Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[CH:33][N:32]=[C:31]([Cl:30])[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccnc(Cl)c1
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
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (858 mg, 1.73 mmol) and 2-chloropyridine-4-boronic acid (327 mg, 2.08 mmol) in dioxane (14.6 mL) was added Pd(PPh3)4 (160 mg, 0.139 mmol) and 2N K2CO3 (3.6 mL, 7.28 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 90° C. for 6 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H27Cl2N2O3S: 529.1; found: 529.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH2:8]2)([O-:3])=[O:2].[CH2:17](N(CC)CC)C>C(O)C.CI>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([CH3:17])[CH2:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: CI
Product: CN1Cn2ncc([N+](=O)[O-])c2-c2ccccc21
Reaction time: 8 h
Yield: 87 %

Procedure:
2.15 g (0.01 mole) of 1-nitro-5,6-dihydropyrazolo[1,5-c]quinazoline are dissolved in a mixture of 10 ml of ethanol and 20 ml of methyl iodide. 10 ml of triethylamine are added to the boiled mixture. The reaction mixture is boiled for 8 hours, then evaporated to dryness, the residue is dissolved in chloroform, washed with water, dried and evaporated. Thus, 2.0 g (87%) of 1-nitro-6-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 172°-173° C.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCN(c2ccccc2C#N)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 36.5 %

Procedure:
To a solution of 1-Boc-homopiperazine(2.18 g, 11.0 mmol) in DMSO (20 mL) was added 2-fluorobenzonitrile (1.21 g, 1.08 mL, 10 mmol) and potassium carbonate (1.52 g, 11 mmol). The mixture was stirred at 80° C. for about 48 hours. The mixture was cooled to r.t. and diluted with diethyl ether (200 mL). The solution was washed with 1N HCl (2×20 mL), H2O (3×20 mL) and brine (20 mL), dried over sodium sulfate and concentrated to a yellow oil. Purification by flash chromatography (3:1 hexanes/ethyl acetate) gave the title compound (1.1 g, 36%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[ClH:12]>C(OCC)C>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([Cl:12])([CH3:11])[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: Cl
Reactant: CC1=CCC2(CC1)OC2(C)C
Solvent: CCOCC
Product: CC1=CCC(O)(C(C)(C)Cl)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 200 ml of diethyl ether held at -10° C. was added dropwise 32 ml of 3.8N ethereal hydrogen chloride. After one hour at 0°-5° C., the mixture was washed with three 50 ml portions of water, dried and distilled to give 14.5 g of the desired product, b.p. 70°-75° C. (0.4 mm).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[Mn]([O-])(=O)(=O)=[O:16].[K+].Cl.C(Cl)Cl>CC(C)=O.O>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)[C:5]([OH:16])=[O:6]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (1.0 g, 4.41 mmol) in acetone (15 ml) and water (3 ml) was added potassium permanganate (0.837 g, 5.3 mmol, 1.2 equiv.) and the corresponding dark violet reaction mixture was stirred for 30 min to achieve full conversion. The solvents were removed under vacuum and the dark suspension was quenched upon addition of sodium sulfite solution (sat., 20 ml). The dark violet solid was filtered off and washed with water (10 ml). The turbid light brown mother liquor was treated with HCl (25%, 3 ml, 92.3 mmol, 20.9 equiv) adjusting the pH to 1 and CH2Cl2 (50 ml) was added. The phases were separated, the organic phase was washed with water (20 ml), whereas the aqueous phase was washed with CH2Cl2 (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was exchanged under vacuum with methyl cyclohexane (35 ml). The turbid suspension was concentrated under vacuum, the white precipitate was filtered off and the crystals were dried under vacuum until weight constancy to yield the product as white crystals (1.02 g, 93.8% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:10]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]([CH3:17])[CH:12]=2)[N:10]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(-c2c[nH]c(C)n2)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2ccc([N+](=O)[O-])c(C)c2)c[nH]1
Temperature: 90 °C
Yield: 36.1 %

Procedure:
2-Methyl-4-(3-methyl-phenyl)-1H-imidazole nitrate (15 g) was added portionwise to 96% sulfuric acid (40 ml) at room temperature. The resulting solution was heated at 90° C. for one hour, cooled, diluted with water (200 ml) and neutralized with aqueous sodium carbonate. The solid which separated out was filtered off, and the filtrate was made strongly alkaline with 10% sodium hydroxide. The base which precipitated was filtered off and dried to give 5 g of the title compound sufficiently pure to be used in the next step.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].S(Cl)(Cl)=O.[F:13][S:14](O)(=[O:16])=[O:15].Cl.[OH-].[K+]>>[C:2]([S:3]([NH:6][S:14]([F:13])(=[O:16])=[O:15])(=[O:5])=[O:4])([F:8])([F:7])[F:1]
Reactant: O=S(=O)(O)F
Reactant: NS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: O=S(=O)(F)NS(=O)(=O)C(F)(F)F
Temperature: 120 °C

Procedure:
A three neck dry round bottom flask equipped with a condenser, argon line adapter, stir bar, and a thermometer is charged with trifluoromethane sulfonamide (8.00 g, 0.054 mole), thionyl chloride (10.12 g. 6.20 ml, 0.085 mole), and fluorosulfonic acid (5.40 g, 3.93 ml, 0.054 mole). The resulting mixture is heated with oil bath to temperature of 120° C. and is stirred for 20 h. The released HCl and SO2 gases are scrubbed with aqueous KOH solution. The obtained crude product is distilled at reduced pressure to afford CF3SO2NHSO2F in very good yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:21][C:3]1[CH:4]=[C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[N:35]=[C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(Cl)c2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)c(Cl)c2)C1
Temperature: 90 °C
Yield: 100.9 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-bromo-3-chlorophenyl)morpholine-4-carboxylate (0.50 g) and benzophenone imine (253 mg) in toluene (5 ml) was added sodium tert-butoxide (204 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (82.7 mg) and tris(dibenzylideneacetone)dipalladium(0) (36.5 mg) were added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was poured into EtOAc and extracted sequentially with dilute aq. HCl, water and saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-chloro-4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (639 mg, quant.) as a yellow oil. MS (ISP): 479.1 ([{37Cl}M+H]+), 477.1 ([{35Cl}M+H]+).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:25])([F:24])[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21].[CH2:26]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:27]>>[CH2:26]([C:28]1[CH:34]=[CH:33][C:31]([N:32]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:20]([CH2:19][CH2:18][C:17]([F:25])([F:24])[F:16])(=[O:22])=[O:21])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:30][CH:29]=1)[CH3:27]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)CCC(F)(F)F)CC3)C2=O)cc1

Procedure:
Light yellow solid. MS (ESI): 419.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 3,3,3-trifluoro-propane-1-sulfonyl chloride and 4-ethyl-aniline.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:30]=[CH:29][CH:28]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25](=[O:26])[NH:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:22][CH:23]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)O)cc3)ccc2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)NCCCCNC(=O)OC(C)(C)C)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
120 mg (0.295 mmol) of 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]phenylacetic acid are suspended in 2 ml of DMF, and 68 μl (0.354 mmol) of N-tert-butyloxycarbonyl-1,4-diaminobutane, 66 μl (0.59 mmol) of 4-methylmorpholine, 41 mg (0.3 mmol) of 1-hydroxybenzotriazole and 114 (0.59 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 24 h and purified by means of preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:20])[CH3:19])=[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Yield: 120.2 %

Procedure:
A solution of intermediate (2) (0.328 mol) and acetic acid, anhydride (0.656 mol) in toluene (1200 ml) was stirred and refluxed for one night. The mixture was evaporated and the product was used without further purification, yielding 139 g (quant.) of N-[4-bromo-2-(3-chlorobenzoyl)phenyl]-acetamide (intermediate 3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.[C:9](=[O:12])([O-])[O-].[K+].[K+].Cl.ClC[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:12][CH2:9][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Br
Reactant: O=C([O-])[O-]
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCCCC2)cc1
Temperature: 90 °C
Yield: 82.5 %

Procedure:
To bromophenol (20.05 g, 116 mmol) and finely powdered potassium carbonate (49.16 g, 356 mmol) is added 250 ml of dimethylformamide and the contents heated with vigorous stirring to 90° C. To this rapidly stirring slurry is added β-chloroethyl piperidine hydrochloride salt (25.6 g, 139 mmol) in portions over 5 minutes. The resulting slurry is heated at 90° C. and stirred for 2 hours. An aliquot at that time shows the reaction about 95% complete. Additional potassium carbonate (4.2 g) and β-chloroethyl piperidine hydrochloride salt (2.33 g) is added to drive the reaction to completion. The reaction is heated for 2 more hours, then cooled and stirred at room temperature overnight. 1H NMR shows the reaction complete therefore the solids are filtered and the filtrate partitioned between water (200 ml) and diethyl ether (200 ml). The ether layer is washed with water (3×200 ml), brine, and 1N hydrochloric acid (2×50 ml). The combined extracts are made basic with 25 ml of 5N sodium hydroxide and extracted with diethyl ether (2×150 ml). The organics are dried over magnesium sulfate, filtered, and concentrated to give 27.2 g of an orange oil which is used as is without further purification. (73%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1ccc(C)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-methylanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone as a white solid. MS (M+H)+, 304.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[C:2]([F:10])([F:11])[F:1])=[O:23])[N:21]=2)[CH:18]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccccc1C(F)(F)F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[Br:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene (27.0 g, 100 mmol)in 1.10 L of chloroform at 60° C. was added bromine (15.98 g, 100 mmol) dropwise dissolved in 200 mL of chloroform. After the addition was complete, the reaction was cooled to room temperature, and the solvent removed in vacuo to provide 34.2 g (100%) of 2-(4-methoxyphenyl)-3-bromo-6-methoxybenzo[b]thiophene as a white solid. mp 83°-850 C. 1H NMR (DMSO-d6) δ7.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H). FD mass spec: 349, 350. Anal. Calcd. for C16Hl3BrO2S: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.C(=CCO[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N:51]=[C:52]=[O:53])=O>>[C:7](=[CH:6][CH2:5][O:39][N:51]([C:46]1[CH:45]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:52]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:53])=[O:8]
Reactant: O=C=CCOc1ccccc1N=C=O
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)N(OCC=C=O)c3ccccc3)CN2C1=O
Yield: 27.1 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2-carbonylethoxyphenyl isocyanate (102 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 18 mg (14%) of 18-(2-carbonylethoxyphenylaminocarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.9% pure (HPLC), MS m/z 758 (M−H)−, HRMS: calcd. 760.3228 and found 760.3226 (M+NH4)+, mp 148-150° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15]1>C1COCC1.CCCCCC>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:24])=[CH:15]1
Reactant: OCCN1CCCC1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCCN1CCCC1)c1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a dry THF solution of 2-(1-pyrrolidinyl)ethanol (1.10 g, 9.6 mmol) was dropwise added under ice-cooling a 1.5M hexane solution of n-BuLi (6.4 ml, 9.6 mmol) over a period of 10 min. followed by stirring for 30 min. The solvent was removed under reduced pressure. To the residue was added dry THF (20 ml). To the resulting pale yellow suspension was added a dry THF solution (5 ml) of indole-3-carboxylic acid chloride (1.00 g, 5.6 mmol) with stirring at room temperature over a period of 10 min. After stirring overnight, a reaction solution was then concentrated under reduced pressure. The residue was extracted with diluted hydrochloric acid followed by washing with ether. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and again extracted with ether. The organic layer was washed successively with water and saturated aqueous sodium chloride, then dried (MgSO4) and concentrated under reduced pressure to give 1.10 g of the title compound as colorless plates. m.p. 145°-146° C.;
Reaction SMILES: [N:1]([C:4]([F:16])([F:15])[C:5]([F:14])([O:9][C:10]([F:13])([F:12])[F:11])[C:6]([O-:8])=[O:7])=[N+:2]=[N-:3].[Na+].S(OC)(O[CH3:22])(=O)=O>>[N:1]([C:4]([F:15])([F:16])[C:5]([F:14])([O:9][C:10]([F:12])([F:13])[F:11])[C:6]([O:8][CH3:22])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(F)(F)C(F)(OC(F)(F)F)C(=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Product: COC(=O)C(F)(OC(F)(F)F)C(F)(F)N=[N+]=[N-]
Yield: 84 %

Procedure:
The resulting solution, which contained sodium 3-azido-2-trifluoromethoxytrifluoropropionate, was stirred with 69.3 g (0.55 mole) of dimethyl sulfate for 3 hr. until an initial exothermic reaction subsided. Volatiles were removed at 50° (2 mm, 2.6×10-1 kPa), and the resulting crude ester was fractionated to yield 111.8 g (84%) of methyl 3-azido-2-trifluoromethoxytrifluoropropionate, bp 38°-41° (24 mm, 2.1 kPa). IR (CCl4): 3010, 2960, and 2850 (sat'd CH); 2150 (N3), 1780 (C=O), and 1100-1250 cm-1 (C-F). NMR (CCl4): 1H 3.89 ppm (s, OCH3); 19F-56.0 (d, JFF 8.6 Hz, 3F, OCF3) and -131.6 ppm (q of t, JFF 8.6, 5 Hz, 1F, CF) with an AB for CF2N3 at -8333 and -8521 Hz (d, JFF 5.0 Hz, 1F) and -8548 and -8763 Hz (d, JFF 5.6 Hz, 1F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[C:24]([O:40][CH3:41])[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([C:28]([C:26]1[CH:25]=[C:24]([O:40][CH3:41])[N:23]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:27]=1)=[O:29])[CH2:31][CH2:32]2
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)cc(OC)n3)CC1)C(=O)N2

Procedure:
633 mg (2.3 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 700 mg (2.28 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 953.6 mg (6.9 mmol) potassium carbonate were stirred in 5 mL of NMP for 8 h at 130° C. The undissolved solid was filtered off and the filtrate was purified by HPLC. The product-containing fractions were combined and concentrated to dryness by rotary evaporation. For further purification the residue was combined with DMF and the undissolved solid was suction filtered and dried.