Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.N1C=CN=C1.NCC[CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH:27]=[CH:26]2>CS(C)=O>[N:8]1([C:6]([NH:3][CH2:2][CH2:1][CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH:27]=[CH:26]3)=[O:7])[CH:9]=[CH:10][N:11]=[CH:12]1
Reactant: NCCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: CS(C)=O
Product: O=C(NCCCOc1ccc2[nH]c(=O)ccc2c1)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of N,N-carbonyldiimidazole (139 g) and imidazole (117 g) in dimethylsulfoxide (2 liters) is added with stirring 6-(3-aminopropoxy)carbostyril (200 g) in portions under ice-cooling. The mixture is further stirred at room temperature for one day, and poured into ice-water. The precipitated crystals are collected by filtration, and washed with water. The crystals thus obtained are further washed successively with ethanol and diethyl ether, and dried to give 6-[3-(1-imidazolyl)carbonylaminopropoxy]carbostyril (162 g) as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)(=[O:3])C.Cl[O-:18].[Na+].[OH-].[Na+].Cl>O1CCOCC1>[CH:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH:15]=[CH:16][C:4]=1[C:1]([OH:3])=[O:18]
Reactant: CC(=O)c1ccc2sc3ccccc3c2c1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2sc3ccccc3c2c1
Reaction time: 5 h

Procedure:
2-Acetyldibenzothiophene (2.24 g.), sodium hypochlorite solution, (47 ml. containing 5.7% available chlorine), Normal sodium hydroxide solution (50 ml.) and dioxan (50 ml.), were heated on a steam bath with stirring for 5 hr. The mixture was acidified with excess hydrochloric acid, and the precipitated colourless solid filtered off, washed with water, and recrystallise twice from acetic acid to give dibenzothiophene-2-carboxylic acid, m.pt. 281°-283° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C1COCC1>[F:22][C:3]1[C:2]([NH:1][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:9]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3F)c12
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1F
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (6.5 mg, 0.022 mmol) and DIPEA (12 μL, 0.066 mmol) in THF (220 μL) at room temperature was added methacryloyl chloride (3.5 mg, 0.033 mmol) and the solution was stirred for 1 hour. The reaction was concentrated and the residues, dissolved in 2 mL of DMSO, were purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophilization of the desired fractions afforded a colorless solid. LRMS (ESI) calc'd for C19H18N4O3F [M+H]+: 369, found 369.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][NH:5][CH2:6][C:7]([CH3:10])([NH2:9])[CH3:8].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.CO>C(Cl)Cl>[CH3:11][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]([CH3:8])([CH3:10])[NH:9][C:17]1=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCNCC(C)(C)N
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCN1CC(C)(C)NC1=O
Reaction time: 20 h
Yield: 1.8 %

Procedure:
To a solution of N1-(2-(dimethylamino)ethyl)-2-methylpropane-1,2-diamine (23.2 mmol) in CH2Cl2 (50 ml) was added CDI (4.51 g, 27.8 mmol). The solution was stirred for 20 h, concentrated in vacuo, the resulting residue suspended in 800 ml diethyl ether, washed with 3× 200 ml 1M Na2CO3, 200 ml sat. NaCl, dried on MgSO4, and concentrated in vacuo. Flash chromatography (2.5%→20% MeOH:CH2Cl2) afforded the title compound as a clear oil (79.3 mg, 0.428 mmol, 2%) as well as additional material heavily contaminated with imidazole g). 1H NMR (CDCl3, 400 MHz) δ 1.24 (s, 6H), 2.23 (s, 6H), 2.41 (m, 2H), 3.24 (s, 2H), 3.34 (m, 2H), 4.96 (s, 1H). ESI/APCI (pos) expected for C9H19N3O: 185.15. Found: 186 (MH+).
Reaction SMILES: [CH:1]1([O:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26])[C:12]([C:14]1[NH:19][C:18](=[O:20])[C:17]([CH3:21])=[CH:16][CH:15]=1)=O.O>C(O)CCC>[Cl:8][C:9]1[CH:10]=[C:11](/[C:12](=[N:7]\[O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:14]2[NH:19][C:18](=[O:20])[C:17]([CH3:21])=[CH:16][CH:15]=2)[CH:22]=[CH:23][C:24]=1[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: NOC1CCCC1
Reactant: Cc1ccc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2)[nH]c1=O
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)[nH]c1=O
Temperature: 200 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
O-cyclopentylhydroxylamine (0.3 mL) was added to a solution of 6-[3-chloro-4-(methylsulfonyl)benzoyl]-3-methylpyridin-2(1H)-one (220 mg) in n-butanol (2 mL) at room temperature, and the mixture was stirred under microwave irradiation at 200° C. for two hours. O-cyclopentylhydroxylamine (0.3 mL) was further added at room temperature, and the mixture was stirred under microwave irradiation at 200° C. for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) and further purified by silica gel column chromatography (chloroform:ethyl acetate=50:1→25:1). The resulting less polar product was powdered with an ethyl acetate/hexane solution, and filtration operation gave (E)-6-{[3-chloro-4-(methylsulfonyl)phenyl](cyclopentyloxyimino)methyl}-3-methylpyridin-2(1H)-one as a white solid (95 mg, 34%). The more polar product was powdered with an ethyl acetate/hexane solution, and filtration operation gave (Z)-6-{[3-chloro-4-(methylsulfonyl)phenyl](cyclopentyloxyimino)methyl}-3-methylpyridin-2(1H)-one as a white solid (36 mg, 13%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C1(C)C=CC=CC=1.OS(O)(=O)=O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[Cl:9])[NH:6][C:14](=[O:15])[CH:13]=[C:12]2[C:11]([F:21])([F:20])[F:10]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)c2cc(Br)c(Cl)cc2[nH]1
Yield: 63.7 %

Procedure:
This compound was prepared according to General Method 11 (EXAMPLE 22) from 4-bromo-3-chloroaniline (2.06 g, 10.0 mmol), ethyl 4,4,4-trifluoroacetoacetate (2.30 g, 12.5 mmol) in 50 mL toluene followed by heating in 33 mL conc. H2SO4 to afford 2.08 g (64%) of 6-bromo-7-chloro-4-(trifluoromethyl)-quinolin-2(1H)-one, an off-white solid. This material was converted to the corresponding imino ether according to General Method 12 (EXAMPLE 22) with isopropyl iodide (4.32 g, 25.4 mmol) and CsF (3.85 g, 25.4 mmol) in 32 mL DMF to afford 1.34 g (57%) of 6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline, a white solid, after flash chromatography (hexanes). Data for 6-bromo-7-chloro-2-isopropoxy-4-(trifluoromethyl)quinoline: 1H NMR (400 MHz, CDCl3) δ 8.22 (broad s, 1H), 8.00 (s, 1H), 7.17 (s, 1H), 5.51 (hept, 1H, J=6.2), 1.40 (d, 6H, J=6.2).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:10].[CH2:25]([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH3:10])=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH:7]=1
Reactant: CC(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(Cl)cc1Br
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(Cl)ccc2C(C)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
N-(1-(2-bromo-4-chlorophenyl)ethyl)-4′-chloro-[1,1′-biphenyl]-4-amine (129 mg, 0.31 mmol), 4-(ethoxycarbonyl)phenylboronic acid (89 mg, 0.46 mmol), Pd(dppf) Cl2 (34 mg, 0.05 mmol), and K2CO3 (106 mg, 0.76 mmol) in wet DMF (3 mL) was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc, washed with water for and saturated aqueous NaHCO3, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:31].[O-]Cl.[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:30])=[O:31])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1OC
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.6 %

Procedure:
3-butyryl-4-(2-methoxyphenylamino)-8-(3-methylthiopropoxy)quinoline (0.30 g, 0.70 mmol) was dissolved in methylene chloride (10 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride methanol 95:5 as the eluent gave 14 mg (4.6%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O>C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH2:18]
Reactant: COC(=O)c1ccccc1Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1Cc1cc(Cl)ccc1N
Temperature: 0 °C
Yield: 47.9 %

Procedure:
To a solution of 2-(2-nitro-5-chlorophenylmethyl) benzoic acid methyl ester (840 mg; prepared in reference example 3) in a mixture of acetic acid-water (5:1; 12 ml) was added steel powder (768 mg) and the mixture was added for 20 minutes at 80° C. The suspension was poured into ice-water and was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried, and was concentrated. The residue was purified by column chromatography on silica gel to give the title compound (363 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: ClCCN1CCCC1
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=597.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OO.C(OCC)(=O)C.CCCCCC.[ClH:24]>>[NH2:1][C:2]1[C:3]([Cl:24])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccncc1N
Reactant: Cl
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccnc(Cl)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a magnetically stirred mixture of 3-Amino-4-methoxypyridine (4.45 g, 35.89 mmole) in 12N HCl (25 mL) cooled in an ice bath was added hydrogen peroxide (5.3 g, 46.65 mmol, 30% solution). The reaction was allowed to slowly warm to room temperature and stirred for 1 h. TLC (50% ethyl acetate/hexane) indicated complete consumption of starting material. The reaction mixture was slowly poured into saturated sodium bicarbonate solution (400 mL) to neutralize the reaction and extracted with ethyl acetate. The resulting organic layers were washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration gave 3-Amino-2-chloro-4 methoxypyridine (4.56 g, 28.77 mmol, 80% yield) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([Cl:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[Cl:25])=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)c(Cl)c2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2Cl)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (2′-chloro-4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][C:20](C2C=CC=CC=2)(C2C=CC=CC=2)[C:21]2[CH:26]=CC=CC=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].N1C=CC=CC=1.BrCCC(Br)=[O:49]>CCOCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:19][C:20](=[O:49])[C@H:21]([CH3:26])[O:15][C@:5](/[CH:10]=[CH:11]/[CH:12]3[CH2:14][CH2:13]3)([C:6]([F:9])([F:8])[F:7])[C:4]=2[CH:3]=1
Reactant: OC(C#CC1CC1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Reactant: O=C(Br)CCBr
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred ice-cooled solition of 291 mg of trans-6-Amino-3-chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part C.) in 13 mL of dry ether was added 0.180 mL of dry pyridine and 0.120 mL of bromopropionyl bromide. After 1 h, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 40 mg of 100% sodium hydride. After 15 min the cooliing bath was removed and stirring was continued at ambient temperature for 20 h. The reaction was poured onto aqueous ammonium chloride and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residie was dissolved in a small amount of ethyl acetate, and addition of hexane resulted in the crystallization of 40 mg of the title compound as colorless crystals: mp 171-172°; HRMS: Calcd. for C16H16NO2ClF3 (M+H)+ : 346.082166. Found: 346.080681. A second crop of slightly less pure product weighed 41 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, light brown solid (0.47 g, 73%), MS (ISP) m/z=298.4 [(M+H)+], mp 176° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-cyano-phenylboronic acid (0.36 g, 2.38 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([NH:14][NH2:15])=[O:13].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O>>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]2[O:13][C:12]([C:7]3[S:8][C:9]([CH3:11])=[C:10]4[C:6]=3[CH2:5][C@H:4]3[C:2]([CH3:16])([CH3:1])[C@H:3]34)=[N:14][N:15]=2)[CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: Cc1sc(C(=O)NN)c2c1C1C(C2)C1(C)C
Product: Cc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(Cl)n1

Procedure:
2-Chloro-6-methyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine is synthesized from 1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid hydrazide and 2-chloro-6-methyl-isonicotinic acid in analogy to Example 5; LC-MS: tR=1.17 min, [M+1]=374.22.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]([CH2:23][C:24]1[CH:50]=[CH:49][C:27]([O:28][CH2:29][C@H:30]([NH:32][CH2:33][C@H:34]([O:41][Si](C(C)(C)C)(C)C)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:31])=[CH:26][CH:25]=1)=[O:22]>O1CCCC1.O>[CH3:19][O:20][C:21]([CH2:23][C:24]1[CH:50]=[CH:49][C:27]([O:28][CH2:29][C@H:30]([NH:32][CH2:33][C@@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[OH:41])[CH3:31])=[CH:26][CH:25]=1)=[O:22]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
870 mg of tetrabutylammonium fluoride were added to a solution of 510 mg of N-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(R)-t-butyldimethylsilyloxy-2-phenylethanamine (prepared as described in Preparation 29) in 15 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was diluted with water, and the aqueous mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 0.23 g of the title compound as crystals, melting at 69°-70° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:16][C:17]([C:19]2([NH:34]C(=O)OC(C)(C)C)[CH2:24][CH2:23][N:22]([C:25]3[C:26]4[CH:33]=[CH:32][NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:34][C:19]1([C:17]([NH:16][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])=[O:18])[CH2:20][CH2:21][N:22]([C:25]2[C:26]3[CH:33]=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC1(C(=O)NC(CCS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 22 °C
Reaction time: 20 h
Yield: 81.3 %

Procedure:
Hydrogen chloride (4M in dioxane, 0.676 mL, 2.70 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-sulfamoylpropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 105) (16 mg, 0.03 mmol) in a mixture of DCM (5 mL) and methanol (5 mL) at 22° C. The resulting solution was stirred at 22° C. for 20 hours. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-sulfamoylpropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (12.00 mg, 90%) as a colourless gum.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH:25]=O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH:25]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (3.23 g) was suspended in 400 ml of toluene to which morpholine (2.8 g) and 2,6-dichlorobenzaldehyde (3.5 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.7 g of aldehyde was added. Reflux was continued for an additional sixteen (16) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/hexane to give 2.18 g of analytically pure product, m.p. 200°-202° C.
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([C:12]([CH2:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][CH:14]([C:12](=[O:13])[C:11]1[CH:22]=[CH:23][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:15][C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17]
Reactant: BrBr
Reactant: CC(C)OC(=O)CCC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)CC(Br)C(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
6.24 g of isopropyl 3-(4-phenoxybenzoyl)propionate were dissolved in 50 ml of chloroform. After a catalytic amount of anhydrous aluminum chloride was added, a solution of 3.62 g of bromine in 20 ml of chloroform was added dropwise over 30 minutes. The reaction mixture was washed with water, then dried over magnesium sulfate. The chloroform was removed by evaporation under reduced pressure to give oily isopropyl 3-bromo-3-(4-phenoxybenzoyl)propionate, which was dissolved, without purification, in 50 ml of dimethylformamide. 3.02 g of potassium acetate were added under ice-cooling, and the mixture was stirred for 30 minutes. Diethyl ether was added to the reaction mixture, which was then washed with water and dried over magnesium sulfate. The diethyl ether was distilled off under reduced pressure and the residue was recrystallized from a mixture of hexane and diethyl ether to give 5.83 g of isopropyl 3-(4-phenoxybenzoyl)acrylate.