Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:11]=[C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]([O:16][CH2:17][CH2:18][OH:19])=[C:14]([CH3:23])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[C:4]([O:26][CH3:27])=[CH:5][C:6]([O:24][CH3:25])=[N:7]2.N([O-])=[O:29].[Na+]>O.Cl>[OH:19][CH2:18][CH2:17][O:16][C:15]1[C:20]([CH3:22])=[CH:21][C:12]([C:10]2[NH:11][C:2](=[O:29])[C:3]3[C:4]([O:26][CH3:27])=[CH:5][C:6]([O:24][CH3:25])=[N:7][C:8]=3[CH:9]=2)=[CH:13][C:14]=1[CH3:23]
Reactant: O=N[O-]
Reactant: COc1cc(OC)c2c(N)nc(-c3cc(C)c(OCCO)c(C)c3)cc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)cc2n1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
2-[4-(5-amino-2,4-dimethoxy-[1,6]naphthyridin-7-yl)-2,6-dimethyl-phenoxyl]-ethanol (0.302 g, 0.82 mmol) in water (5 mL) and conc. Hydrochloric acid (3 mL) were mixed with stirring. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (0.305 g, 4.42 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 40 min. To the reaction mixture was added 1 N hydrochloric acid (10 mL) and heated at 55° C. for 50 min and then stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane and the aqueous layer was basified with aqueous 5% NaOH and saturated NaHCO3 solution. Water was evaporated and the organic compound was washed with a dichloromethane/methanol solution and concentrated to leave a crude which was purified by silica gel (50 g) column chromatography, employing 50% ethyl acetate in hexane and hexane/ethyl acetate/methanol (3:2:1) as eluent, to obtain 7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (0.080 g, 26%). Selected data: MS (ES) m/z: 371.1; MP 224.9-225.4° C.
Reaction SMILES: [CH:1]([CH:4]1[CH:8]([C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6](=[O:17])[NH:5]1)([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1(C)C=CC=CC=1>[CH:1]([CH:4]1[CH:8]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:19])[NH:7][C:6](=[O:17])[NH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1NC(=O)NC1C(=O)c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CC(C)C1NC(=O)NC1C(=S)c1ccccc1

Procedure:
To a stirred mixture of 10 g of 4-isopropyl-5-benzoyl-2-imidazolidone in 100 ml toluene is added 10 g phosphorus pentasulfide. The mixture is stirred, refluxed for 24 hours and the solvent is evaporated. The residue is purified by crystallization to give the title compound.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=O)[C:9]=2[CH:8]=[CH:7][CH:6]=1>>[OH:2][CH2:1][CH2:3][N:4]=[C:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:15]=2[CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: NCCO
Product: OCCN=C1c2ccccc2CCc2ccccc21

Procedure:
600 ml. of ethanolamine are added to 208 g. of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one. The mixture is heated under reflux conditions in an inert gas atmosphere for 16 hours. The refluxing ethanolamine is recycled into the reaction vessel through a Soxhlet attachment filled with 2 × 130 g. of 4A molecular sieve (bead form, 2 mm; Merck). The resulting mixture is then evaporated. The residue is dissolved in ether. The ether solution is washed with water and extracted with ice-cold 1N nitric acid. The acid extracts are washed with ether, adjusted to a pH value of 10-12 by addition of cold concentrated sodium hydroxide solution and subsequently extracted with methylene chloride. The methylene chloride extract is washed with water, dried over calcium chloride and evaporated under reduced pressure. The N-(2-hydroxy-ethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-imine which is obtained melts at 93°-94° C. after recrystallization from acetone/petroleum ether: 3:5.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][N:17]=[C:16]([O:19][CH2:20][CH2:21][NH2:22])[C:15]=3[CH:23]=2)=[CH:7][CH:6]=1.CS([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)(=O)=O.C(N(CC)CC)C>C(O)C>[F:25][C:3]([F:2])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][N:17]=[C:16]([O:19][CH2:20][CH2:21][NH:22][C:30]4[N:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:15]=3[CH:23]=2)=[CH:7][CH:6]=1
Reactant: NCCOc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: CS(=O)(=O)c1ncccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)Oc1ccc(-c2ccc3onc(OCCNc4ncccn4)c3c2)cc1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethanamine hydrochloride (57 mg, 0.152 mmol) and 2-(methylsulfonyl)pyrimidine (96 mg, 0.608 mmol) were dissolved in 2 mL ethanol in a microwave vial. Triethylamine (0.1 mL) was added and the mixture was heated at 120° C. for one hour in the microwave. All volatiles were removed under vacuum and the residue was purified on 12 g silica gel with 0-100% ethyl acetate in hexane to give the title compound (40 mg, 0.096 mmol). MS: 417 (MH+).
Reaction SMILES: C([N:3](CC)CC)C.[NH2:8][C:9]1[C:14]2[CH2:15][CH2:16][O:17][C:13]=2[C:12]([C:18](O)=[O:19])=[CH:11][C:10]=1[Cl:21].ClC(OCC)=O.N>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]2[CH2:15][CH2:16][O:17][C:13]=2[C:12]([C:18]([NH2:3])=[O:19])=[CH:11][C:10]=1[Cl:21]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(Cl)c(N)c2c1OCC2
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
Triethylamine (0.16 mol) was added to a solution of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.16 mol) in chloroform (600 ml) at a temperature below 10° C. Ethyl chloroformate (15.3 ml) was added afterwards and the reaction mixture was stirred for 45 minutes, while cooling on an ice-bath. Gaseous ammonia was allowed to bubble through the mixture and the reaction mixture was stirred for 3 hours at RT. The precipitate was filtered off and consecutively washed with water, 5% NaOH solution, and again water, and dried, yielding 23.5 g (69%) of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxamide (intermediate 7).
Reaction SMILES: Br[CH2:2][CH:3]1[O:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[CH2:4]1.[C:11]1([S-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:11]1([S:17][CH2:2][CH:3]2[O:9][CH:8]3[N:5]([C:6](=[O:10])[CH2:7]3)[CH2:4]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [S-]c1ccccc1
Reactant: O=C1CC2OC(CBr)CN12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC2OC(CSc3ccccc3)CN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
(3RS, 5SR)-3-Bromomethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (210 mg, 1.0 mmole) in dry dimethylformamide (2 ml) was added dropwise to a stirred solution of sodium thiophenolate (1.2 mmole) in dry DMF (5 ml). The solution was stirred at room temperature with exclusion of moisture for 16 hours and was then diluted with ethyl acetate (30 ml). The solution was washed three times with water, dried, and the solvent removed to give a colourless oil. The oil was chromatographed on silica gel (15 g) using ethyl acetate/petroleum ether to give the title compound as a colourless gum (205 mg, 87%). (Found : M+, 235.06551. C12H13NO2S requires 235.06669. νmax (CHCl3) 1785 (β-lactam C=O)cm-1 δ p.p.m. (CDCl3) 2.6 - 3.5 [complex, 5H, C(6)H2, C(2)H, CH2SPh[; 4.10 [dd, J 11.5Hz, J' 6Hz, 1H, C(2)H]; 4.52 [quin., J 6Hz, 1H, C(3)H]; 5.43 [d, J 2.5Hz, 1H, C(5)H]; 7.48 (5H, aromatic H). m/e : 235 (M+, 100%), 192 (30), 123 (71).
Reaction SMILES: C(OC(=O)[O:5][C:6]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=2[C:12]([O:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:11]2[C:7]=1[N:8]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:9]=[N:10]2)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C1C=CN=CC=1)C.O>[CH:29]([O:28][C:12]1[C:13]2[C:14](=[O:27])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:16](=[O:18])[C:17]=2[C:6]([OH:5])=[C:7]2[C:11]=1[N:10]=[CH:9][N:8]2[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(c(O)c3c(ncn3Cc3ccccc3)c2OC(c2ccccc2)c2ccccc2)C(=O)N1Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 94 %

Procedure:
Carbonic acid 8-benzhydryloxy-3-benzyl-6-(4-fluoro-benzyl)-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 257 (130 mg, 0.20 mmol) was dissolved in THF (5 mL, 0.1 M) along with DMAP (24 mg, 0.40 mmol, 2 equiv.). A solution of K2CO3 (276 mg, 1.99 mmol, 10 equiv.) was dissolved separately in H2O (6 mL) before transferring to the reaction mixture. The reaction was allowed to stir for 18 hr and quenched with HCl (20 mL, 1 N) and extracted with ethyl acetate (2×30 ml). The organic layer was washed with saturated NH4Cl solution (25 mL), brine solution (25 mL) and dried over Na2SO4 and concentrated in vacuo to yield 4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione 258 (94%, 103 mg, 0.188 mmol) as an off white oil. 1H NMR (300 MHz) CDCl3 δ 8.28 (bs, 1 H), 7.94 (s, 1 H), 7.89 (s, 1 H), 7.64-7.43 (m, 4 H), 7.17-7.43 (m, 12 H), 6.98-7.04 (s, 2 H), 5.57 (s, 2 H), 4.77 (s, 2 H). MS: 584.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[CH3:12][N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=2[CH:16]=[CH:15][C:14]1=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH:18]1[CH2:19][CH2:20][CH2:21][C:22]2[N:13]([CH3:12])[C:14](=[O:24])[CH:15]=[CH:16][C:17]1=2
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc(Cl)cc1Cl)CCC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 42 %

Procedure:
A mixture of 2-(2,4-dichlorophenyl)ethylamine (3.8 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (256 mg) was heated in refluxing toluene (50 ml), with azeotropic removal of water, for 40 hrs. An additional 2.0 g of the amine was added and the mixture was refluxed for 36 hrs. The solution was cooled and concentrated in vacuo. Sodium borohydride (0.6 g) was added to a solution of the residue in 50 ml of ethyl alcohol, and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate/hexanes provided 2.5 g (42%) of product, mp 102°-103° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc(OCc2ccccc2)ccn1
Yield: 43.8 %

Procedure:
A solution of 4-(benzyloxy)pyridin-2(1H)-one (9.92 g, 49.3 mmol), methyl iodide (4.60 mL, 74.0 mmol) and silver carbonate (13.6 g, 49.3 mmol) in chloroform (50 mL) was stirred with heating under reflux for four hours. After leaving to cool, the insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 2:1) to obtain the title compound (4.65 g, 44%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].O.C(Cl)[Cl:15]>>[Cl:15][C:10]1[C:3]([O:2][CH3:1])=[C:4]([C:7]([O:11][CH3:12])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cccc(OC)c1C=O
Reactant: ClCCl
Solvent: O
Product: COc1ccc(Cl)c(OC)c1C=O
Temperature: 50 °C

Procedure:
A solution of commercially available 2,6-dimethoxybenzaldehyde (3.000 g; 18.10 mmol) in DCM (12 ml) was treated dropwise with a solution of sulfuryl dichloride SO2Cl2 (2.437 g; 18.10 mmol) in DCM (9 ml), and the resulting mixture was heated to 50° C., under nitrogen, for 30 min. After cooling to rt, water was added and the separated aq. layer was further extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=3/1) afforded 3-chloro-2,6-dimethoxybenzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 201.03 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:19][C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[S:13]([NH:12][C:10]([NH:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)=[O:11])(=[O:15])=[O:14])=[O:20])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCc2ccccc2)n1

Procedure:
To 1.75 g of 2-(4,6-dimethylpyrimidin-2-ylaminocarbonylsulfamoyl)benzoic acid was added 0.51 g of triethylamine in 10 ml tetrahydrofuran and 0.88 g of benzyl bromide in 10 ml of tetrahydrofuran. The mixture was heated to reflux for 1.5 hours, filtered and the tetrahydrofuran evaporated in-vacuo. The residue was extracted with hot 1-chlorobutane, diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and the solvents evaporated in-vacuo. The resultant residue was crystallized from 1-chlorobutane to a melting point of 157°. This product showed absorption peaks in the infrared region at 1720, 1600, 1560 cm-1 consistent for the desired ester and absorption by nuclear magnetic resonance at 2.45δ, singlet, for CH3 ; 5.3δ singlet, CH2 on benzyl; 6.65δ singlet CH of pyrimidine and aryl peaks at 7-8δ.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 41.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 158 mg, 0.5 mmol) in pyridine (5 mL) at 25° C. was treated with trifluoromethanesulfonyl chloride (60 μL, 0.57 mmol). The reaction was stirred at 25° C. for 7 h and was then concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 40/60 heptane/ethyl acetate) afforded the 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonylamino-phenyl)-propionamide (93.8 mg, 41.9%) as a tan solid: mp 70-74° C.; EI-HRMS m/e calcd for C18H20F3N3O3S2 (M+) 447.0898, found 447.0894.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:8][CH2:7][CH2:6]1.C([N-]C(C)C)(C)C.[Li+].[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1([C:9]2[S:10][C:11]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][N:13]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COCOC1(c2nccs2)CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(OCOC)CCC2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of the 2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1B) (5.67 g, 28.5 mmol) in tetrahydrofuran (95 mL) was added a solution of lithium diisopropylamide (34.1 mmol) in tetrahydrofuran (30 mL) dropwise. The solution was stirred at −78° C. for 45 minutes, and tributyltin chloride (9.26 mL, 34.1 mmol) was added dropwise. The cold bath was removed, and the reaction warmed to room temperature. The ambient reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and ether. The layers were separated, and the aqueous layer was extracted with additional ether. The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 490 [M+H]+.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+].CCOCC>O1CCCC1.CN(C)C1C=CN=CC=1>[C:1]1(=[O:24])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][C:8]([NH2:27])=[O:9])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 35.6 %

Procedure:
To a stirred solution of 3-phthalirnido-3-(3,4-dichlorophenyl)propionic acid (1.10 g, 3.02 mmol) in 20 mL of tetrahydrofuran at room temperature under nitrogen was added carbonyldiimidazole (0.51 g, 3.17 mmol) and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 45 in and then concentrated ammonium hydroxide (0.21 nL, 3.2 mmol) was added. The reaction mixture was stirred for 10 minutes and then the tetrahydrofuran was removed under reduced pressure. To the resulting mixture was added 20 mL of water, a light yellow oil was formed. To the mixture was added 3 mL of ether, the mixture was stirred at room temperature for 1 hour. The resulting slurry was filtered, the solid was washed with water and air-dried to afford 0.73 g of the crude product as a white solid. The crude product was purified by flash chromatography (silica gel, hexane/methylene chloride, 22-0% (v/v)) to afford 0.39 g (36%) of 3-phthaiimido-3-(3,4-dichlorophenyl)propionamide as a white powder: 1H NMR (DMSO-d6, 250 MHz) δ7.83 (m, 4H, Ar), 7.35-7.75 (m, 4H), 6.93 (br s, 1H), 5.72 (t, 1H, J=8 Hz), 3.25 (dd, 1H, J1=8 Hz, J2=15 Hz), 3.14 (dd, 1H, J1=8 Hz, J2=15 Hz); 13C NMR (DMSO-d6) δ170.8, 167.6, 140.2, 134.6, 131.2, 131.0, 130.7, 130.3, 129.2, 127.7, 123.2, 49.3, 36.5. Anal. Calcd for C17H12N2O3Cl2. Theoretical C, 54.69; H, 3.54; N, 7.53. Found C, 54.69; H, 3.38; N, 7.15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:31](=[O:33])[CH3:32])=[CH:24][CH:25]=1)[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:30]
Reactant: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(O)cc4)c3c2F)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCN(C)CC4)c(F)c32)cc1
Reaction time: 16 h

Procedure:
6,8-Difluoro-7-(4-methyl-1-piperazinyl)-1-(4-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.14 g) is dissolved in dry pyridine (5 ml) and acetic anhydride (5 ml), and the mixture is allowed to stand at room temperature for 16 hours. Excess acetic anhydride and pyridine are distilled off under reduced pressure, and the resulting residue is dissolved in dichloromethane. The dichloromethane solution is washed with diluted hydrochloric acid, saturated aqueous sodium chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in this order, and dried over sodium sulfate. The solvent is distilled off, and the residue is recrystallized from ethanol-chloroform to give 6,8-difluoro-7-(4-methyl-1-piperazinyl)-1-(4-acetyloxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.12 g) as pale yellowish white crystals, m.p. 247°-251° C.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]3[CH2:29][CH2:28][CH2:27][CH2:26][C:24]=3[S:25][C:19]=2[N:18]=[C:17]1[CH3:30]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]5[CH2:29][CH2:28][CH2:27][CH2:26][C:24]=5[S:25][C:19]=4[N:18]=[C:17]3[CH3:30])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1nc2sc3c(c2c(=O)n1N)CCCC3
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1nc2sc3c(c2c(=O)n1NC(=O)CC12CC4CC(CC(C4)C1)C2)CCCC3

Procedure:
1-Adamantaneacetyl chloride (BBB-SCI) and 3-amino-2-methyl-5,6,7,8-tetrahydro-3 H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.57-1.72 (m, 13 H) 1.72-1.85 (m, 4 H) 1.89-1.99 (m, 3 H) 2.08 (m, 1 H) 2.15 (m, 1H) 2.35 (s, 3 H) 2.69-2.78 (m, 2 H) 2.79-2.88 (m, 2 H) 10.78 (s, 1 H); MS (ESI+) m/z 412 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1F
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccccc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 2-fluoro-benzylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C43H49Cl2FN5O3 [(M+H)+] 772.3191, observed 772.3185.