphosphine. The solution was stirred at 0° C. for 1 hour, and then 0.15 ml of a 1M solution of ethylmagnesium bromide in tetrahydrofuran were added. The mixture was stirred at 0° C. for 30 minutes, and then 0.5 ml of water were added, and stirring was continued for 5 minutes. The mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and with brine. The organic phase was dried over sodium sulfate, evaporated in vacuo, and the residual oil was chromatographed on silica gel using acetone/hexane (1:4, v/v) as eluent. The (tert-butyldimethylsilylated)-product obtained was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield 5 mg of tert-butyl (4R, 7S)-1,3,4,5,6,7,8,10-octahydro- 14-hydroxy-12-methoxy-11-methyl-4-propionyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([O:40]C)=[O:39])[CH:34]=[CH:35][CH:36]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([OH:40])=[O:39])[CH:34]=[CH:35][CH:36]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCCN3CCOCC3)Cc3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCCN3CCOCC3)Cc3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-29 (200 mg) and lithium hydroxide (100 mg) were added to tetrahydrofuran (15 ml) and water (5 ml) and the same manner as Example 2-12 was conducted to give the titled compound as a white solid. Yield: 130 mg (66%); MS APCI+ve 570 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11].FC1C=CC([B:22]([OH:24])[OH:23])=C(O[C@H](CC=C)C)C=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11])=[C:2]([B:22]([OH:24])[OH:23])[CH:7]=1
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Product: C=CC[C@H](C)Oc1ccc(F)cc1B(O)O
Yield: 100 %

Procedure:
Prepared from (S)-2-bromo-4-fluoro-1-(pent-4-en-2-yloxy)benzene in 100% yield following the same procedure as (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. NMR is complex and suggests an oligomeric mixture. The material, however, was used as is and was fully compentent for undergoing a Suzuki coupling.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Reactant: CCCCC1CCNCC1
Solvent: CC#N
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 54.3 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.329 g, 1.0 mmol) and 4-butylpiperidine (0.283 g, 2.0 mmol) in MeCN (2 mL) and shaken at 60° for 20 h. The reaction mixture was concentrated, and the product purified by flash CC (SiO2; EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH47-A) (0.186 g, 54%). 1H NMR (CD3OD) δ 7.26-7.19 (M, 3H), 7.04-7.00 (m, 1H), 2.93-2.88 (m, 3H), 2.77 (d, J=10.4 Hz, 2H), 2.62-2.58 (m, 2H), 2.29-2.06 (m, 3H), 1.93-1.86 (m, 2H), 1.68-1.62 (m, 2H), 1.31-1.22 (m, 9H), 0.91-0.86 (m, 2 CH3); 13C NMR (CD3OD) δ 173.2, 140.3, 129.1, 128.5, 128.4, 124.4, 166.9, 64.9, 56.0, 55.6, 37.5, 36.9, 33.4, 33.3, 32.9, 30.1, 30.1, 26.2, 24.0, 17.2, 14.4.
Reaction SMILES: [OH:1][CH:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1.OC(CCCCCCC)C(=O)CC1C=CC(O)=C(OC)C=1>>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: CCCCCCCCCC(O)C(=O)Cc1ccc(O)c(OC)c1
Agent: CCCCCCCC(O)C(=O)Cc1ccc(O)c(OC)c1
Product: CCCCCCCCCC(O)CCc1ccc(O)c(OC)c1

Procedure:
Of potential interest is 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecanone [3.91]. This substance is a homologue of the cardiotonic 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decanone [3.92].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27]2[NH:29][CH:30]=[CH:31][C:26]2=[C:25]([N+]([O-])=O)[CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[N:28]=[C:27]2[NH:29][CH:30]=[CH:31][C:26]2=[C:25]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[F:9])[CH:24]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc(Cl)nc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2-fluorophenol (0.77 g, 6.07 mmol) is dissolved in DMF. Potassium tert-butoxide (0.68 g, 6.07 mmol) is added, and the mixture is stirred at room temperature for 30 minutes. Powdered potassium carbonate (0.35 g, 2.53 mmol) and 1 g (5.06 mmol) of 6-chloro-4-nitro-1H-pyrrolo[2,3-b]pyridine (from example XXX) are then added successively. The mixture is stirred at 120° C. for 12 hours. After cooling, the mixture is diluted with ethyl acetate (200 ml). The suspension is filtered off with suction through Celite®, and the filtercake is washed with ethyl acetate. The solution is extracted successively with aqueous sodium bicarbonate solution and sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, mobile phase: DCM:acetone=5:1). This gives 0.95 g (67% of theory) of product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[ClH:15].NCC1C=C(C=C(OC)C=1)C(OC)=O>>[ClH:15].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: COC(=O)c1cc(CN)cc(OC)c1
Agent: Cl
Product: COC(=O)c1ccc(OC)c(CN)c1

Procedure:
Methyl 3-(aminomethyl)-4-methoxybenzoate hydrochloride was prepared from methyl 3-cyano-4-methoxybenzoate in an analogous manner to Intermediate 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])(=[O:19])[CH3:18]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1N
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(C(=O)CCC(=O)O)cc1NC(C)=O

Procedure:
A mixture of 3-(3-amino-4-methoxybenzoyl) propionic acid (15.61 g.) with acetic anhydride (7.14 g.) was treated with concentrated sulphuric acid (2 drops) and heated on the steam bath for 3 hours. It was then cooled and decomposed by the addition of ice. The resultant solid was collected and crystallised from methanol to yield the product, (10.5 g.), m.p. 184°-185° C.
Reaction SMILES: O.[OH-].[Li+].OO.C([C@@H]1COC(=O)N1[C:19]([CH:21]1[CH2:26][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])[C:24](=[O:38])[CH2:23][CH2:22]1)=[O:20])C1C=CC=CC=1.S([O-])(O)=[O:40].[Na+]>O.O1CCCC1>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][N:25]1[C:24](=[O:38])[CH2:23][CH2:22][CH:21]([C:19]([OH:20])=[O:40])[CH2:26]1
Reactant: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)CCC2=O)c(OC)c1
Reactant: O=S([O-])O
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CC(C(=O)O)CCC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
To a solution of lithium hydroxide monohydrate (316 mg) in water (10 ml) was added dropwise a 30 wt % aqueous solution of hydrogen peroxide (1.8 ml) under ice-cooling and the mixture was stirred for 10 minutes. To this reaction solution was added tetrahydrofuran (10 ml), and then a solution of the low-polarity component of 5-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one (3.37 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the mixture was stirred for additional 1 hour. To this reaction solution was added an aqueous solution of sodium hydrogen sulfite (1.81 g) was added dropwise, and then the mixture was warmed to room temperature, and stirred for 30 minutes. This mixed solution was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue was added ethyl acetate, and the mixture was stirred at room temperature. The insoluble substance was collected by filtration, and dried under reduced pressure to give the titled compound (1.36 g). An analysis of this solid by HPLC analysis condition 2 showed that an isomer with shorter retention time was a main product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[Na].O.C(O)(=O)C.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1nc(N)nc(Cl)c1[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)nc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Amino-4-chloro-6-methyl-5-nitropyrimidine (Boon et al., J. Chem. Soc., 96-102 (1951)) (1.24 g, 6.58 mmol) was added to a solution of sodium (0.21 g, 9.13 mmol) in benzyl alcohol (14 mL) under argon. The solution was heated in a 135° C. oil bath for 3.5 h, and was poured into water (70 mL) with constant stirring for 10 min. After neutralization with glacial acetic acid, a yellow precipitate formed which was collected by filtration and washed with water. This solid was crystallized from benzene to give 5b as a bright yellow crystalline solid: yield, 0.57 g (33%); mp 159-160° C.; UV (pH 1) λmax 268 nm (ε=0.783×104), 345 (sh) (0.104×104); (pH 6.9) 282 (0.564×104),345(sh) (0.338×104); (pH 13) 282 (0.549×104), 345 (sh) (0.332×104); 1H NMR δ 2.35 (s, 3H, CH3), 5.44 (s, 2H, ArCH2), 7.34-7.46 (m,5H, ArH), 7.64(b s, 2H, NH2, exchange with D2O); MS (EI) calcd. m/z for C12H12N4O3 260.0908, found 260.0913; Anal. (C12H12N4O3) C, H, N.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[F:33][C:34]([F:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:15](=[O:16])[C@H:14]([N:5]2[CH2:6][C@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C@@H:3]([CH2:1][N:40]3[CH2:41][CH2:42][CH:37]([CH2:36][CH2:35][C:34]([F:33])([F:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:38][CH2:39]3)[CH2:4]2)[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: FC(F)(CCC1CCNCC1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCC(F)(F)c4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Reaction time: 4 h
Yield: 66.2 %

Procedure:
Molecular sieve pellets (3 A) were added to a solution of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid (4-methoxy)benzyl ester (34 mg, 0.078 mmol, from EXAMPLE 33, Step E) and 4-(3,3-difluoro-3-phenylpropyl)piperidine (20 mg. 0.084 mmol, from EXAMPLE 154, Step D) in 1,2-dichloroethane (0.75 mL). The mixture was stirred for 45 min. at RT before the addition of sodium triacetoxyborohydride (19.9 mg, 0.094 mmol). After 4 h, the mixture was diluted with EtOAc (20 mL) and washed with saturated aq. NaHCO3 (10 mL) followed by saturated aq. NaCl (10 mL). The organic layer was dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 92:8 v/v, then 86:14 v/v hexanes/EtOAc, gave 34 mg of the title compound as a colorless film. 1H NMR (400 MHz, CD3OD) δ 7.47-7.40 (m, 5H), 7.36 (d, J=8,22H), 7.23 (t, J=7, 2H), 7.15 (t, J=7, 1H), 7.10 (d, J=7, 1H), 6.90 (d, J=8, 2H), 5.12 (s, 2H), 3.18 (dd, J=9, 7, 1H), 3.12-3.06 (m, 2H), 2.80-2.56 (m, 4H), 2.51 (dd, J=9, 7, 11H), 2.30-2.19 (m, 3H), 2.12 (tm, J=16, 2H), 1.94 (bd, J=12, 1H), 1.86-1.50 (m, 9H), 1.31-0.89 (m, 10H); ESI-MS 659 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[H-].[Na+].Cl.Cl[CH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:18][C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: ClCc1ncccn1
Reactant: O=C1NCCOc2ccc(Br)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ccc2OCCN1Cc1ncccn1
Temperature: 25 °C

Procedure:
7-Bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (1.0 g, 4.13 mmol) was dissolved in DMF (10 ml) cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (363 mg, 9.08 mmol) portion wise. After 10 min a solution of 2-(chloromethyl)pyrimidine hydrochloride (813 mg, 4.96 mmol) in DMF (4 ml) was added, the reaction mixture warmed up to room temperature and quenched with 12 mL of water after it was complete. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purified by silica gel chromatography (95% DCM/MeOH) to afford 7-bromo-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.
Reaction SMILES: Cl[Si:2](Cl)(Cl)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.O>CO>[SiH3:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cl[Si](Cl)(Cl)CCc1ccccn1
Solvent: O
Solvent: CO
Product: [SiH3]CCc1ccccn1
Reaction time: 1 h

Procedure:
A solution of 2-(2-silylethyl)pyridine oligosilsesquioxane pillar material was prepared from a methanol solution of 2-(2-trichlorosilylethyl)pyridine (24 grams of 2-(2-trichlorosilylethyl)pyridine in 175 ml of methanol by adding 10.5 ml of water. The mixture was stirred for 1 hour while maintaining the temperature below 30° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][CH2:26][C:27]([OH:29])=O)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH:30]([C:27](=[O:29])[CH2:26][CH2:25][C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][N:12]1[C:14]([N:16]([CH3:17])[CH3:18])=[O:15])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)O)c1ccccc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 40 mg (0.10 mmol) of acid 24-1 in DMF was added 11 μL (0.12 mmol) of aniline, 29 mg (0.15 mmol) of EDCI, 17 mg (0.13 mmol) HOAT, and 28 μL (0.20 mmol) of triethylamine. After stirring overnight at room temperature, the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 24-2 as a white solid. Data for 24-2: 1HNMR (500 MHz, d6-DMSO) δ 9.8 (s, 1H), 7.5-7.0 (m, 13H), 6.2 (s, 1H), 5.0 (m, 1H), 4.8 (m, 1H), 3.0 (m, 1H), 2.75 (s, 6H), [(˜2.5, under solvent peak (m, 1H)], 2.2 (m, 2H) ppm. HRMS (ES) calc'd M+H for C28H27F2N3O2: 476.2144. Found: 476.2162
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][OH:25])[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([O:17][S:34]([CH3:33])(=[O:36])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1C(O)c1cc(F)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1C(OS(C)(=O)=O)c1cc(F)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of (±)-(2-benzyloxy-5-fluoro-phenyl)-(2-hydroxymethyl-phenyl)-methanol (500 mg, 1.48 mmol, 1.00 eq.) and DMAP (9 mg, 0.07 mmol, 0.05 eq.) in DCM (30 mL), NEt3 (0.82 mL, 5.91 mmol, 4.00 eq.) and methanesulfonyl chloride (0.24 mL, 3.10 mmol, 2.10 eq.) were added dropwise. The mixture was stirred at 0° C. for 1 hour and further at r.t. for 2 hours. The reaction mixture was diluted with H2O (50 mL) and DCM (50 mL). The layers were separated. The aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with water (1×150 mL), sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (±)-methanesulfonic acid 2-[(2-benzyloxy-5-fluoro-phenyl)-methanesulfonyloxy-methyl]-benzyl ester.
Reaction SMILES: COC([CH:5]1[C:12](=[O:13])[C:9]2([CH2:11][CH2:10]2)[C:8]2([CH2:15][CH2:14]2)[NH:7][C:6]1=[O:16])=O>C(#N)C.O>[CH2:11]1[C:9]2([C:12](=[O:13])[CH2:5][C:6](=[O:16])[NH:7][C:8]32[CH2:14][CH2:15]3)[CH2:10]1
Reactant: COC(=O)C1C(=O)NC2(CC2)C2(CC2)C1=O
Solvent: CC#N
Solvent: O
Product: O=C1CC(=O)C2(CC2)C2(CC2)N1
Temperature: 25 °C

Procedure:
8,10-Dioxo-7-aza-dispiro[2.0.2.4]decane-9-carboxylic acid methyl ester (628 mg; 2.2 mmol) in acetonitrile/water (9 ml/0.9 ml) is refluxed for 50 minutes, cooled to room temperature, filtered and the filtrate evaporated to deliver the title compound as colorless solid (386 mg; 98%).