Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[C:35]([F:40])[CH:34]=1)[CH3:25].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:25][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[C:35]([F:40])[CH:34]=1)[CH3:23]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Reactant: CN(C)Cc1ccccc1-c1ccc(N)c(F)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)Cc1ccccc1-c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 55, 90 mg, 0.28 mmol) and 4-(2-dimethylaminomethyl-phenyl)-2-fluoro-phenylamine (80 mg, 0.33 mmol) in pyridine (3 mL) cooled in an ice-bath, POCl3 (0.050 mL, 0.55 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (38 mg). MS 549.1 and 551.2 (M+H, Cl pattern).
Reaction SMILES: Cl.[CH2:2](NC(N1CCN(C(C2CCCC2)=O)CC1)=O)C.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([NH2:32])[CH:23]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:31][O:30][C:29]1[CH:28]=[C:25]2[C:24](=[CH:23][C:22]=1[O:21][CH3:20])[N:32]=[CH:2][N:27]=[CH:26]2
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CCNC(=O)N1CCN(C(=O)C2CCCC2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cncnc2cc1OC
Reaction time: 0.5 h

Procedure:
Ethyl-4-(cyclopentylcarbonyl)piperazin-1-yl-for-mamidate hydrochloride (0.01 mole) is added to a solution of 4,5-dimethoxy-2-aminobenzonitrile (0.01 mole) in 30 ml. of N,N-dimethylformamide. Sodium hydride (0.02 mole of a 56% suspension in mineral oil) is added and the mixture stirred 0.5 hr. at room temperature and then at 100° C. for a period of 12 hr. When the reaction period is complete, water is added providing 4-amino-2-[4-cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[I:22]I>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([I:22])=[CH:8][C:6]=2[N:7]=1
Reactant: II
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2oc(I)cc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (50 mg, 1.0 eq) dissolved in THF (2.1 ml) at −78° C. was added 1.6M solution of n-butyllithium (0.17 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture was stirred at −78° C. for 30 minutes. A solution of iodine (159 mg, 3.0 eq) in THF (0.6 ml) was added and reaction mixture was allowed to slowly warm up to room temperature and stirred for 45 minutes. The reaction mixture was quenched with saturated aq. Na2S2O3, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 (63 mg, 83%): MS (Q1) 366 (M)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:31]4[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=4)(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)cc1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-methoxybenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:31])[NH:20][C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[N:22]2)=[C:17]([O:32][CH3:33])[CH:16]=1.O>CS(C)=O.C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:31])[NH:20][C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[N:22]2)=[C:17]([O:32][CH3:33])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(F)cc2nc(-c3ccncc3)[nH]c(=O)c12
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OCCOCc2ccccc2)cc2nc(-c3ccncc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-benzyloxy-ethanol (2 mL) in dimethyl sulfoxide (3 mL) was added sodium hydride (0.30 g, 7.4 mmol) in portions, and the reaction mixture was stirred at room temperature for 45 minutes. To this mixture was added 7-fluoro-5-methoxy-2-pyridin-4-yl-3H-quinazolin-4-one (0.20 g, 0.74 mmol) and the reaction mixture was heated at 80° C. for 16 hours. Water was added, the mixture was acidified with acetic acid to pH approximately 4-5, and the precipitated solid was filtered off, to obtain a crude product, which was purified by preparative HPLC to obtain the title compound as a light yellow solid. Yield: 0.12 g (40%). MP 228.2-229.9° C. 1H NMR (400 MHz, DMSO-d6): δ12.29 (s, 1H), 8.77 (d, 2H), 8.08 (d, 2H), 7.36 (m, 5H), 6.82 (s, 1H), 6.62 (s, 1H), 4.58 (s, 2H), 4.32 (t, 2H), 3.87 (s, 3H), 3.83 (t, 2H). MS (ES+) m/z: 404.51 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].C(Cl)[Cl:30].Cl>C(OCC)(=O)C.CCOCC>[ClH:30].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: ClCCl
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Yield: 85 %

Procedure:
[4-Nitro-2-(2-methylphenyl)benzoyl]methionine methyl ester was reduced to a corresponding amine by stannous chloride in ethyl acetate at 78° C. The free amine was treated with methylene chloride and 3 N HCl in ether to give [4-amino-2-(2-methylphenyl)benzoyl]methionine methyl ester hydrochloride (85% yield); [α]25D=−28.3 (c=1.0, methanol); 1H NMR (CD3OD) δ 7.74 (d, J=8.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.23-7.30 (m, 5H), 4.47 (m, 1H), 3.69 (s, 3H), 2.06-2.18 (m, 4H), 1.99 (s, 3H), 1.97 (m, 2H), 1.74 (m, 1H); 13C NMR (CD3OD) δ 173.3, 170.8, 143.3, 139.7, 138.1, 137.2, 133.5, 131.49 130.8, 130.6, 129.6, 128.8, 126.2, 123.1, 66.9, 52.9, 31.5, 30.8, 20.4, 15.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH2:13][CH3:14])[C@:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1.ClC1N=C(N2CC(CC)C(C3CC3)(C#N)C2=O)C=CN=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH2:13][CH3:14])[C@@:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1
Reactant: CC[C@@H]1CN(c2ccnc(Cl)n2)C(=O)[C@]1(C#N)C1CC1
Agent: CCC1CN(c2ccnc(Cl)n2)C(=O)C1(C#N)C1CC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC[C@@H]1CN(c2ccnc(Cl)n2)C(=O)[C@@]1(C#N)C1CC1
Yield: 109.8 %

Procedure:
To a mixture of 3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (3.7 g) obtained in Step B of Example 376, 2,4-dichloropyrimidine (3.1 g), cesium carbonate (13 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.71 g) in tetrahydrofuran (55 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.38 g), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3SR,4RS)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) and (3SR,4SR)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g). (3SR,4RS)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (500 mg) having a shorter retention time and (3R,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (510 mg) having a longer retention time. (3SR,4SR)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (560 mg) having a shorter retention time and (3R,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (600 mg) having a longer retention time.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1.C(O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2OC)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(COc2ccc(CNc3ccc(Br)cc3N)cc2OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
To a stirred suspension of 4-bromo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline (7.71 g, 16.30 mmol) in tetrahydrofuran (100 mL), ethanol (25 mL), and water (25 mL) was added ammonium chloride (0.44 g, 8.15 mmol) and iron powder (9.10 g, 163 mmol). The mixture was heated to reflux. After 5 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite with the aid of ethanol. The filtrate was concentrated, and the residue partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to provide 6.73 g (95%) of 4-bromo-N1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:22])[CH2:15]P(OC)(OC)=O.C[O-].[Na+].Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:15]/[C:14]([O:13][CH3:12])=[O:22])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Yield: 97.2 %

Procedure:
To a solution of 3-nitro-benzaldehyde (15 g, 0.1 mol), (dimethoxy-phosphoryl)-acetic acid methyl ester (27 g, 0.148 mol) in DMF (100 ml) was added NaOMe (10.7 g 0.198 mol). The reaction was monitored by TLC. After reaction was completed, the reaction mixture was adjusted to pH=1 with aqueous HCl solution and evaporated. The resulting solid was washed with water to afford (E)-methyl 3-(3-nitrophenyl)acrylate as a yellow solid (20.14 g, 98%).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[NH:16]1[CH2:17][CH2:18][CH2:19][CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([NH:4][CH2:3][CH:2]([CH3:27])[CH3:1])=[O:6])[CH2:8][CH2:9]2)[CH2:14][CH2:15]1
Reactant: CC(C)CNC(=O)C1CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNC(=O)C1CCN(C2CCCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (1.95 g, 5.1 mmol) was dissolved in DCM (16 mL) and TFA (4 mL) was added. The reaction mixture was stirred at rt for 2 h under nitrogen, then the solvents were removed in vacuo, to give 1-(azepan-4-yl)-N-(2-methylpropyl)piperidine-4-carboxamide TFA salt (2.02 g), Intermediate 5, as a dark yellow oil which was used directly without further purification.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:26]1[CH2:29][CH:28]([CH2:30][C:31]([OH:33])=[O:32])[CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:26]3[CH2:29][CH:28]([CH2:30][C:31]([OH:33])=[O:32])[CH2:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(O)CC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(CC(=O)O)C3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (700 mg, 1.9 mmol), azetidin-3-ylacetic acid hydrochloride (495 mg, 3.3 mmol) and DIPEA (4 mL) in DMF (20 mL), provided the title compound as a crude product (600 mg, 70%), which was used directly in Step A.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]23[C:34]4[CH:33]=[CH:32][C:31]([CH:35]([OH:38])CO)=[CH:30][C:29]=4[O:28][CH2:27][CH:8]2[C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=2[C:23]([F:26])([F:25])[F:24])=[N:10][O:11]3)[CH2:3][CH2:2]1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]23[C:34]4[CH:33]=[CH:32][C:31]([CH:35]=[O:38])=[CH:30][C:29]=4[O:28][CH2:27][CH:8]2[C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:13]=2[C:23]([F:25])([F:26])[F:24])=[N:10][O:11]3)[CH2:5][CH2:6]1
Reactant: OCC(O)c1ccc2c(c1)OCC1C(c3onc(-c4ccccc4)c3C(F)(F)F)=NOC21N1CCOCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)OCC1C(c3onc(-c4ccccc4)c3C(F)(F)F)=NOC21N1CCOCC1
Reaction time: 1 h

Procedure:
To a homogeneous solution of 1-(9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazol-7-yl)ethane-1,2-diol (Preparation 60E, 0.074 g, 0.139 mmol) in a mixture of THF (2.0 mL) and water (0.13 mL) at room temperature was added sodium periodate (0.045 g, 0.209 mmol). The reaction mixture was stirred for 60 min. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate, washed with water, and washed with brine. The organic layer was collected, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford a quantitative yield of 9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole-7-carbaldehyde as a yellow oil. The product had an HPLC ret. time=3.02 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=499.9.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([CH:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1)=[O:12].[NH+]1C=CC=CC=1>CC1C=CC(C)=CC=1.C(OCC)(=O)C.O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]=[C:11]([CH:13]3[CH2:17][S:16][C:15](=[O:18])[NH:14]3)[O:12][C:2]=2[CH:7]=1
Reactant: COc1ccc(NC(=O)C2CSC(=O)N2)c(O)c1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccc(C)cc1
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C3CSC(=O)N3)oc2c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To 2-oxo-thiazolidine-4-carboxylic acid (2-hydroxy-4-methoxy-phenyl)-amide (50 mg) in p-xylene (3 mL) was added pyridinium p-toluenesolfonate (42 mg). The reaction mixture was refluxed for 2 h and then allowed to cool to room temperature. The mixture was diluted with ethyl acetate and water was added. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), and concentrated. Flash chromatography on silica gel eluting with 3% methanol-methylene chloride afforded 42 mg (90%) of the title compound as a solid. MS: 251 (MH+) HPLC tR: 1.60 min.
Reaction SMILES: Br[CH2:2][C:3](=[O:34])/[C:4](=[N:31]/[O:32]C)/[C:5](N[C@@H]1C(=O)N2[C@@H]1SCC(CSC1N(C)N=C(O)C(=O)N=1)=C2C(O)=O)=[O:6].[C:35]([O:39]C(=O)CC(C)=O)([CH3:38])([CH3:37])[CH3:36].N([O-])=O.[Na+]>C(O)(=O)C.O>[C:35]([O:39][C:5](=[O:6])/[C:4](=[N:31]\[OH:32])/[C:3](=[O:34])[CH3:2])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CO/N=C(/C(=O)CBr)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The (6R,7R)-7-[4-bromo-2-[(Z)-methoxyimino]-3-oxobutyramido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows: 592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. To this solution is added dropwise at 5°-10° C. during 21/2 hours a solution of 290.6 g of sodium nitrite in 655 ml of water. The resulting yellow suspension is stirred for 30 minutes at 20° C., treated with 940 ml of water and stirred for a further 2 hours. The mixture is treated with 900 ml of water and 900 g of ice and extracted in the stirring vessel three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 of water each time, then treated with 5 l of water and the pH-value is adjusted to 6.8 with sodium hydrogen carbonate. After separating the aqueous phase, the organic phase is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated in vacuo at 40° C. There is obtained (Z)-2-hydroxyimino-3-oxo-butyric acid tert-butyl ester as a yellow oil which is dried for a further 9 hours in a high vacuum at 40° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11](O)[CH:12]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][OH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH:12]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)C(c1ccc(Cl)c(Cl)c1)[C@H](O)CCO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@H](CCO[Si](C)(C)C(C)(C)C)C1c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
49.9 g (98.1 mmole) of 4-t-butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)-1-[N-(t-butoxycarbonyl)-N-(2-hydroxyethyl)amino]-2-butanol [prepared as described in step (a) above] and 30.9 g (118 mmole) of triphenylphosphine were dissolved in 600 ml of dried toluene. 51.3 g of a 40% w/v toluene solution containing 118 mmole of diethyl azodicarboxylate were added dropwise to the resulting solution at room temperature under a nitrogen atmosphere, and the mixture was stirred for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 47:3 to 23:2 by volume as the eluent, to give 43.2 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:48]=[CH:47][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=4)=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([NH:15][CH2:16][C:17](O)=[O:18])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][CH:38]=4)=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([NH:15][CH2:16][C:17]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:18])=[O:14])=[O:10])=[CH:47][CH:48]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)O)cc3)nc2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)NS(C)(=O)=O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
TEA (32.1 μl, 0.23 mmol) was added to a suspension of (S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)glycine Compound 297 (75.0 mg, 0.11 mmol), methanesulfonamide (12.1 mg, 0.13 mmol), HATU (52.6 mg, 0.14 mmol) and DMAP (1.41 mg, 0.01 mmol) in DCM (2 mL). The resultant yellow suspension was stirred at room temperature for 3 h. The reaction mixture was washed with saturated aqueous NaHCO3 (2 mL) and the mixture passed through a phase separation cartridge. The organic phase was concentrated in vacuo to afford a yellow solid. The crude product was purified by chromatography (EA/1% AcOH in hexanes) to afford 9 mg (11%) (S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide, Compound 381 as a yellow solid. LCMS-ESI (m/z) calculated for C40H49N5O6S: 727.3. found 728.0 [M+H]+, tR=10.51 min (Method 10).
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19](O)=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[C:19](=[O:20])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:24]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine