Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]2)[CH3:2]>C(OCC)(=O)C>[CH2:12]1[C:13]2[C:8](=[C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:10][NH:11]1
Reactant: CCOC(=O)COc1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc2c1CCNC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a solution of tert-butyl 5-(2-ethoxy-2-oxoethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (400 mg, 1.19 mmol) in ethyl acetate (10 mL), cooled in an ice-water bath, was added (10 mL, 1N) drop wise. The mixture was stirred at 25° C. for 16 h and then concentrated under vacuum to give the crude product (275 mg, 98%) which was used to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Thionyl chloride (10 mL) was added to isonicotinic acid (370 mg, 3 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried in vacuum to get isonicotinoyl chloride. 3-Hydroxyanthranilic acid (153 mg, 1.0 mmol) and pyridine (240 mg, 3.0 mmol) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. Then isonicotinoyl chloride (420 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, PE: ethyl acetate 20:1 to 5:1) to obtain 3-hydroxy-2-(isonicotinamido)benzoic acid as a solid (200 mg, yield 77%). LC-MS (ESI) m/z 259 [M+1]−.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH2:24][C:25]#N)[CH2:4][CH3:5])[CH3:2].P(=O)(O)(O)[OH:28].[OH-].[Na+]>O>[CH2:1]([CH:3]([N:6]1[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[CH2:24][C:25]1=[O:28])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1CC#N
Reactant: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(CC)N1C(=O)Cc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A mixture of [4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetonitrile (800 mg, 2.27 mmol), 6 ml of 85% phosphoric acid and 2 ml of water was heated at reflux for 2 hours and cooled to room temperature. The reaction mixture was neutralized with 2N NaOH and extracted twice with chloroform. The chloroform layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using hexane to 6% ethyl acetate in hexane as eluent to give 730 mg (92.2%) of a white solid. 1H NMR (CDCl3) δ 6.87(s,2H), 6.5(s,1H), 4.1(m,1H), 3.12(s,2H), 2.38(s,3H), 2.30(s,3H), 2.10(s,3H), 1.7–2.0(m,4H), 0.8(t,6H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].O.[OH-].[Li+]>C1COCC1.O>[C:15]([O:14][C:5]1[CH:6]=[CH:7][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:19])=[O:2])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To 5.52 mmol 2-tert-butoxy-5-methanesulfonyl-benzoic acid methyl ester in 25 ml THF was added a solution of 8.34 mmol lithium hydroxide monohydrate in 25 ml water and the reaction mixture was stirred at room temperature for 4 hours. After such time the THF was removed in vacuo and to the remaining aqueous solution was added 8 ml of 1 N aq HCl leading to precipitation of the compound. The precipitate was filtered off and washed several times with water to yield the title compound (67%) as a white solid. MS (m/e): 289.9 (M+NH4+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH:6]1[S:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:7]1=[O:22].O>CN(C=O)C>[N:1]([CH:6]1[S:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:7]1=[O:22])=[N+:2]=[N-:3]
Reactant: O=C1C(Cl)SCN1c1cccc(OC(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1SCN(c2cccc(OC(F)(F)F)c2)C1=O
Yield: 70.4 %

Procedure:
Sodium azide (2.78 g) was added to a solution of 5-chloro-3-(3-trifluoromethoxyphenyl)thiazolidin-4-one (7.50 g) in DMF (50 ml). After 2 hours the mixture was poured into water, extracted with ethyl acetate (x3), dried (MgSO4) and concentrated in vacuo to give the sub-title compound (5.40 g), which was used directly in the next step.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:34][CH:35]1[C:61](=[O:62])[N:37]2[C:38]([C:45]([O:47][CH:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])=[C:39]([CH2:42][S:43][CH3:44])[CH2:40][S:41][C@H:36]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([NH:34][CH:35]2[C:61](=[O:62])[N:37]3[C:38]([C:45]([O:47][CH:48]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])=[C:39]([CH2:42][S:43][CH3:44])[CH2:40][S:41][C@H:36]23)=[O:23])[N:19]=1)=[O:13]
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 99.2 %

Procedure:
Vilsmeier reagent prepared from phosphorus oxychloride (1.23 ml) and N,N-dimethylformamide (1.1 ml) was suspended in dry tetrahydrofuran (40 ml). To the suspension was added 2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (4.0 g) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 50 minutes to prepare the activated acid solution. On the other hand, benzhydryl 7-amino-3-methylthiomethyl-3-cephem-4-carboxylate (4.66 g) and trimethylsilylacetamide (8.6 g) were dissolved in methylene chloride (50 ml). To the solution was added the activated acid solution at -20° C. at a time, and the mixture was stirred at the same temperature for an hour. Water (100 ml) and ethyl acetate (200 ml) were added to the resultant solution, and the organic layer was separated, washed with 5% aqueous sodium bicarbonate and an aqueous sodium chloride, and then dried over magnesium sulfate, followed by evaporation under reduced pressure to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]- 3-methylthiomethyl-3-cephem-4-carboxylate (syn isomer) (8.0 g), mp 132°-138° C.
Reaction SMILES: [CH2:1]1[C:15](=[O:16])[C:14]2[C:5](=[C:6]([OH:20])[C:7]3[C:12]([C:13]=2[OH:17])=[C:11](O)[CH:10]=[CH:9][C:8]=3O)[C:3](=[O:4])[CH2:2]1.[NH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:8]1[C:7]2[C:6](=[O:20])[C:5]3[C:14](=[C:15]([OH:16])[CH:1]=[CH:2][C:3]=3[OH:4])[C:13](=[O:17])[C:12]=2[C:11]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)c2c1c(O)c1c(O)ccc(O)c1c2O
Reactant: NCCCN
Product: NCCCNc1ccc(NCCCN)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Temperature: 45 °C
Reaction time: 17 h

Procedure:
A suspension of 10.0 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone in 120 ml. of de-aerated 1,3-diaminopropane is stirred and heated at 45° C. under nitrogen for one hour and then for 10 minutes as air is bubbled into the suspension. The mixture is then evaporated to dryness and the residue is extracted with 650 ml. of ethanol in a Soxhlet apparatus for 17 hours. The extract is filtered while hot, concentrated to 95 ml. and then diluted with 900 ml. of diethyl ether. The mixture is cooled and the solid is collected, washed with ethanol-diethyl ether, then diethyl ether giving the desired product as 9.57 g. of a blue solid, mp. 115°-130° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].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.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][C:24]=3[CH3:23])[C:28]([OH:30])=[O:29])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
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: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 150 °C
Yield: 62.4 %

Procedure:
To a stirring solution of 3-iodo-4-methylbenzoic acid (60 g, 0.22 mol, 1 eq) in degassed DMF (1400 mL, 23.3 vol.) was charged 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (81.4 g, 0.32 mol, 1.4 eq) followed by potassium acetate (112 g, 1.14 mole, 5 eq) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18.7 g, 0.02 mole, 01.eq). The resulting mixture was placed under a nitrogen atmosphere and was heated to 80° C. with the exclusion of light overnight. The mixture was then concentrated under high vacuum and the residue partitioned between EtOAc and 2M HCl. The mixture was then filtered and the layers separated. The aqueous phase was re-extracted with EtOAc. The combined organics were then washed with brine, dried and evaporated to yield a brown solid that was applied to a silica plug then eluted with 2:1 cyclohexane:ethyl acetate. Fractions were then combined and evaporated to yield a brown foam that was triturated with cyclohexane, collected by filtration then dried in vacuo to yield 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. (CDCl3) 8.50-8.49 (1H, d), 8.04-8.02 (1H, dd), 7.27-7.25 (1H, d), 2.61 (3H, s), 1.36 (12H, s) 5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.58 mmol) was mixed with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.23 g), K2CO3 (0.485 g), dioxane (18 mL) and H2O (6 mL). The resultant mixture was passed through by a stream of argon for 10 min, mixed with Pd(PPh3)4 (34 mg) and heated at 150° C. for 1 h. It was filtered through celite, mixed with 1 mL acetic acid and washed with brine. The organic layers were collected, dried over MgSO4, filtered and concentrated and the residue was purified by flash column chromatography to provide the title compound (160 mg). LC-MS m/z 443.2 (M+H)+, 1.98 min (ret. time).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:36].[ClH:38].CO>>[ClH:36].[ClH:38].[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:16]=2)=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.38 %

Procedure:
Combine a solution of 4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (28.00 g; 1.00 equiv; 57.79 mmol) in DCM (280.00 mL; 4.37 mol) with a 4 M solution of hydrogen chloride in methanol (50.56 mL; 3.50 equiv; 202.25 mmol). Stir the green suspension at RT for 3 h. Evaporate the solvent, and add EA (100 mL) and evaporate again. Add EA (200 mL) and stir the suspension for 30 m. Filter on a glass fritted funnel to obtain the title compound (26.00 g; 56.85 mmol; 98.38% yield) as a green solid. m/z (M+H): 385.2
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:12]1[C:17](=[O:18])[C:16]([CH:19]2OC(C)CC[O:20]2)=[C:15]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:14]=[N:13]1)([CH3:11])([CH3:10])[CH3:9].O>C(OCC)(=O)C>[C:8]([N:12]1[C:17](=[O:18])[C:16]([CH:19]=[O:20])=[C:15]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:14]=[N:13]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC1CCOC(c2c(NCc3ccncc3)cnn(C(C)(C)C)c2=O)O1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(C=O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 3 ml of a trifluoroacetic acid solution of 0.22 g of 2-tert-butyl-4-(4-methyl-1,3-dioxan-2-yl)-5-(4-pyridylmethylamino)pyridazin-3-(2H)-one obtained in Preparation Example 4 (2), 0.5 ml of deionized water was thoroughly dropwise added at room temperature. The mixture was stirred at room temperature for one hour. Then, 80 ml of ethyl acetate was added to the system, and the mixture was washed with a saturated sodium chloride aqueous solution. Then, the ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography, and using an eluent (ethyl acetate:methanol=40:1), 0.15 g of the desired product (Compound No. 24) having a melting point of from 90° to 93° C. was obtained.
Reaction SMILES: [C:1](O)(=[O:3])C.[CH3:5][N:6]([CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)=[O:21])=[CH:15][CH:16]=2)[NH:11][CH2:10]1)[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[CH3:7][N:6]([CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:21])=[CH:15][CH:16]=2)[N:11]([CH:1]=[O:3])[CH2:10]1)[CH3:5]
Reactant: CN(C)CC1CNc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CN(C)CC1Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2N(C=O)C1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Anhydrous acetic acid (0.1 ml) was added to formic acid (1 ml), which was stirred at 55° C. for 2 hours. N-[3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydo-7-quinolinyl]-4-biphenylylcarboxamide (80 mg) was added to the reaction mixture under ice-cooling, which was stirred at room temperature for 72 hours. 10% aqueous potassium carbonate solution was added to the reaction mixture to make the mixture alkaline, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized using THF-IPE to give the titled compound (80 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])[CH3:37]>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:42]4[CH2:43][CH2:44][N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40][CH2:41]4)[N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CCNCC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (250 mg, 0.471 mmol) in 1,4-dioxane (5 mL) was added 1-isopropylpiperazine (302 mg, 2.36 mmol). The reaction mixture was stirred at room temperature for 2.5 h and concentrated to give the product which was used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: FC1C=CC(N)=C(C2CCC3C(=CC=C(OC)C=3)C2)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][CH2:49][C:50]2C=CC(OCCN3CCCCC3)=C(F)C=2)=[C:44]([CH:66]2[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=3)[CH2:67]2)[CH:43]=1>>[CH2:49]([N:48]([C:45]1[CH:46]=[CH:47][C:42]([F:41])=[CH:43][C:44]=1[CH:66]1[CH2:75][CH2:74][C:73]2[C:68](=[CH:69][CH:70]=[C:71]([O:76][CH3:77])[CH:72]=2)[CH2:67]1)[CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[CH3:50]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2c(c1)CCC(c1cc(F)ccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Agent: COc1ccc2c(c1)CCC(c1cc(F)ccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccc(F)cc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 4-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (448 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[4-fluoro-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (395 mg). This compound (393 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (300 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1CCC1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS(N=C=O)(=O)=O>C(OC(=O)C)C>[C:9](=[O:10])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH2:11]
Reactant: O=C1CCN1C(=O)OCc1ccccc1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: NC(=O)OCc1ccccc1

Procedure:
Solution A 1.99 g benzyloxycarbonyl-azetidinon and 1.29 g chlorosulfonyl isocyanate were stirred for 1 hour in 50 ml ethylacetate at 5° C. A solution of (S)-[1[[chlorosulfonyl)amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1>CN(C)C=O.C(OCC)(=O)C.C(OCC)C.CCCCCC>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:39][C:40](=[O:41])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([CH2:22][N:23]5[CH2:26][CH2:25][CH2:24]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:38])=[CH:34][CH:35]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (36.2 mg) in N,N-dimethylformamide (1 ml) was added a solution of 0.25 M 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (1.14 ml) under a nitrogen atmosphere, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (1.5 ml) and hexane (3 ml). The solid was filtered off and dried under aeration to provide the titled compound (23.4 mg, 44.0%) as white powder.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH3:10][N:11]([CH3:21])[C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][Si:23]([CH3:26])([CH3:25])Cl>C(OCC)C>[CH3:21][N:11]([C:12]([O:20][Si:23]([CH3:26])([CH3:25])[CH3:22])=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:10]
Reactant: CN(C)C(=O)Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CN(C)C(=Cc1ccccc1)O[Si](C)(C)C
Temperature: -70 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
Methyllithium in diethyl ether (140 ml of 1.8 M solution, 0.25 mol) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of dry diethyl ether. The reaction mixture was cooled to -70° C. and a solution of 26.1 g (0.16 mol) of N,N-dimethylbenzeneacetamide in 75 ml of diethyl ether was added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of trimethylchlorosilane were added dropwise. The reaction mixture was stirred at 25° C. overnight, the solid was filtered off, and the filtrate was distilled to give 7.65 g of β-(N,N-dimethylamino)-β-trimethylsiloxystyrene as a light yellow oil: bp 75°-78° C. (0.5 mm); 1H NMR (CDCl3) δ 2.18 ppm (s, 6H), 4.83 ppm (s, 1H), 6.7-7.6 ppm (m, 5H) and 0.04 ppm (s, 9H). Anal. Calcd. for C13H21NOSi: C, 66.33; H, 8.99; N, 5.95; Found: C, 66.47; H, 9.11; N, 5.78.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:13]=[CH:14][C:15]([F:22])=[C:16]2[C:21]=1[NH:20][CH2:19][CH2:18][CH2:17]2)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH2:19]2)=[C:15]([F:22])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCC2
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1CCC3
Yield: 555.1 %

Procedure:
A solution of [(S)-1-(5-fluoro-1,2,3,4-tetrahydroquinolin-8-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (15 mg, 0.044 mmol) in AcOH (1 mL) was stirred at 100° C. for 2 h, then concentrated in vacuo. A further portion of [(S)-1-(5-fluoro-1,2,3,4-tetrahydroquinolin-8-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (90 mg, 0.267 mmol) in AcOH (5 mL) was stirred at 100° C. for 1 h, then concentrated in vacuo. The combined residues were purified by column chromatography (Si—PCC, gradient 30-60% EtOAc in cyclohexane) affording the title compound as a colourless gum (78 mg, 79%). LCMS (Method J): RT 2.19 min [M+H]+ 320