Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH2:42])=[CH:31][CH:30]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:53][N:54]=[C:55]=[O:56]>C(Cl)Cl>[CH2:2]([O:9][C:10]([NH:12][C:13]([CH3:45])([CH3:44])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:55]([NH:54][CH3:53])=[O:56])=[CH:33][CH:34]=2)[C:18]1=[O:43])=[O:15])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN=C=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.1 %

Procedure:
To a solution of 8.57 g (13.7 mmol) of 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, hydrochloride (Step I) in 75 mL of dry methylene chloride under nitrogen atmosphere was added 2.28 mL (16.4 mmol) of triethylamine followed by 0.89 mL (15 mmol) of methyl isocyanate. After stirring at room temperature for 45 minutes the solvent was removed under vacuum. The resulting material was dissolved in methylene chloride and purified by flash column chromatography on silica gel eluting with ethyl acetateethanol (96:4) to afford 7.73 g (87%) of product as a white foam. 1H NMR (200 MHz, CD3OD): δ 1.39 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m, 3H), 2.63 (s, 3H), 4.13 (s, 2H), 4.36 (m, 1H), 4.86 (d, 15 Hz, 1H), 4.85 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.08-7.43 (m, 17H). FAB-MS: calculated for C38H41N5O5 647; found 648(M+H, 80%).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[N-:7]=[N+:8]=[N-:9].[Na+].[Cl-].[NH4+]>CO>[N:7]([C@@H:6]1[CH2:5][O:4][CH2:3][C@H:2]1[OH:1])=[N+:8]=[N-:9]
Reactant: C1OCC2OC12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1COC[C@H]1O
Temperature: 75 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
3,4-Epoxytetrahydrofuran (9 g, 105 mmol) was added to a stirred solution of sodium azide (27 g, 415 mmol) and ammonium chloride (9 g, 159 mmol) in aqueous methanol (95%, 200 ml). The reaction was heated to 75° C. and stirred for 20 hours. The reaction was cooled, filtered and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate, dried and evaporated under reduced pressure to afford the title compound as a colourless oil, 10 g, 74% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COc1ccccc1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Yield: 51.9 %

Procedure:
The diaryl product was obtained using the same synthetic methods as shown in Example 25, step 5, using 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.1 mmol, 1.00 equiv) and anisole (16 g, 148.1 mmol, 5.00 equiv) as reactants. Purification via silica gel column (ethyl acetate/petroleum ether (1:10)) afforded 4.0 g (52%) of 1,2-bis(4-methoxyphenyl)ethanone as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:11]1([NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:29]3[CH2:28][CH:27]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH2:31][CH2:30]3)[N:3]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:5]=2)[CH2:13][CH2:12]1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NC2CC2)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 44a) was treated with 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-cyclopropylamino-6-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=395.
Reaction SMILES: [CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].C(O)(=O)C.[Br:24]Br>C(Cl)(Cl)(Cl)Cl>[Br:24][C:6]1[C:7](=[O:8])[C:3]([CH2:1][CH3:2])([CH3:19])[O:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4.5 g of 2-ethyl-2-methyl-5-{4-(methylsufonyl)phenyl}-3(2H)-furanone dissolved in 100 ml carbon tetrachloride, were added acetic acid (3 ml) and bromine (1 ml). The reaction solution was stirred for 1 hour at room temperature. Then the reaction was quenched by adding saturated aqueous sodium thiosulfate solution until the characteristic color of bromine disappeared. The reaction solution was extracted with dichloromethane (30 ml×3) and the organic layer was concentrated in vacuo. The resulting residue was purified by column chromatographic separation (hexane/ethylacetate=1:1) to give 4 g of 4-bromo-2-ethyl-2-methy-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. NMR: δ0.91 (t, J=7.2 Hz, 3H), 1.52 (s, 3H), 1.95 (qd, J=7.2, 3.0 Hz, 2H), 3.11 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 8.41 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1703, 1583, 1316, 1160, 552.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:22]([O:1][C:2]1[C:9]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:23][CH3:24]
Reactant: O=Cc1cccc(OC(F)(F)F)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(C=O)cccc1OC(F)(F)F
Temperature: 37 °C
Yield: 96.1 %

Procedure:
To a solution of 2-hydroxy-3-trifluoromethoxybenzaldehyde (1.00 g, 4.82 mmol) in DMF (10 mL) was added K2CO3 (1.46 g, 10.6 mmol) followed by 1-bromopropane (0.65 mL, 7.2 mmol). The solution was heated to 37° C. for 6 h. The reaction was quenched with H2O (40 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (1.15 g, 96%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.38 (t, J=7.9 Hz, 1H), 4.09 (t, J=6.4 Hz, 2H), 1.81-1.72 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])[CH:7]=1)=O.CO.[CH3:29][NH2:30].[BH4-].[Na+].O>CO>[CH3:29][NH:30][CH2:1][C:3]1[CH:4]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C(=O)OC)c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
Methyl 2-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate (664 mg) was dissolved in methanol (10 mL), 40% methylamine methanol solution (419 mg) was added at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added sodium borohydride (227 mg) at 0° C., the mixture was stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→0:1) to give the title compound as a pale-yellow oil (yield 472 mg, 68%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[NH2:31])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].O>CN(C)C(=O)C>[C:20]([C:19]1[CH:28]=[CH:29][C:30]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:17]([O:16][CH3:15])[CH:18]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(C(=O)c2ccccc2)ccc1N
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)c2ccccc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.52 g) in N,N-dimethylacetamide (5 mL) was rapidly added thionyl chloride (0.39 g) and the mixture stirred at -10° to -20° C. for 1 hour. 3-Methoxy-4-aminobenzophenone (0.50 g) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent methylene chloride then 2% ethyl ether in methylene chloride) gave the title compound (0.37 g) as an off-white solid; mp 126°-128° C. Analysis for C18H16F3NO4.0.25 H2O: Calculated: C, 58.14; H, 4.47; N, 3.77; Found: C, 58.29; H, 4.48; N, 3.78.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:7][C:5]([NH2:6])=[C:4]([N+:18]([O-])=O)[CH:3]=1.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Nc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A suspension of 4-bromo-5-(2,4-difluorophenoxy)-2-nitroaniline (0.406 g, 1.18 mmol) in tetrahydrofuran (5.0 mL) was treated with iron (0.657 g, 11.8 mmol), followed by acetic acid (4.9 mL, 87 mmol) and stirred at 60° C. for 1 h. The reaction mixture was diluted with ethyl acetate and quenched carefully with saturated sodium bicarbonate. The organic layer was separated and washed again with saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (371 mg, quantitative) that was used immediately without further purification. LCMS calculated for C12H10BrF2N2O (M+H)+: m/z=315.0, 317.0. found: 315.0, 316.9.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[F:11][C:12]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>ClCCl>[F:11][C:12]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:13]=1[C:14]([NH:6][CH3:4])=[O:15]
Reactant: O=C(Cl)c1cc(I)ccc1F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
Add methylamine hydrochloride (0.57 g, 8.4 mmol) and triethylamine (2.17 mL, 15.5 mmol) to a solution of 2-fluoro-5-iodobenzoyl chloride (2.0 g, 7.0 mmol) in dichloromethane (100 mL) at 0° C. Warm to room temperature and stir 20 h. Concentrate and purify by silica gel chromatography, eluting with a gradient of 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (1.7 g, 87%).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([C:16]2[C:28]([Cl:29])=[CH:27][C:19]3[NH:20][C:21]([S:23]([CH3:26])(=[O:25])=[O:24])=[N:22][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:10]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:15]=[CH:14][C:13]([C:16]2[C:28]([Cl:29])=[CH:27][C:19]3[N:20]([CH2:8][O:7][CH2:6][CH2:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[N:22][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
SEMCl (2.28 mL, 12.87 mmol) was added to a solution of 5-biphenyl-4-yl-6-chloro-2-(methylsulfonyl)-1H-benzimidazole (3.79 g, 9.9 mmol) and Hunig's base (2.08 mL, 11.88 mmol) in THF (20 mL) at 0° C. The reaction was stirred at rt for 3 h then partitioned between EtOAc and saturated aqueous NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. Chromatography over silica eluting with 5-25% EtOAc/hexanes afforded the desired product as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24]I>>[CH3:24][N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20]
Reactant: CI
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Product: CN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a yellow semi-solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and methyl iodide. MS (ESI): 343.1 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C:8]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]=2[CH2:6]1.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1>CN(C)C=O.O>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][O:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][C:8]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]=3[CH2:6]2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: Clc1ccc2c(c1)CC(OCCBr)c1ccccc1S2
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C1CCN(CCOC2Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Temperature: 63 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A mixture of 10-(2-bromoethoxy)-2-chloro-10,11-dihydrodibenzo[b,f]thiepine (5.19 g, 14 mmol, prepared similarly as described in example 2), 4-piperidinecarboxylic acid ethyl ester (2.20 g, 14 mmol) and anhydrous potassium carbonate (4.70 g, 34 mmol) in dry N,N-dimethylformamide (25 ml) was stirred at 60-66° C. for 6 h. After standing overnight at room temperature, benzene (50 ml) and water (50 ml) were added, and the phases were separated. The organic layer was washed with water (2×50 ml), dried (K2CO3) and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel using benzene as eluent, affording 4.28 g (68%) of oily 1-(2-(2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piperidinecarboxylic acid ethyl ester. The oil was dissolved in dry acetone (40 ml), oxalic acid dihydrate (1.76 g, 14 mmol) and ether were added, and the formed hydrogen oxalate was crystallised from a mixture of acetone and ether.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:18][C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][C@H:15]1[CH:27]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.CCCCCC>[CH2:7]([N:14]1[CH2:18][C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][C@H:15]1[CH:27]=[CH2:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Yield: 83.7 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.07 g) was portionwise added potassium t-butoxide (337 mg) with stirring under ice-cooling. The mixture was stirred at ambient temperature for 2 hours. To the solution cooled on ice-bath was added dropwise (2S,4R)-1-benzyl-2-formyl-4-(t-butyldimethylsilyloxy)pyrrolidine (0.92 g) in toluene (2 ml) and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a mixture of water (10 ml) and ethyl acetate (20 ml). The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. To the residue was added n-hexane (30 ml). The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The resulting residue was chromatographed on silica gel (1 g) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-benzyl-2-vinyl-4-(t-butyldimethylsilyloxy)pyrrolidine (765 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[S:44]1[CH:48]=[C:47]([CH2:49][N:50]2[C:58]3[C:53](=[CH:54][C:55]([NH2:59])=[CH:56][CH:57]=3)[CH:52]=[N:51]2)[N:46]=[CH:45]1>ClCCCl>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:59][C:55]1[CH:54]=[C:53]3[C:58](=[CH:57][CH:56]=1)[N:50]([CH2:49][C:47]1[N:46]=[CH:45][S:44][CH:48]=1)[N:51]=[CH:52]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Nc1ccc2c(cnn2Cc2cscn2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol), triphenylphosphine (603 mg, 2.3 mmol) and carbon tetrachloride (2.2 ml, 23 mmol) in 1,2-dichloroethane (5 ml) was stirred at 45° C. for 2 hours. 1-(1,3-Thiazol-4-ylmethyl)-1H-indazol-5-amine (184 mg, 0.8 mmol) was added and the solvents were evaporated under vacuum. Acetonitrile (5 ml) was added. The mixture was stirred at 75° C. for 2 hours. After cooling, the solvents were evaporated under vacuum. The residue was diluted in 6N methanolic ammonia and the solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 3% to 5% methanol in DCM) to give the title compound as a beige foam (215 mg, 60%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.80 (s, 2H), 6.81 (d, 1H), 6.93 (s, 1H), 7.48 (m, 2H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.08 (s, 1H), 8.43 (s, 1H), 8.62 (s, 1H), 8.78 (s, 1H); Mass spectrum 474.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C@H:22]([CH2:23][O:24][CH2:25][C:26](O)=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C@H:22]([CH2:23][O:24][CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:43][CH2:42]3)=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3C[C@H]2COCC(=O)N2CCN(CC3CCN(C)CC3)CC2)c(C)c1
Reaction time: 2 h

Procedure:
N,N′-Carbonyldiimidazole (131 mg, 0.813 mmol) was added to a solution of (S)-2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-acetic acid (step d, Example 127) (325 mg, 0.775 mmol) in dichloromethane (5 ml), and stirring was carried out for 2 h at 30° C. A solution of 1-((1-methylpiperidin-4-yl)methyl)piperazine (152 mg, 0.775 mmol) in dichloromethane (5 ml) was then added at room temperature, and the reaction mixture was stirred for 15 h at that temperature. Saturated sodium hydrogen carbonate solution (10 ml) was added to the mixture, and the aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) using ethyl acetate/methanol/ammonia solution (25% aq.) (40:10:0.5). Yield: 263 mg (57%); MS, m/z 599.3 (MW).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:37])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[S:23])=[CH:17][CH:16]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:22](=[S:23])[NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:13](=[O:37])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[CH:16][CH:17]=2)=[O:36])=[CH:31][CH:30]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1ccc(NC(=S)NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCCN)cc2)cc1

Procedure:
Boc protected amine 32 (20 mg, 0.04 mmol) was stirred in CH2Cl2 (1 mL) and trifluoroacetic acid (166 μL) at rt for 30 min. Concentration in vacuo gave 33 as a pale yellow oil.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([B:13]([OH:15])[OH:14])=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:17]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:21]([CH3:31])[N:20]=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C:22]2[C:17]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([B:13]([OH:15])[OH:14])[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)=[N:18][CH:19]=[N:20][C:21]=2[CH3:31])=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc2c(c1)CNCCO2
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCOc3ccc(B(O)O)cc3C2)c1Cc1ccc(F)cc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylboronic acid hydrochloride salt (1.20 g, 5.2 mmol), 4-chloro-5-(4-fluorobenzyl)-6-methylpyrimidine (reagent preparation 5) (1.24 g, 5.2 mmol), diisopropylethylamine (0.40 mL, 2.10 mmol) 50% aqueous 1,4-dioxane (50 mL) was deoxygenated for five minutes by bubbling nitrogen gas then stirred at 95° C. for 18 hours. The reaction mixture was concentrated, diluted with water (50 mL), adjusted to pH 14, and then washed with isopropyl acetate (3×30 mL). The aqueous mixture was adjusted to pH 8 and the white solid precipitated was collected by filtration, washed with water and dried to give (4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (0.72 g, 35% yield). MS (EI) for C2H21BFN3O3: 394 (MH+).