Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.O.[C:7](=[O:10])(O)[O-].[Na+].[CH:12]([N:15]([CH2:23][C:24]#[CH:25])[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:13]>CN(C=O)C>[OH:22][C:18]1[CH:17]=[C:16]([N:15]([CH:12]([CH3:14])[CH3:13])[CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][C:19]=1[CH:7]=[O:10]
Reactant: O=C([O-])O
Reactant: C#CCN(c1cccc(O)c1)C(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCN(c1ccc(C=O)c(O)c1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
After DMF (13.30 mL, 172.6 mmol) was cooled to 0° C. and POCl3 (2.68 mL, 28.79 mmol) was added dropwise thereto, the mixture was stirred for 20 minutes, warmed to room temperature, and then stirred for 1 hour. To this reactant, a solution in which the 3-(isopropyl(prop-2-ynyl)amino)phenol compound of Chemical Formula 3 (2.18 g, 11.51 mmol) was dissolved in DMF (10 mL) was added, and then the mixture was stirred for 12 hours. Distilled water (30 mL) was added to the post-reaction mixture, and the result was neutralized to between pH 7 and 8 by adding sodium bicarbonate solid. After this mixture was partitioned to acetic acid (100 mL) and distilled water (30 mL), the organic layer was separated, washed with saturated salted water (10 mL), dried with anhydrous sodium sulfate, filtered and vacuum distilled, and the residue obtained was column chromatographed on silica gel (hexane/ethyl acetate (7:1)) to give 2-hydroxy-4-(isopropyl(prop-2-ynyl)amino)benzaldehyde (2.05 g, 82%). 1H NMR (500 MHz, CDCl3) d 11.52 (s, 1H), 9.55 (s, 1H), 7.33 (d, 1H, J=8.7 Hz), 6.46 (dd, 1H, J=2.3, 8.7 Hz), 6.29 (d, 1H, J=2.3 Hz), 4.19-4.22 (m, 1H), 3.98 (d, 2H, J=2.7 Hz), 2.23 (t, 1H, J=2.7 Hz), 1.29 (d, 6H, J=6.9 Hz); 13C NMR (125 MHz, CDCl3) d 192.7, 164.2, 154.7, 135.3, 112.4, 105.4, 98.5, 80.4, 72.0, 49.1, 33.3, 20.2 (2).
Reaction SMILES: [Cl:1][C:2]([Cl:8])([Cl:7])[C:3](=[NH:6])OC.[N+:9]([C:12]1[CH:13]=[C:14](N)[C:15]([NH2:18])=[CH:16][CH:17]=1)([O-:11])=[O:10].O.C(OCC)(=O)C>C(O)(=O)C>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:3]([C:2]([Cl:8])([Cl:7])[Cl:1])[NH:6][C:14]=2[CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(C(Cl)(Cl)Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 6.3 g (35.9 mmol, 1.1 eq.) of methyl 2,2,2-trichloroethaneimidoate were added dropwise to a solution of 5.0 g (32.7 mmol) of 4-nitrobenzene-1,2-diamine in 150 ml of glacial acetic acid. The reaction mixture was stirred at RT for 3 h and then added to 400 ml of water, and 300 ml of ethyl acetate were added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed twice with in each case 130 ml of saturated aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure and dried. The crude product was triturated with pentane and left to stand overnight. The solid was then filtered off, washed with pentane and dried under reduced pressure. Yield: 10.1 g (purity 77%, 85% of theory)
Reaction SMILES: C[Li].Br[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[NH:7][CH3:8].C([Li])(C)(C)C.[B:17](OC)([O:20]C)[O:18]C.Cl>C(OCC)C.O1CCCC1>[CH3:8][NH:7][C:6]1[CH:5]=[C:4]([B:17]([OH:20])[OH:18])[CH:11]=[CH:10][CH:9]=1
Reactant: CNc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
166 mL (0.242 mol, 1.2 eq) of 1.6 M methyllithium in diethyl ether are added to a solution cooled to −70° C. of 37.6 g (0.202 mol, 1 eq) of 3-bromo-N-methylaniline (prepared in Example 7c) in 300 ml of tetrahydrofuran. The reaction medium is stirred at −70° C. for one hour and 306 mL (0.444 mol, 2.2 eq) of 1.5 M tert-butyllithium in diethyl ether are then added. The reaction medium is stirred at −70° C. for 45 minutes and 103.5 mL (0.808 mol, 4 eq) of trimethyl borate are then added. The reaction medium is stirred at room temperature for one hour and then hydrolyzed by addition of ice, acidified with 1 L of 2N hydrochloric acid and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 4.2 g (14%) of 3-(methylamino)phenylboronic acid are obtained. The aqueous phase is basified and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 3.4 g (11%) of 3-(methylamino)phenylboronic acid are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][N:27]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16](Br)[CH:17]=1)=[O:9])(=[O:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][N:27]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)Nc1cc(C(=O)NCc2cnc(OCC(F)(F)F)c(Br)c2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C(=O)NCc2cnc(OCC(F)(F)F)c(-c3ccccc3)c2)ccn1
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 2-acetamido-N-((5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isonicotinamide (20 mg, 0.05 mmol, Step-1), phenylboronic acid (11 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium (3 mg, 2.2 microM) in dioxane (2 mL) is added saturated aqueous sodium hydrogencarbonate (0.4 mL). The mixture is heated at 100° C. for 1 hr. After cooled to room temperature, the mixture is extracted with ethyl acetate, dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by short column chromatography on amine gel eluting with ethylacetate, and then purified by preparative LC-MS to give 6 mg (30% yield) of the title compound.
Reaction SMILES: Br.[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([O:32][C:33]([NH:2][CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:5])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(CN)c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CNC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 4.64 g of (±)-4-(2-amino-1-methylethyl)phenol hydrobromide, 100 ml of ethyl acetate, 6.92 g of potassium carbonate, 40 ml of water and 3.75 g of benzyloxycarbonyl chloride is stirred at room temperature overnight. After the reaction, the ethyl acetate layer is separated therefrom, washed, dried, and then evaporated under reduced pressure to remove the solvent. 4.82 g of (±)-4-(2-benzyloxycarbonylamino-1-methylethyl)phenol are obtained as pale yellow oil.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.Cl>O1CCCC1.O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:20][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:21])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1

Procedure:
In 60 ml of tetrahydrofuran was suspended 18.7 g of 60% sodium hydride followed by addition of 39.4 of diethyl carbonate. Then, a solution of 25 g of p-methoxyacetophenone in 70 ml of THF was added dropwise with refluxing and the mixture was further refluxed for 5 hours. After cooling, the reaction mixture was poured slowly into iced water, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oil was distilled under reduced pressure to provide 30.1 g of the desired compound as a pale yellow oil. b.p. 161°-164° C. (3 mmHg).
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:2]([C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][C:35]=3[Cl:37])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)cn12
Yield: 50 %

Procedure:
The title compound (5.5 mg, 50%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2,4-dichlorophenylboronic acid (7.5 mg, 0.039 mmol, K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethylpyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=2.04 min, [M+H]+=547.2.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:31])[C:19]([C:23]3[N:24]=[C:25]([NH:28][CH:29]=[O:30])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:32])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].O.O.[Cl-].[Ca+2].[Cl-]>CO>[CH:29]([NH:28][C:25]1[S:26][CH:27]=[C:23]([C:19](=[N:20][O:21][CH3:22])[C:18]([NH:17][CH:16]2[C:15](=[O:32])[N:10]3[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][CH3:1])[CH2:7][S:8][C@H:9]23)=[O:31])[N:24]=1)=[O:30]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(NC=O)n1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 0.58 h
Yield: 66.6 %

Procedure:
1 g of sodium 3-acetoxymethyl-7-[2-(2-formylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate were dissolved in 12 ml of 50% v/v aqueous methanol, and 20 g of calcium chloride dihydrate were added. The mixture was then stirred at 70° C. for 35 minutes, after which it was diluted with 30 ml of ice-water and insolubles were filtered off. The filtrate was acidified with hydrochloric acid and extracted three times, each time with 50 ml of ethyl acetate. The extracts were combined, washed with an aqueous solution of sodium chloride, dehydrated over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, and diethyl ether was added thereto. The resulting solid was separated, giving 0.6 g (yield 66.7%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.[CH:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)C1CCC1)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (80 mg, 0.26 mmol, 1.0 eq.), cyclobutanecarboxylic acid (36 mg, 0.34 mmol, 1.5 eq.), N,N-diisopropylethylamine (63 mg, 0.51 mmol, 2.0 eq.) in dichloromethane (4 mL) was added a solution of phosphorus oxychloride (45 mg, 0.3 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 30 min. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water and extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2:1) to afford 54 mg of methyl 2-(2-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 53%. MS (ESI+APCI) M+1=393.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:13][C@H:14]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C@H:15]2[C:26]([O:28]CC)=[O:27])=[O:12])=[CH:2]1.C1COCC1.CCO.[OH-].[Li+].Cl>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:13][C@@H:14]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][C@H:15]2[C:26]([OH:28])=[O:27])=[O:12])=[CH:2]1
Reactant: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(Cc1c[nH]c2ccccc12)N[C@@H]1C(=O)N(c2ccccc2)C[C@H]1C(=O)O
Reaction time: 2.5 h
Yield: 25.7 %

Procedure:
To the title compound of example 8 (520 mg, 1.28 mmol) in 1:4 THF/EtOH (20 ml) was added lithium hydroxide (46 mg (1.92 mmol) in H2O (10 ml) and stirred for 2.5 h. The reaction mixture was acidified with 1N HCl to pH 3 and concentrated in vacuo. The mixture was purified by chromatography on silica gel (CH3OH/HOAc/CH2Cl2 gradient 10/1/89 to 20/1/79) to give 124 mg (18%) of the title compound. MS calcd for C21H19N3O4 : 377, found 377.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13]S(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+].C(OCC)(=O)C.O>CS(C)=O>[C:18]([O:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of (R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (20 g) in dimethyl sulfoxide (200 ml) was added sodium benzoate (22 g) under nitrogen. After stirring at 100° C. for 1 hour, the solution was taken up into a mixture of ethyl acetate and water. The organic layer was separated, and washed with water and brine successively. The dried solvent was evaporated to give (S)-3-benzoyloxy-1-t-butoxycarbonylpyrrolidine (22 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2cc(F)ccc21
Yield: 41.6 %

Procedure:
5-Fluoro-2,3-dihydro-1H-inden-1-one (I-78c: 1.2 g, 8.0 mmol) in TFA (20 mL) was reacted with sodium azide (1.7 g, 26.4 mmol) to afforded 550 mg of the product (46.2% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2([C:12](Cl)=[O:13])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH2:17][C:18]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][N:21]=[C:20]2[S:31][CH:32]=[CH:33][C:19]=12>>[NH2:17][C:18]1[N:23]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:12]([C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=4)[CH2:11][CH2:10]3)=[O:13])=[CH:28][CH:29]=2)[CH2:22][N:21]=[C:20]2[S:31][CH:32]=[CH:33][C:19]=12
Reactant: O=C(Cl)C1(c2cccc(C(F)(F)F)c2)CC1
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)C2(c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 469, using 1-(3-Trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine of choice. MS(ES) m/e 455 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][N:7]=[CH:6]1.[CH3:15]O>>[NH:5]1[C:9]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:7]=[CH:6]1
Reactant: CO
Reactant: O=C(O)CCc1cnc[nH]1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cnc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Add thionyl chloride (0.75 mL) to a −78° C. solution of 3-(1H-imidazol-5-yl)propanoic acid (2.0 g; 1.0 equiv; 14.27 mmoles) in methanol (18 mL). Allow the reaction mixture to warm to ambient temperature and stir for 30 minutes. Add saturated sodium bicarbonate (10 mL) to the reaction mixture and concentrate. Suspended the resulting residue in methanol (10 mL) and filter, then concentrate to afford methyl 3-(1H-imidazol-5-yl)propanoate (2.2 g; 100%) as a white solid: MS (m/z): 155(M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:39]=[C:40]([OH:44])[CH:41]=[CH:42][CH:43]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:37])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(O)c1cccc(O)c1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2cccc(O)c2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=504.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([C:47]2[S:48][CH:49]=[C:50]([CH2:52][CH2:53][C:54]([OH:56])=O)[N:51]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH3:46])[CH3:36]>ClCCl.O>[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([C:47]2[S:48][CH:49]=[C:50]([CH2:52][CH2:53][C:54]([N:25]([O:26][CH3:27])[CH3:24])=[O:56])[N:51]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH3:46])[CH3:36]
Reactant: CCOc1ccc(-c2nc(CCC(=O)O)cs2)cc1OCC
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(-c2nc(CCC(=O)N(C)OC)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
1-hydroxybenzotriazole (22.91 g, 149.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (28.68 g, 149.6 mmol), N,O-dimethylhydroxylamine hydrochloride (13.93 g, 136 mmol) and triethylamine (41.7 ml, 299.2 mmol) were added to a solution (1.0 l) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionic acid (43.71 g, 136 mmol) in dichloromethane, followed by stirring at room temperature for 4 hours. Water was added to separate the reaction mixture into layers, and the aqueous layer was further subjected to extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, and the residue was recrystallized from an ethyl acetate/n-hexane mixed solvent, to thereby obtain 42.4 g (yield: 68%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamide as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH:15][CH:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:13]=1[CH3:14].BrC(C)C([C:28]1[CH:33]=[CH:32][C:31](Cl)=CC=1Cl)=O.[H-].[Na+]>O1CCCC1.C1(CBr)CC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:15]([CH:16]([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:31][CH:32]2[CH2:28][CH2:33]2)[S:12][C:13]=1[CH3:14]
Reactant: Cc1sc(NC(C)c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Agent: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1sc(N(CC2CC2)C(C)c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., add 0.5 g of 4-(2,4-dichlorophenyl)-5-methyl-2-[N-(α-methylbenzyl)amino]thiazole (prepared from Compound 92 and Compound 15 according to the process described in Example 1), dissolved in 5 ml of anhydrous tetrahydrofuran, and 66 mg of sodium hydride. After 30 minutes of stirring at room temperature, run in 0.67 ml of cyclopropylmethyl bromide dropwise. Leave for eight hours under reflux, cool and dilute the reaction medium with methylene chloride, then pour it onto ice.
Reaction SMILES: Cl.CN[O:4][CH3:5].CCN=C=NCCC[N:14]([CH3:16])C.CN1CCOCC1.[CH3:24][C:25]([CH3:35])([O:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=O)=[O:29])[CH3:26]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:5][O:4][CH2:16][NH:14][C:32](=[O:34])[CH2:31][NH:30][C:28](=[O:29])[O:27][C:25]([CH3:24])([CH3:26])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCNC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.95 g), EDCI (3.83 g), N-methylmorpholine (2.2 ml) and DMAP (2.44 g) were added to a solution of N-[(1,1-dimethylethoxy)carbonyl]glycine (3.5 g) in dichloromethane (60 ml) and then stirred at room temperature for 3 days. Dichloromethane (100 ml) was added and then the solution was washed with 2M hydrochloric acid (three times), NaHCO3 solution (three times) and water (three times) and then dried (MgSO4). The organic layer was separated and the aqueous layer was further extracted twice. The solvent was evaporated to give the sub-title compound (3.42 g).