Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.Cl[CH2:10][CH:11]=O.C(N(C(C)C)CC)(C)C.O>C(O)CCC>[CH3:8][S:7][C:4]1[S:3][C:2]2=[N:1][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CSc1nnc(N)s1
Reactant: O=CCCl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1nn2ccnc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.2 %

Procedure:
2-Amino-5-methylthio-1,3,4-thiadiazole (10.00 g; 67.92 mmol; 1.00 eq.) was reluxed in 1-butanol (100.00 ml) until complete dissolution of starting material. Then, chloroacetaldehyde (21.91 ml; 169.81 mmol; 2.50 eq.) was slowly added and the reaction was refluxed for 2 h. Diisopropyethylamine (11.63 ml) was slowly added over 2 h using a syringe pump. After 18 h, the reaction was allowed to cool to room temperature. Then, water was added and the aqueous phase was extracted 4 times with EtOAc. The combined organics were washed with brine, dried over MgSO4 to give 17 g of a viscous brown oil. The crude was purified by flash chromatography (preabsorption using MeOH an silica) using 95/5 dichloromethane/methanol. The combined fractions gave 3.05 g of the desired product as a pale orange solid.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:42])[C@@H:24]([NH:25][C:26](=[O:41])[CH2:27][C:28]4[N:29]=[C:30]([NH:33]C(OC(C)(C)C)=O)[S:31][CH:32]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:43][CH:44](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:45][C:46]2[N:47]=[N:48][NH:49][CH:50]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:33][C:30]1[S:31][CH:32]=[C:28]([CH2:27][C:26]([NH:25][C@@H:24]2[C:23](=[O:42])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:43][CH2:44][S:45][C:46]4[N:47]=[N:48][NH:49][CH:50]=4)[CH2:19][S:20][C@H:21]23)=[O:41])[N:29]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 0.83 h
Yield: 59.1 %

Procedure:
To a solution of 7β-[2-(2-t-butoxycarbonylaminothiazol -4-yl)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (779 mg : 0.784 mMol.) in a mixture of anisole (3 ml) and nitromethane (12 ml) at -40° C. is added a solution of aluminum chloride (0.83 g : 6.24 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 50 minutes. The reaction mixture is mixed with 1N-hydrochloric acid (6.3 ml), diluted with water, washed with ethyl acetate, and concentrated under reduced pressure to remove the remaining organic solvents. The residual solution is subjected to the chromatography over styrene-divinylbenzene copolymer (methanol : water=4:1) and resulting powder is washed with ethyl acetate to give 7β-[2- (2-aminothiazol-4yl)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem -4-carboxylic acid (225 mg) as white powder. Yield: 59%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=C[CH:41]=[CH:40][C:39]=1C.C(N)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:38][CH2:39][CH2:40][CH3:41])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCCN
Product: CCCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (12 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, propylamine (10 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-propylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (18 mg, 33%) as a white solid: ESI-LRMS m/e calcd for C24H33ClN4O4S [M+] 508.2, found 509.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.84 (t, J=7.4 Hz, 3H, CH3), 1.07-1.22 (m, 2H, CH2), 1.36-1.96 (m, 10H, 5×CH2), 2.18-2.30 (m, 1H, CH), 2.62 (t, J=6.4 Hz, 2H, COCH2), 3.11-3.19 (m, 2H, CONCH2), 3.27 (s, 3H, SO2CH3), 3.56 (t, J=7.6 Hz, 1H, CH), 4.30 (t, J=6.4 Hz, 2H, NCH2), 5.49 (br.t., 1H, NH), 6.58 (d, J=2.3 Hz, 1H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.93 (s, 1H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:17])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])C.C1COCC1.O>CO>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]([NH:9][CH2:8][C:7]([OH:17])=[O:6])=[O:11]
Reactant: CCOC(=O)CNC(=O)c1cccs1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
LiOH.H2O (110 mg, 2.63 mmol) was added to a solution of [(thiophene-2-carbonyl)-amino]-acetic acid ethyl ester (140 mg, 0.66 mmol) in a mixture of MeOH (5 mL), THF (2.5 mL) and H2O (2.5 mL). The resulting mixture was stirred for 3 hrs at room temperature. The MeOH and THF were evaporated and the resulting residue was diluted with water (2 mL), acidified with citric acid and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford [(thiophene-2-carbonyl)-amino]-acetic acid in 70% yield. LC-MS purity: 92%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[CH2:21][O:22][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCc1cc(-c2nc(-c3cccc(CO)c3)no2)ccc1-c1ccccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCc1cc(-c2nc(-c3cccc(COCC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanol, prepared as in example 159, step 1, (500 mg, 1.29 mmol) in toluene (10 mL) were added tert-butyl bromoacetate (215 μl, 1.45 mmol) and tetrabutylammonium hydrogen sulfate (45 mg, 0.13 mmol), followed by a 33% aqueous solution of sodium hydroxide (10 mL). The biphasic mixture was stirred strongly at RT for 45 minutes. The aqueous layer was removed. The organic layer was diluted with Et2O (20 mL) and washed with water (10 mL), then brine (10 mL). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure to give a yellow oil. This oil was purified by flash chromatography on silica (cHex/EtOAc) to give the title compound as a colorless oil. LC/MS (Method A): 501.4 (M+H)+. HPLC (Method A) Rt: 6.52 min (purity: 99.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:30])[C:10](=[C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([CH2:28][OH:29])=[CH:27][C:21]=3[NH:20]2)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.C[N+]1([O-])CCOCC1>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[C:9]([C:10](=[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([CH:28]=[O:29])=[CH:27][C:21]=2[NH:20]1)[C:11](=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:30]
Reactant: O=C(C(C(=O)c1cc(F)cc(F)c1)=C1Nc2ccc(CO)cc2N1)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)NC(=C(C(=O)c1ccccc1)C(=O)c1cc(F)cc(F)c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
Into a dichloromethane solution (5 ml) of the compound (174 mg) obtained in Example 405 were added NMO (100 mg) and MS4A, followed by 10 minutes of stirring at room temperature. TPAP (8 mg) was further added thereto, followed by 30 minutes of stirring at room temperature. The reaction solution was purified by silica gel column chromatography (eluent: chloroform:methanol=40:1 (v/v)) to obtain 2-[1-(3,5-difluorobenzoyl)-2-oxo-2-phenylethylidene]-2,3-dihydro-1H-benzimidazol-5-carbaldehyde (76 mg, 44%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:11]=3[O:10][C:9](=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:19]>>[C:1]1([C:7]2[C:16]3[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][C:11]=3[NH:19][C:9](=[O:10])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2oc(=O)cc(-c3ccccc3)c21
Reactant: N
Product: O=C1CCCc2[nH]c(=O)cc(-c3ccccc3)c21

Procedure:
Prepared from 4-phenyl-5,6,7,8-tetrahydro-cumarin- 5-one (melting point: 167°-168° C., prepared from ethyl benzoylacetate and cyclohexan-1,3-dione) and methanolic ammonia in an autoclave over a period of one hour at 135° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([OH:32])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C(O)C.[OH-].[Na+:38]>CC(C)=O>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([O-:32])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[Na+:38]
Reactant: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1[O-]

Procedure:
5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-N-[2-(methylsulfonyl)benzyl]-1,6-naphthyridine-7-carboxamide (53 mg, 0.108 mmol) was suspended in a 1:1 mixture of ethanol and acetone (1 mL each). NaOH (130 uL, 1 M) was added and the starting material dissolved. After 1 hour the sodium salt precipitated. The sample was concentrated in vacuo to afford the desired material as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:34](=[N:36]O)[NH2:35]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:34]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:35]=1
Reactant: NC(=NO)c1ccc(F)cc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4F)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 47 mg (47% of theory)
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=[O:16])[C:10]1C=C[CH:13]=[CH:12][CH:11]=1.C(O)(=O)C1C=CC=CC=1.C(O)CCC#C>C(N(CC)CC)C.Cl[Pd]Cl.[Cu]I.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:16])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(C#CCCCO)cc1
Temperature: 50 °C
Yield: 130.1 %

Procedure:
A mixture of 4-bromoaniline (1.72 g, 10 mmol), benzaldehyde (0.27 g, 2.5 mmol), benzoic acid (0.05 g, 0.4 mmol), PdCl2 (2 mg) and triethylamine (3.5 g) was deaerated by bubbling nitrogen and then heated to reflux for 45 min. Thin-layer chromatography showed the formation of N-benzylidene 4-aminophenylbromide). The reaction mixture was cooled to 50° C. and treated with triphenylphosphine (73 mg in 1 g of triethylamine) followed by a slurry of CuI (20 mg) and 4-pentyn-1-ol (1.1 g, 13 mmol). This reaction mixture was heated at reflux for 10 hr. The mixture was cooled and diluted with triethylamine (5 mL) and treated with water (6 mL). The aqueous layer was separated and the triethylamine layer was concentrated under vacuum. Toluene was added and the mixture again concentrated. Then aqueous HCl (10 mL, 7%) was added. The resulting aqueous solution was cooled, basified with 50% NaOH, and extracted with ethyl acetate. The ethyl acetate extract was evaporated under vacuum and the residue was flash chromatographed (20% ethyl acetate-dichloromethane, silica) to yield 0.57 g of 5-(4-aminophenyl)-4-pentyn-1-ol as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH3:15][Si:16]([CH3:33])([CH3:32])/[CH:17]=[CH:18]/[Sn](CCCC)(CCCC)CCCC>ClC(Cl)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:18]=[CH:17]/[Si:16]([CH3:33])([CH3:32])[CH3:15]
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/[Si](C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (0.5 g, 1.513 mmol), (E)-trimethyl(2-(tributylstannyl)vinyl)silane (0.589 g, 1.513 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.106 g, 0.151 mmol) were combined in dichloroethane (3 mL) and stirred at 70° C. overnight. The reaction mixture was concentrated onto celite then purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (285 mg, 0.941 mmol, 62.2% yield) as an orange solid: mp 103-105° C.; 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=19.8 Hz, 1H), 6.21 (d, J=19.9 Hz, 1H), 4.72 (s, 2H), 3.89 (s, 3H), 0.19 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −139.10; ESIMS m/z 301 [(M−H)−].
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a cooled (0° C.), stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 ml) was added DIAD (11.4 ml, 0.06 mol), and the reaction mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (30 ml) and TFA (30 ml). The solution was stirred at room temperature for 30 min. and the solution was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaRCO3, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to CHCl3—MeOH (9:1, v/v) as eluent to give benzyl (S)-4-(2-amino-1-propoxy)benzoate (6.63 g, 2 steps, 60%) as a yellow oil. 1H-NMR (CDCl3) δ1.18 (d, J=6.3 Hz, 3 H), 3,35-3.39 (m, 1 H), 3.71-3.75 (m, 1 H), 3.90-3.93 (m, 1 H), 5.34 (s, 2 H), 6.90-6.93 (m, 2H), 7.32-7.46 (M, 5H), 8.01-8.04 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([OH:13])[CH2:7][NH:8]C(C)(C)C)=[CH:4][C:3]=1[Cl:17].Cl.[CH3:19]O>>[ClH:16].[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([O:13][CH3:19])[CH2:7][NH2:8])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CO
Agent: Cl
Product: COC(CN)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C

Procedure:
In 100 ml of methanol, 10 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is stirred in an ice bath and dry HCl gas is introduced into the solution. After saturation of the solution, the mixture is stirred at room temperature for an hour and evaporated to dryness. The solid is then stirred in ethyl acetate to afford the title product, which is collected by filtration.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4C(NCC(O)=O)=O)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1COCC1.C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][NH:22]4)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C(=O)NCC(=O)O)no2)cc1OCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1OCC
Yield: 43 %

Procedure:
To a solution of the product of Step B (0.06 g; 0.172 mmol) in 1M BH3 in THF (0.35 ml; 0.35 mmol) TFA (0.4 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min), the reaction was quenched with H2O (0.5 ml) and solvents were removed under reduced pressure. The residue was diluted to 10 ml with EtOAc and was washed with 10% NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.026 g; 43%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 7.78 (dd, 1H, J=1.9, 7.2 Hz); 7.68 (d, 1H, J=1.9 Hz); 7.52 (d, 1H, J=7.2 Hz); 7.17 (t, 1H, J=7.7); 6.97 (d, 1H, J=8.5 Hz); 6.75 (d, 1H, J=7.7 Hz); 4.19 (m, 4H); 3.65 (t, 2H, J=8.9 Hz); 3.45 (tr, 2H, J=8.9 Hz); 1.7 (broad s, 1H+H2O); 1.49 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:47])([F:46])[CH2:26][C@@H:27]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[CH3:48][CH:49](O)[CH3:50].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:47])([F:46])[CH2:26][C@@H:27]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:28]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH:49]([CH3:50])[CH3:48])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a solution of the material from Step 9 (150 mg, 0.222 mmol), 2-propanol (0.034 mL, 0.443 mmol) and Ph3P (116 mg, 0.443 mmol) in THF (1 mL) at 0° C. was slowly added diisopropyl azodicarboxylate (0.086 mL, 0.443 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed about 50% conversion, more 2-propanol (0.034 mL, 0.443 mmol), Ph3P (116 mg, 0.443 mmol) and diisopropyl azodicarboxylate (0.086 mL, 0.443 mmol) were added, stirred for 8 hours, LCMS showed no progress. It was concentrated to dryness and the residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) to afford 81 mg of the title compound as a colorless foam. LCMS (M+1)=719.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
5-Chloropyridine-2-carboxylic acid (2.00 g, 12.7 mmol) was dissolved in THF (12 mL) at 0° C. and added to a solution of borane-THF (19.0 mL, 1 M in THF, 19.0 mmol). THF (10 mL) was added and the reaction mixture was warmed to room temperature, stirred for 2 h and heated under reflux at 70° C. for 3 h. The reaction mixture was cooled to 0° C., quenched with aq 6 M HCl solution (4 mL) and the solution was stirred for 2 h and concentrated in vacuo. The residue was partitioned between H2O (75 mL) and DCM (75 mL). The aq layer was washed with DCM (3×75 mL), adjusted to pH 9 with 4 M aq NaOH (3 mL) and extracted with DCM (3×75 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give 5-chloropyridine-2-methanol (0.83 g, 45%) as a brown gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[N:8]1([NH:7][C:6](=[O:21])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NN1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NN1CCNCC1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Tert-butyl(4-benzylpiperazin-1-yl)carbamate (42.22 g, 145 mmol) prepared in Reference Example 35 was dissolved in ethanol (300 ml). To which 20% palladium hydroxide/carbon (6.0 g) was added, and the mixture was stirred at room temperature under an atmospheric pressure of hydrogen for 20 minutes, and then at 50° C. for 30 minutes. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Thus obtained solid was washed with IPE, collected by filtration, and dried under reduced pressure to afford tert-butyl piperazin-1-yl-carbamate (28.9 g, yield 99%) as a colorless crystalline powder.