Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.C(N=CC1CCCCC1)CCC.C[O:25][C:26](=[O:35])[C@H:27]([CH2:33]O)[N:28](Cl)[C:29](=O)[CH3:30]>C(COC)OC>[CH2:29]1[C:30]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:33][CH:27]([C:26]([OH:25])=[O:35])[NH:28]1
Reactant: COC(=O)[C@H](CO)N(Cl)C(C)=O
Reactant: CCCCCC
Agent: CCCCN=CC1CCCCC1
Agent: [Li]CCCC
Solvent: COCCOC
Product: O=C(O)C1CC2(CCCCC2)CN1
Reaction time: 1 h

Procedure:
6.4 g of butyllithium (in the form of a hexane solution) were added to 16.7 g of butyliminomethylcyclohexane in 300 ml of anhydrous dimethoxyethane at -76° C. under protective gas (argon). 15 min. after completion of addition, 18 g of N-acetylchloroserine methyl ester in 100 ml of DME were added dropwise, with efficient cooling. The mixture was stirred for a further 1 hour at a low temperature, allowed to warm up and evaporated to a small volume in vacuo. The crude mixture was acidified with 200 ml of 2N HCl and heated to reflux for 45 min. The mixture was evaporated in vacuo, the residue was taken up in glacial acetic acid, 1 g of Pt/C (10% Pt) was added and hydrogenation was carried out under normal pressure. The mixture was filtered, evaporated and chromatographed over a silica gel column with the system chloroform/methanol/glacial acetic acid/water 25:15:2:2. The amino acid crystallized from the appropriate eluate after evaporation.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:16]C(C1C=CC=CC=1)C)([CH3:15])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1>C(O)(=O)C.CCO.[OH-].[OH-].[Pd+2]>[CH3:15][C:3]([NH2:16])([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH2:1]
Reactant: CC(NC(C)(CN)CC1CCc2ccccc2C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)(CN)CC1CCc2ccccc2C1
Reaction time: 20 h

Procedure:
A suspension of 0.50 g (1.55 mmol) of the compound obtained in Step 3 and 0.14 g of Pd(OH)2 in a mixture of 0.8 ml of acetic acid and 50 ml of EtOH is hydrogenated at 20° C. under 1 bar for 20 hours. After filtration of the mixture and concentration in vacuo, the residue is taken up in 1N aq. NaOH (10 ml) and extracted with CH2Cl2 (3×10 ml); the combined organic phases are washed with saturated aq. NaCl, dried and concentrated to yield the title compound in the form of an oil, which is used in the following reaction without being otherwise purified.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[C:33]1(C)[C:34]([CH:39]=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH:34]1([CH:39]([OH:40])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Reactant: Cc1ccccc1C=O
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Yield: 85.4 %

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from o-tolualdehyde (5.78 g), 4-dimethylamino-1-(2-methylphenyl)-2-phenyl-2-buten-1-ol (Z) hydrochloride (10.2 g) is obtained in the form of a white powder melting at 204° C. after recrystallisation from ethanol (100 cc).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: OC1CCNCC1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCC(O)CC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 2.5 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 100 ml. of methylene chloride is treated with 10 g. of 4-hydroxy-piperidine and stirred at room temperature under an argon atmosphere for 70 hours. The separated precipitate is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl racemic-6-(4-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 265°-266° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16].C(N1CCOCC1)C.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH:16][C:8]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=C(O)c1ncccc1O
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1ncccc1O
Reaction time: 12 h
Yield: 69.7 %

Procedure:
3-Hydroxypyridine-2-carboxylic acid (6.96 g, 50 mmol), 6.28 g of glycine methyl ester hydrochloride, 6.4 ml of N-ethylmorpholine and 13.53 g of 1-hydroxy-1H-benzotriazole were suspended in 300 ml of anhydrous dichloromethane and a solution of 10.83 g of DCC (=N,N'-dicyclohexylcarbodiimide) in 50 ml of dichloromethane was added to this suspension at 0° C. After 12 hours, the mixture was filtered and the filtrate was washed with water and with a saturated aqueous solution of NaHCO3. Drying and concentrating yielded 7.33 g (70%) of N-(3-Hydroxypyridine-2-carbonyl)glycine methyl ester, m.p. 59°-61° C. (ethyl acetate/heptane), cf. example 1c) as well.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11](OCC)=[O:12])[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=O)C.[Li+].[BH4-]>C1COCC1>[C:19]([O:18][C:16]([N:8]1[CH2:7][C@@H:6]([CH2:4][OH:3])[C@H:10]([CH2:11][OH:12])[CH2:9]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a ice-cooled solution of (3S*,4S*)-pyrrolidine-1,3,4-tricarboxylic acid 1-tert-butyl ester 3,4-diethyl ester (36 g, 114.15 mmol) in THF (1 L), is added dropwise a solution of LiBH4 (228.3 mmol) in THF (250 mL). The reaction mixture is stirred overnight at room temperature and quenched with an aqueous solution of NaOH 2N (400 mL). Ether is added, the layers are separated and the aqueous one back extracted twice with ether. The combined organic extracts are dried over Na2SO4, filtered and concentrated to give the title compound which is used without further purification in the next step. TLC, Rf (CH2Cl2/MeOH 95:5)=0.14. MS (LC-MS): 232.2 [M+H]+; tR (HPLC, C18 column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.37 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:29][C@H:30]([CH3:52])[CH2:31][O:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=2)(=[O:19])=[O:20])[CH:14]=[C:13]([O:29][C@H:30]([CH3:52])[CH2:31][OH:32])[N:12]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(=O)n(C)c2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COc1ccccc1
Solvent: CO
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(=O)n(C)c2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-4-pyrimidinyl]-1,6-dihydro-1-methyl-6-oxo-3-pyridinesulfonamide (the product from step (0.16 g) in MeOH (10 mL) was added p-toluenesulfonic acid (50 mg) and anisole (0.22 g). The reaction was then stirred at room temperature for 18 h. The reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was then further extracted with EtOAc (2×100 mL). Combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC using TFA (0.2%)/MeCN to give a white solid. Yield: 9 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH:25]=2)O1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Product: Fc1ccc(-c2ccc3scnc3c2)nc1

Procedure:
Compound 5-(5-fluoropyridin-2-yl)benzo[d]thiazole (W208) was prepared using the general procedure for Suzuki coupling reaction between 2-bromo-5-fluoropyridine (39 mg, 0.22 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (53 mg, 0.2 mmol), as a white solid (20 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1 H), 8.65 (d, J=1.6 Hz, 1 H), 8.59 (d, J=2.8 Hz, 1 H), 8.14 (dd, J=8.4, 2.0 Hz, 1 H), 8.06 (d, J=8.4 Hz, 1 H), 7.85 (dd, J=8.8, 4.0 Hz, 1 H), 7.52 (td, J=8.4, 2.8 Hz, 1 H); MS (ESI) m/z 231 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[N:18]([CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:20][N:21]=3)[CH2:12]2)=[O:9])=[N:6][CH:7]=1.[C:25]1(B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28][CH2:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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]>[C:25]1([C:2]2[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]3[CH2:15][CH2:14][N:13]([C:16]4[C:17]5[N:18]([CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:20][N:21]=4)[CH2:12]3)=[O:9])=[N:6][CH:7]=2)[CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(C2=CCCC2)cn1
Temperature: 120 °C
Yield: 70.4 %

Procedure:
To a solution of (S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.10 g, 0.27 mmol, 1 eq) in 1.8 mL of DMF was added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g, 0.77 mmol, 2.8 eq), followed by K2CO3 (0.18 g, 1.3 mmol, 4.8 eq) in 0.2 mL of H2O and Pd(dppf)Cl2 (0.02 g, 0.03 mmol, 0.09 eq). After heating for 1 h at 120° C. the mixture was concentrated and purified by silica gel flash chromatography (EtoAc:MeOH 1:1) followed by HPLC to afford (S)-5-(cyclopent-1-en-1-yl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.070 g, 0.19 mmol, 69%).
Reaction SMILES: CN(C)N.ClC1C=CC([NH:12][C:13]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH3:20])=[O:14])=CC=1C=O.C(O)(=O)C>CO>[CH3:20][C:16]1[O:17][CH:18]=[CH:19][C:15]=1[C:13]([NH2:12])=[O:14]
Reactant: Cc1occc1C(=O)Nc1ccc(Cl)c(C=O)c1
Agent: CN(C)N
Solvent: CC(=O)O
Solvent: CO
Product: Cc1occc1C(N)=O

Procedure:
To the solution of 1,1-dimethylhydrazine (0.6 mL) in methanol (15 mL) was added, in portions, a suspension of N-(4-chloro-3-formylphenyl)-2-methyl-3-furancarboxamide (2 g) in methanol (30 mL) at such a rate that the temperature of the solution was maintained at -5° C. to 0° C. The resultant mixture was stirred overnight at ambient temperature. Acetic acid (0.1 mL) was then added to the reaction mixture which was then refluxed for 30 minutes, solvent was evaporated and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) filtered and evaporated to produce N-[4-chloro-3-[dimethylhydrazono)methyl]phenyl]-2-methyl 3-furancarboxamide as a white solid, m.p. 109-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:25]N1C(=O)CCC1=O>ClC(Cl)C>[Br:25][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:21]([F:22])([F:24])[F:23])[O:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)cc2)=NO1
Yield: 39 %

Procedure:
A solution of 5-(3,5-dichlorophenyl)-3-(4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (5.3 g), N-bromosuccinimide (3.7 g) and 2,2′-azobisisobutylonitrile (0.1 g) in dichloroethane (40 mL) was heated to reflux for 3 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with t-butylmethylether, and the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to obtain 3-[4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (2.5 g).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:17][CH2:16]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.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]>[CH:15]1([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:25]5[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=5)[CH:19]=[CH:18][C:5]=4[N:6]=3)[CH2:10][CH2:11]2)[CH2:17][CH2:16]1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc3nc(N4CCN(C5CC5)CC4)sc3c2)cc1OC
Temperature: 60 °C

Procedure:
To a solution of 6-bromo-2-(4-cyclopropylpiperazin-1-yl)benzothiazole (500 mg, 1.48 mmol) and 3,4-dimethoxyphenylboronic acid (323 mg, 1.78 mmol) in THF—H2O (20 mL, 5:1) was added Pd2(dba)3 (240 mg, 0.148 mmol), followed by P(t-Bu)3BF4 (86 mg, 0.296 mmol) and K3PO4.H2O (1.97 g, 7.4 mmol). The mixture was heated at 60° C. for 3 h. The mixture was filtered and the filtrate was evaporated. the residue was diluted with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give the crude product, which was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH (1:50). This afforded 258 mg (49%) of 2-(4-cyclopropyl-piperazin-1-yl)-6-(3,4-dimethoxybenzo)benzothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[CH:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2ncc(-c3ccccc3)c2n1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2ncc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-3-phenyl-pyrazolo-[1,5-a]pyrimidine (47.7 mg, 0.181 mM), then morpholine (31.6 μL, 0.362 mM) was added to the solution and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off, and the resulting solid was washed with methanol to thus obtain the title compound (46.8 mg, yield: 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](O)=[O:6].Cl.[CH3:15][NH:16][CH3:17].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([N:16]([CH3:17])[CH3:15])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 2,6-dimethoxybenzoic acid (102 mg, 0.56 mmol), dimethylamine hydrochloride (91 mg, 1.12 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (234 mg, 0.73 mmol) and diisopropylethylamine (390 μL, 2.24 mmol) in DMF (1 mL) was stirred at ambient temperature overnight. The reaction mixture was taken up in ethyl acetate (50 mL) and aqueous. NaHCO3(50 mL). The organic phase was washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with ethyl acetate to provide titled compound (66 mg). MS (APCI(+)) m/e 210 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:30]=O)=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9].Cl.[NH2:33]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:30]#[N:33])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9]
Reactant: CCOCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOCCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A mixture of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.00 g), hydroxylamine hydrochloride (0.5547 g), sodium acetate (1.1382 g) in acetic acid (10 ml) was stirred for 30 minutes at room temperature. To this mixture was added acetic anhydride (1.4 ml) and the resultant mixture was stirred for an hour at room temperature and refluxed for an hour. The acetic acid was distilled off under reduced pressure, and to the residue was added water. The resultant mixture was neutrallized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The extract was washed with water and an aqueous solution saturated with sodium chloride and dried. The solvent was distilled off and thus obtained viscous oily substance (3.19 g) was subjected to column chromatography on silica gel with an eluent [a mixture of 5 parts of benzene and one part of ethyl acetate by volume] and a yellow oil (1.74 g) was obtained from the fraction which contained the designated product. The oil turned into crystals (1.56 g). These crystals were recrystallized from benzene to give yellow powder (1.5 g) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.1/3benzene, m.p. 89° to 91° C. Thus obtained yellow powder was further recrystallized from a mixture of diethyl ether and n-hexane to give crystals of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate, m.p. 115° to 116° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]([CH3:21])([N:6]([CH3:20])[S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:9])=[O:8])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH3:21][C:4]([N:6]([CH3:20])[S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])=[O:9])([CH3:5])[C:3]([OH:22])=[O:2]
Reactant: COC(=O)C(C)(C)N(C)S(=O)(=O)c1cccc2cccnc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C(C)(C)C(=O)O)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
methyl-2-methyl-2-(N-methylquinoline-8-sulfonamido)propanoate (650 mg, 2.01 mmol) was charged, and dissolved through addition of THF (5 ml) and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, adjusted with 2N—HCl to pH 5-6, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-methyl-2-(N-methylquinoline-8-sulfonamido)propionic acid (610 mg, 1.97 mmol, 98%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH2:12][CH2:13][OH:14])=[O:9])([CH3:6])[CH3:5].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:14][CH2:13][CH2:12][C@H:11]([NH:10][C:8]([O:7][C:4]([CH3:3])([CH3:5])[CH3:6])=[O:9])[C:15]([OH:17])=[O:16])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a mixture of sodium hydride (913 mg, 22.8 mmoL) in DMF at 0° C. was added N-t-Boc-L-homoserine (2 g, 9.13 mmoL). This reaction mixture was stirred at 0° C. for 15 min, and then allyl bromide (1.38 g, 11.4 mmoL) was added. The mixture was warmed up to rt, and stirred for 2 h. It was then concentrated in vacuo. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH 3 with 1 N HCl. This acidic aqueous solution was extracted with ethyl acetate. The organic phase was dried (MgSO4), and concentrated in vacuo to yield 2.2 g (93%) of (S)-4-allyloxy-2-(tert-butoxycarbonylamino)butyric acid as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9 H), 1.80-1.90 (m, 1 H), 2.04-2.16 (m, 1 H), 3.50-3.54 (m, 2 H), 3.97 (d, J=4.39 Hz, 2 H), 4.23 (dd, J=8.78, 4.39 Hz, 1 H), 5.15 (d, J=10.25 Hz, 1 H), 5.26 (dd, J=17.38, 1.65 Hz, 1 H), 5.84-5.97 (m, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[O:24][CH2:25][CH2:26][C:27]=23)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-benzofuran-4-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=494.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[CH:4]=1.[Br:13]N1C(=O)CCC1=O>CC#N>[Br:13][C:8]1[CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[C:5]([CH3:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc(C)c([N+](=O)[O-])cc1Br
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a solution of nitrobenzene 11 (2.2 g, 13.1 mmol) in CH3CN (8 mL) in a pressure tube was added N-bromosuccinimide (8.2 g, 45.8 mmol). The tube was sealed and the contents were heated to 140° C. overnight on an oil bath. The reaction mixture turned brownish-red overnight. After the reaction was quenched with saturated aqueous Na2S2O3 solution (150 mL), the product was extracted with Et2O (2×150 mL), dried (Na2SO4), and purified by chromatography (hexane/EtOAc 3:1) to afford brominated product 12 along with other byproducts that were not separable by chromatography (hexane/EtOAc 3:1). The product mixture (2.8 g, 87%) was used directly in the next step: Rf0.29 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 2.66 (s, 3H), 3.98 (s, 3H), 6.76 (s, 1H), 8.31 (s, 1H); 13C NMR (CDCl3) δ 21.7, 56.8, 108.9, 114.3, 125.2, 130.4, 136.3, 141.9, 159.3; ESI-HRMS [M-Br—CH3—H]− C7H6NO3 calcd for m/z 152.0348, found 152.0349.