Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:13]3[NH:14][CH:15]=[N:16][CH:17]=3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(Cc2cnc[nH]2)c2c(c1)OCCO2
Yield: 72.3 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanol (Intermediate A3) (1 g, 2.11 mmol) in dichloromethane (30 mL) was reacted with TFA: trifluoroacetic acid (5.3 mL, 68 mmol)) and triethylsilane (TES) (2.8 mL, 17 mmol) at rt for 24 h. The mixture was evaporated under reduced pressure and quenched with solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 5% NH3-MeOH:CH2Cl2 to yield 5-(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-1H-imidazole (Intermediate A4) 330 mg (72%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[CH:5][C:4]=1[F:17])#[N:2].[Br-].[CH2:19]([Zn+])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:19]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:17])[CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2ccccc2)cc1F
Temperature: 65 °C
Yield: 65 %

Procedure:
To a room temperature solution of 1.5 g (5.57 mmol) of the triflate from Step A above, 0.32 g (0.56 mmol) of bis(dibenzylideneacetone)palladium and 1,1′-bis(diphenylphosphino)-ferrocene in 15 mL of tetrahydrofuran is added to 12.25 mL (6.13 mmol) of a 0.5 M solution of benzylzinc bromide in tetrahydrofuran via syringe. The mixture is heated to 65° C. for 16 hr and cooled to room temperature. The mixture is poured into saturated ammonium chloride and extracted two times with ethyl acetate. The combined organic portions are dried (MgSO4), filtered, and concentrated in vacuo. Chromatography (Biotage, 100% toluene) of the residue affords 0.76 g (65%) of the title compound.
Reaction SMILES: C(NS(C1C=CC=CC=1C1C=CC(C[N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([Cl:31])[N:24]=[C:23]2[CH2:32][CH2:33][CH2:34][CH3:35])=CC=1)(=O)=O)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:32]([C:23]1[NH:22][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([Cl:31])[N:24]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nc(Cl)c(C(=O)OC)[nH]1
Yield: 214.9 %

Procedure:
1-((2'-((tert-butylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid, methyl ester (75.0 mg, 0.145 mmol) was stirred in trifluoroacetic acid (1.0 ml) containing anisole (20 μl) under nitrogen at room temperature for 24 hours. The trifluoroacetic acid was removed in vacuo and the residue chromatographed (silica gel, 35% ethyl acetate-hexane) to afford 1-((2'-aminosulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid, methyl ester (67.5 mg, 100%) as a white solid; 1H NMR (300 MHz, CD3OD/CDCl3) δ8.08 (d, J=7.7 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.26 (d, J=7.7 Hz, 1H), 7.04 (d, J=8.1 Hz, 2H), 5.57 (s, 2H), 3.80 (s, 3H), 2.64 (t, J=7.4 Hz, 2H), 1.62 (quin, J=7.4 Hz, 2H), 1.31 (sext, J=7.4 Hz, 2H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(OCC)(=O)C.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)cc2)CC1
Reactant: Brc1ncccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cc2)CC1
Temperature: 100 °C

Procedure:
4-(4-Bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (19.5 g, 0.058 mol), bis(pinacolate)diboron (22.0 g, 0.086 mol), PdCl2(dppf).CH2Cl2 (4.74 g, 0.0058 mol), potassium acetate (17.0 g, 0.17 mol) were weighted into a 1 L 2-necked round bottomed flask equipped with a reflux condenser. Methyl sulfoxide (400 ml) was added and the mixture was purged with nitrogen for 20 min before it was heated at 100° C. for 2 hr under nitrogen. The mixture was cooled to r.t. Potassium carbonate (40 g, 0.29 mol), 2-bromopyrimidine (11.0 g, 0.070 mol) and water (200 ml) were added. The mixture was again purged with nitrogen for 20 min. Palladium tetrakistriphenylphosphine (2.4 g, 0.0029 mol) was added and the final mixture was stirred at 100° C. for a further 2 hr. After being cooled to r.t., ethyl acetate and water were added. The mixture was filtered through a pad of Celite. Layers were separated and the organic layer was washed with water (×2). The combined aqueous layers were extracted with ethyl acetate (×1). The combined organic layers were stirred with enough charcoal to give a yellow solution. The mixture was filtered through a pad of Celite and the solvents in the filtrate were removed in vacuum to give 4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as dark brown oil.
Reaction SMILES: CC(C)=[O:3].C(C(C)=O)C.[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([Br:18])[C:12]=1[O-:19].[Na+:20]>O>[OH-:3].[Na+:20].[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([Br:18])[C:12]=1[O-:19].[Na+:20]
Reactant: CC(C)=O
Agent: [Na+]
Agent: [O-]c1c(Br)cc(Br)cc1Br
Solvent: CCC(C)=O
Solvent: O
Product: [OH-]

Procedure:
It has been found that a liquid ketone such as acetone or methyl ethyl ketone when present in this reaction mixture tends to ensure that the desired tris(2,4,6-tribromophenoxy)-s-1,3,5-triazine product is formed in high purity. In experiments wherein a refluxing mixture of water and an alkanol (methanol), was used as the reaction medium for step d), it was found that some of the chloro groups in the cyanuric chloride reacted with the methanol to form bis-(tribromophenoxy)-methoxy-s-1,3,5-triazine as an impurity. On the other hand, when acetone or methyl ethyl ketone was used as the organic solvent in step d), the chloro groups were found to react exclusively with the sodium 2,4,6-tribromophenolate despite of the presence of a large amount of water in the reaction mixture which was carried over from the prior bromination step and the prior use of aqueous NaOH to form the sodium 2,4,6-tribromophenolate.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:13]=[N:14][N:15]=2)[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][N:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17]1>C(O)C>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[N:4]2[CH:13]=[N:14][N:15]=[C:3]2[C:2]([N:16]2[CH2:19][CH:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:17]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(-c2cccs2)n2cnnc12
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(c2ncc(-c3cccs3)n3cnnc23)C1
Yield: 31.7 %

Procedure:
A 50 mL round bottom flask was charged with 8-chloro-5-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (0.25 g, 1.1 mmol), tert-butyl azetidin-3-ylcarbamate (540 mg, 3.1 mmol) and ethanol (5 mL). The resulting solution was refluxed overnight. Work-up: the solvent was evaporated. The residue was purified by flash column chromatography on silica gel with a 1:2 EtOAc/petroleum ether and then a 1:50 methanol/dichloromethane, to afford 130 mg (33%) of the product as a white solid. MS m/z: 373 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCN1CCN(c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.2 %

Procedure:
A mixture of 1-[3-(methyloxy)-4-nitrophenyl]-4-propylpiperazine (0.204 g, 0.73 mmol) and nickel(II) chloride hexahydrate (0.087 g, 0.37 mmol) was stirred in 2:1 MeOH/THF (7 mL) under N2 at rt. To this mixture was added NaBH4 (0.097 g, 2.6 mmol) in 2 equal portions over 5 min. The reaction was stirred at rt for about 45 min, then concentrated under vacuum. The residue was dissolved in DCM and poured through Celite, washing with DCM and EtOAc. The filtrate was concentrated and chromatographed on silica gel to give the title compound of step B (170 mg, 0.68 mmol, 93%) as a grey oil. 1H NMR (400 MHz, DMSO-d6): δ 6.50 (d, 1H, J=8.25), 6.47 (d, 1H, J=2.38 Hz), 6.26 (dd, 1H, J=2.47 and 8.34 Hz), 4.19 (br s, 2H), 3.72 (s, 3H), 2.90-2.94 (m, 4H), 2.43-2.47 (m, 4H), 2.25 (t, 2H, J=7.42 Hz), 1.44 (q, 2H, J=7.39 Hz), 0.86 (t, 3H, J=7.33 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>CC(N(C)C)=O.CCOC(C)=O.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]>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc([N+](=O)[O-])c(N)c1C#N
Temperature: 68 °C
Reaction time: 16 h

Procedure:
2-Amino-6-chloro-3-nitro-benzonitrile (see Goldberg et al., J. Med. Chem., 2003, 1344; 800 mg, 4.05 mmol), 2-methoxyphenylboronic acid (800 mg, 5.26 mmol), and potassium phosphate (2.23 g, 10.5 mmol) were combined in DMA (10 mL) in a flask purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (185 mg, 0.2 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethyl-amino)biphenyl (159 mg, 0.4 mmol) were added, and the reaction stirred at 68° C. under nitrogen for 16 h. The solution was diluted with EtOAc (50 mL), and washed with 1N HCl and brine. Organics were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].Cl[C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[S:27][CH2:28][C:29]([OH:31])=[O:30].Cl>C(O)C.O>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[S:27][CH2:28][C:29]([OH:31])=[O:30])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
2.6-bis(1,1-Dimethylethyl)-4-mercaptophenol (0.73 g, 0.0031 mole) was added to freshly prepared sodium ethoxide [sodium (0.16 g, 0.007 mole)] in ethanol (10 ml). Once dissolved, the product of Example 4 (0.50 g, 0.0026 mole) was added and the reaction mixture was stirred for 90 minutes and poured into water (50 ml) containing 1N hydrochloric acid (25 ml). The mixture was extracted three times with 20 ml of diethyl ether, and the combined extracts were washed with water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR and elemental analysis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[CH2:17]([N:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30]([OH:35])[CH:31]=2)[N:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30]([O:35][CH:14]3[CH2:15][CH2:16][C:11]4([O:10][CH2:9][CH2:8][O:7]4)[CH2:12][CH2:13]3)[CH:31]=2)[N:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCC2(CC1)OCCO2
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
At 50° C. 16.0 g potassium carbonate and 20.0 g of 8-methanesulphonyloxy-(1,4-dioxa-spiro[4,5]decan are added to 20.0 g 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150 ml N,N-dimethylformamide and the mixture is vigorously stirred for 18 hours at 80° C. To complete the reaction potassium carbonate and 8-methanesulphonyloxy-(1,4-dioxa-spiro[4,5]decane are each added three times more and in each case the mixture is stirred for several hours at 80° C. The reaction mixture is cooled and slowly combined with a total of 500 ml of water. The precipitate is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=O)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Yield: 10 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4-(methanesulfonyl)-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=50:30:20 to 20:60:20, 36 mg, 10%) which was obtained as a white solid. MS: m/e=382.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[C:9]([O:12][C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[CH:10]=2)[O:5][C:3](=[O:4])[CH:2]=1.O.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:26]([O:24][C:8]1[C:9]([OH:12])=[CH:10][C:11]2[CH:1]=[CH:2][C:3](=[O:4])[O:5][C:6]=2[CH:7]=1)[CH3:27]
Reactant: O=c1ccc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)cc2o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc2oc(=O)ccc2cc1O
Reaction time: 5 h

Procedure:
110 g (300 mmol) esculine×1.5 H2O, 70 g (450 mmol) ethyl iodide and 82.8 g (600 mmol) of potassium carbonate are agitated in 400 ml DMF for 30 h at 85° C. This was followed by filtration, reduction of the filtrate to approximately 250 ml, the addition of approximately 200 ml ethanol and crystallization at 0° C. The crystals were boiled in 800 ml of 2N sulfuric acid for 5 h under reflux. The product was vacuum filtered, washed with water and recrystallized from water and ethanol: yield 43.2 g (70%), fusion point 145° to 146° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@@H:23]([O:26][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@@H](O)CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](CSC[C@H](COS(C)(=O)=O)OS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((S)-2,3-dihydroxypropylthio)propanoate (1 eq) was stirred in dry DCM (0.1M) in an ice bath (0° C.) under an atmosphere of N2. Pyridine (8.0 eq) was then carefully added at 0° C. Methanesulfonyl chloride (4.0 eq) and DMAP (0.1 eq) were added with the reaction slowly warming to room temperature, then stirred overnight. The crude reaction mixture was then loaded directly onto a silica column and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 100% Hex, 0-20% EtOAc/Hex, 20-50% EtOAc/Hex, 100% EtOAc to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7].[C:21](OC(=N)C(Cl)(Cl)Cl)([CH3:24])([CH3:23])[CH3:22].B(F)(F)F.CCOCC.C(Cl)Cl>O1CCCC1>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:4]([CH2:5][C:6]([O:8][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:7])[C:3]([O:2][CH3:1])=[O:20])[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)C(CC(=O)O)Cc1cc(C)c2[nH]ncc2c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1cc(C)c2[nH]ncc2c1
Reaction time: 3.5 h

Procedure:
To a solution of 4-methoxy-3-((7-methyl-1H-indazol-5-yl)methyl)-4-oxobutanoic acid (0.9764 g, 3.54 mmol) and t-butyl-2,2,2-trichloroacetoimidate (3.78 mL, 21.22 mmol) in tetrahydrofuran (25 mL) was added 1M boron trifluoride etherate (0.2 mL) at room temperature. Heat generation was observed and the reaction was stirred for 3.5 h before passing it through a pad of silica gel. Evaporation of the filtrate gave a white solid. Methylene chloride (20 mL) was added and the resulting white solid was removed by filtration. The filtrate was concentrated and the final product was obtained via silica gel chromatography eluting with 0% to 50% ethyl acetate/hexane. (0.605 g, 52%) HPLC tR=1.51 min, MS(ESI)[M+H]+=332.77.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:19])[CH3:18].[F-].[Cs+]>O1CCOCC1.CN(C=O)C.CCOC(C)=O.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]>[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]=[N:6][C:5]([O:8][C@@H:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)=[CH:4][CH:3]=2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The product of Example 33A (240 mg, 1 mmol) was coupled with the product of Example 34B (0.72, 2 mmol) under the catalysis of Pd2(dba)3 (24 mg, 0.025 mmol) and (tBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) in dioxane (8 mL) and DMF (Aldrich, 1 mL) at 80° C. under N2 for 16 hours. After the reaction went to completion, it was cooled down to room temperature and diluted with EtOAc (50 mL), washed with brine (2×10 mL). The organic solution was and concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.3) as yellow solid (350 mg, 79%). 1H NMR (300 MHz, MeOH-D4) δ 1.40 (s, 9 H), 1.51-1.70 (m, 1 H), 1.70-1.98 (m, 2 H), 2.00-2.23 (m, 1 H), 2.37-2.51 (m, 1 H), 2.71-3.18 (m, 5 H), 3.47-3.69 (m, 1 H), 5.33-5.49 (m, 1 H), 7.30 (d, J=9.2 Hz, 1 H), 7.54 (d, J=8.5 Hz, 1 H), 7.62 (s, 1 H), 8.14 (d, J=9.5 Hz, 1 H), 8.37 (dd, J=8.1, 2.0 Hz, 1 H), 8.80 (d, J=2.0 Hz, 1 H) ppm. MS (DCl/NH3): 442 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH:15]([NH2:18])([CH3:17])[CH3:16].C(O)(=O)C>CO>[CH:15]([NH:18][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NCc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-propylamine (2.03 g, 34.4 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at 0° C. with stirring. Warm the mixture to room temperature and stir overnight. Add water (100 mL), saturated aqueous K2CO3 (50 mL), and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (300 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (1.53 g, 38%). MS (APCI+) m/z: 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:9]=O)[CH:7]=1.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:26][CH2:9][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)CN
Reactant: O=CC(c1ccccc1Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)CNCC(c1ccccc1Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of α-(5-chloro-2-nitrophenyl)-2-chlorophenylacetaldehyde (1.68 g) in methanol(15 ml) were added glycine methyl ester hydrochloride (0.69 g) and sodium acetate (0.45 g). The mixture was stirred for 30 minutes at room temperature, to which was added sodium cyanoborohydride (0.35 g). To this mixture was added hydrogen chloride for 5 minutes. This mixture solution was stirred for 3 hours at 50° C., to which was added a 1N aqueous solution of sodium hydroxide (50 ml), followed by extraction with dichloromethane. The extract solution was washed with water, then the solvent was distilled off. The residual oily product was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=3:1 v/v as an eluent) to give 1.1 g of an oily compound.