Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[Cl:8][C:9]1[C:18]([NH2:19])=[C:17]([NH:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[C:18]([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:17]([NH:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH:23]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (5.5 g, 45 mmol) was added dropwise to a solution of 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (15.00 g, 40.67 mmol) and triethylamine (8.5 mL, 61 mmol) in dichloromethane (200 mL) at 6° C. After the reaction was stirred for 30 minutes, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (1.01 g) was added. The stirring was continued, and over the course of five hours, a total of 13 g of ethoxyacetyl chloride was added. The work-up procedure described in Part A of Example 19 was followed to provide N-[2-chloro-4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)quinolin-3-yl]-2-ethoxyacetamide as an orange solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:19])[CH2:13][CH2:14][NH:15][CH:16]([CH3:18])[CH3:17].CCN(CC)CC>CC#N>[Br:1][C:2]1[C:3]([N:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][CH2:13][C:12]([NH:11][CH3:10])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CNC(=O)CCNC(C)C
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)CCN(c1nc(Cl)ncc1Br)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.83 g, 8.00 mmol), N-methyl-3-(propan-2-ylamino)propanamide (Intermediate 14, 1.16 g, 8.00 mmol) and Et3N (1.2 mL, 8.16 mmol) were combined in MeCN (50 mL) and shaken at ambient temperature for 3 days before the solvent was removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 2-10% MeOH to DCM) to afford the title compound (2.08 g, 78%) as a gum.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:4]=1.[H-].[Na+].[CH3:39]I.Cl>CN(C=O)C.O>[CH3:39][O:1][CH2:2][C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:4]=1
Reactant: CI
Reactant: CCOC(=O)CCCCCCn1cc(CO)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cn(CCCCCCC(=O)O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (Example 3)(50 mg, 0.103 mmol) in dry DMF (1 ml) under nitrogen was treated with NaH (60% in mineral oil) (4.53 mg, 0.113 mmol) and the resulting mixture was stirred at RT for 15 minutes. Methyl iodide (7.08 μl, 0.113 mmol) was added and stirring continued at RT overnight. The mixture was added to water (30 ml) and the pH was adjusted to pH1 by addition of 2M HCl. The aqueous was extracted with DCM (×3) and the combined organic portions were passed through a phase separating column and concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 0-50% EtOAc/iso-hexane. Further purification was carried out by dissolving the product in DCM (minimal) and loading onto a 20 cm×20 cm preparative TLC plate. The plate was run using a solvent system of 67% EtOAc in iso-hexane (300 ml) and the appropriate strip of silica was scrapped off the plate. The Si was suspended in 10% MeOH/DCM and sonicated. The suspension was filtered, rinsing the solid with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:29]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:4]=1)[CH3:9])=[N+:30]=[N-:31]
Reactant: CC(O)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A round bottom flask was charged with 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanol (8.5 g, 32.44 mmol) and toluene (100 mL). Diphenyl phosphoryl azide (8.4 mL, 38.93 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.8 mL, 38.93 mmol) were added at 0° C. and the mixture was stirred over night at room temperature. The volatiles were removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography to get the product (2.4 g, 28% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>N1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(Cl)CCCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-aminobenzoate (5 g) in pyridine (50 mL) was added 4-chlorobutanoyl chloride (3.6 mL) at 0° C., and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.03 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[NH2:26]/[C:27](/[CH3:35])=[CH:28]\[C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30]>C(O)C>[C:15]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:28]([C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30])=[C:27]([CH3:35])[NH:26][C:23]=1[CH3:24])(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCOC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)c1ccccc1
Solvent: CCO
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccccc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
250 mg (0.75 mmol) of 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-1-phenylbutane-1,3-dione are dissolved with 143 mg (1.0 mmol) of n-propyl 3-aminocrotonate in 5 ml of ethanol and heated under reflux under argon for 24 h. The reaction solution is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][N:19]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>CCOC(C)=O>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:3][C:2]=2[F:1])=[O:23])=[CH:20][N:19]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(-c2ccc(F)cc2F)cc1F
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccc(F)cc2F)cc1F)c1ccc(Cl)nc1

Procedure:
6-Chloro-N-(3,2′,4′-trifluoro-biphenyl-4-yl)-nicotinamide was prepared from 3,2′,4′-trifluoro-biphenyl-4-yl amine and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after a silica gel column chromatography with 0-30% EtOAc in hexanes. H1 NMR (300 MHz, chloroform-d) d ppm 6.91 (m, 2H), 7.15 (apparent t, J=8.1 Hz, 1H), 7.24-7.1 (m, 3H), 7.95 (dd, J=10.5 8.1 Hz, 2H), 8.69 (d, J=2.1 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[NH2:11])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[S:24](Cl)(Cl)=[O:25]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:9]=[C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][S:24]2=[O:25])=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=S1NC(c2c(F)cccc2Cl)=NN1c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in step-4 of Intermediate-1 using N′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbo hydrazonamide (step-3 of Intermediate-1, 0.100 g, 0.292 mmol), CHCl3 (10 mL), pyridine (2.0 mL) and thionyl chloride (1.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 0.5% MeOH:DCM to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.45 (t, J=6.9 Hz, 3H), 7.51-7.68 (m, 4H), 12.05 (br s, 1H); MS (m/z): 388.02 my.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=1.[F:16][C:17]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[CH:19][N:18]=1>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[C:22]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]2[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CCNc1ncccc1-c1sccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1sccc1-c1cccnc1F
Temperature: 75 °C
Yield: 31.2 %

Procedure:
A mixture of 3-bromo-2-(2-ethylaminopyridin-3-yl)thiophene (0.085 g), 2-fluoro-3-tributylstannylpyridine (0.26 g) and Pd(Ph3P)2Cl2 (0.014 g) in N-methylpyrrolidinone (2 mL) was heated at 75° C. under argon for 1 day. The mixture was diluted with ethyl acetate, washed, dried, filtered and evaporated. The residue was chromatographed to give 3-(2-fluoropyridin-3-yl)-2-(2-ethylaminopyridin-3-yl)thiophene (0.028 g). mp 86-89° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.[Br:18][C:19](Br)=[N:20][OH:21]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:21][N:20]=[C:19]([Br:18])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ON=C(Br)Br
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CC(Br)=NO1

Procedure:
To a solution of N-tert-butoxycarbonyl allyl amine, 20 gm, in 700 ml of ethyl acetate and containing 65 gm of NaHCO3 and 50 ml of water, was added portion-wise 80 gm of dibromoformaldoxime at room temperature with vigorous stirring. After completion of the reaction, the organic portion was washed with water (2×100 ml), 100 ml each of 5% NaHCO3, brine and dried over anh. MgSO4 and concentrated to give an oil. Purification by chromatography on silica gel gave the desired product as an oil which solidified on standing. IR(KBr): 3322, 2988, 1680, 1529 cm-1. 1H NMR (80 MHz, CDCl3): delta 1.45 (s, 9H, t-butyl), 2.8-3.5 (m, 4H, CH2CHO, CH2N), 4.6-5.1 (broad s, superimposed on a multiplet, 2H, NH, CHO).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[S:5])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([NH:18][C:19]2[N:28]=[CH:27][C:26]3[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][N:22]([CH:31]([CH3:33])[CH3:32])[C:21]=3[N:20]=2)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[S:5])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([NH:18][C:19]2[N:28]=[CH:27][C:26]3[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][N:22]([CH:31]([CH3:33])[CH3:32])[C:21]=3[N:20]=2)[CH:9]=1)[CH3:2]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(C(F)(F)F)c3)nc21
Reactant: CCOC(=S)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=S)Nc1cc(Nc2ncc3c(n2)N(C(C)C)CC(=O)N3C)cc(C(F)(F)F)c1
Yield: 68 %

Procedure:
Ethylchlorothioformate (0.754 ml; 7.230 mmol) was added dropwise to a cooled (0° C.) suspension of 2-(3-Amino-5-trifluoromethyl-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (2.5 g; 6.573 mmol) in 10 ml of dry Pyridine. The reaction mixture was allowed to reach room temperature and maintained at that temperature 2 h. Water was added to the reaction mixture and the precipitated formed was filtered washed with water and dried in vacuo. 2.1 g (4.48 mmol; 68% yield) of a yellow powder were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)=O)C.C1(C)C=CC=CC=1>ClCCl.CC(C[AlH]CC(C)C)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]=[O:3])=[N:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To 5-fluoro-pyridine-2-carboxylic acid ethyl ester (94 mg, 0.556 mmol) in dichloromethane (4.0 mL), 1 M DIBAL in toluene (1.23 mL, 1.23 mmol) was added at room temperature and the mixture was stirred for 30 min. The reaction mixture was quenched with 2 M sodium carbonate and extracted with dichloromethane. The dichloromethane was dried and concentrated to give 39 mg (54.7%) of crude 5-fluoro-pyridine-2-carbaldehyde which could be used for the next step reaction without further purification. GC-MS (M+): 125
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1[C:4]([OH:24])=[O:5]
Reactant: CC(C)=O
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde (4.5 g, 13.2 mmole) in 40 ml of acetone was added 13 ml (26 mmole) of Jones' reagent. The solution was stirred at ambient temperature for 2 hours and poured into 400 ml of water. The resulting solid was filtered and air dried overnight to afford 4.5 g (96%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluoro-benzoic acid as a white solid. An analytical sample was recrystallized from ether/hexanes; mp 179°-181° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH:11]([OH:13])[CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][C:15]1([CH3:39])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:25]3[CH2:31][C:30]4[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:29]=4[O:28][CH2:27][CH2:26]3)[C:17]=2[CH2:16]1>>[CH3:14][C:15]1([CH3:39])[CH2:24][CH2:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:25]3[CH2:31][C:30]4[CH:32]=[C:33]([C:2]5[CH:3]=[C:4]6[N:10]=[C:9]([CH:11]([OH:13])[CH3:12])[NH:8][C:5]6=[N:6][CH:7]=5)[CH:34]=[CH:35][C:29]=4[O:28][CH2:27][CH2:26]3)[C:17]=2[CH2:16]1
Reactant: CC(O)c1nc2cc(Br)cnc2[nH]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC(O)c1nc2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2[nH]1

Procedure:
Prepared according to the method of example 5 by using 1-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)ethanol (reagent preparation 19) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.56 (br, 1H), 8.34 (s, 1H), 8.11 (br, 1H), 7.61 (s, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 5.11 (m, 1H), 4.73 (s, 2H), 4.37 (m, 2H), 3.95 (m, 2H), 2.79 (t, 2H), 2.48 (s, 2H), 1.68 (t, 2H), 1.64 (d, 3H), 0.88 (s, 6H); MS (EI) for C27H30N6O2: 471 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: COC(=O)c1c(F)cccc1NC(=O)OC(C)C
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1cccc(F)c1C(=O)OC
Reaction time: 1 h
Yield: 68 %

Procedure:
Add a solution of 2-Isopropoxycarbonylamino-6-fluor-benzoic acid methyl ester (3.0 g, 11.76 mmol) in DMF (43 mL) to a suspension of sodium hydride 60% dispersion mineral oil (471 mg, 11.76 mmol) in DMF (43 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (2.5 mL, 17.64 mmol) and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the title compound (2.96, 68%). MS (ES+): 370 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].ClC1C=CC=C(C(OO)=[O:49])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28]([CH3:37])[C:29]([C:31]2[CH:32]=[CH:33][N+:34]([O-:49])=[CH:35][CH:36]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-methyl-carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide (Example G-17) (0.051 g, 0.073 mmole) in dichloromethane (0.44 ml) was added by small portions 3-chloroperbenzoic acid (purity 70%) (0.027 g, 0.11 mmole). After 2.5 hours stirring at 25° C., the yellow solution was quenched with aqueous sodium sulfite, diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate, then with brine. The organic solution was dried over sodium sulfate. The product (Compound G18 of Table G) was isolated after removal of the solvent, as a white powder (melting range: 105-194° C.) showing, by LC-MS analysis (method 6 described hereunder) a retention time of 0.99 min and a M+H+ peak of 716.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1)=[O:4].Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2[CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH3:29])=[C:7]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:15]2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-aminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (0.255 g, 0.62 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.149 g, 0.62 mmol), and DIPEA (0.32 mL, 1.87 mmol) in n-butanol (4 mL) was stirred in a sealed vial at 100° C. for 2 h, then at 90° C. for 16 h. After cooling to RT, volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording the title compound as a colourless gum (0.301 g, 79%). LCMS (Method J): RT 2.29 min [M+H]+ 611.
Reaction SMILES: [C:1](=[O:4])([O-])[NH2:2].N[C@H:6]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])=[C:11]([CH3:24])[N:10](CC2C(C(F)(F)F)=CC=CC=2F)[C:9]1=[O:37].C([O-])([O-])=O.[K+].[K+].C(=O)=O>O.CN(C=O)C>[F:23][C:16]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[C:13](=[O:14])[N:8]([CH2:7][C@H:6]([NH:2][C:1](=[O:4])[C:12]([CH3:15])([CH3:13])[CH3:11])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:9](=[O:37])[NH:10][C:11]=1[CH3:24]
Reactant: NC(=O)[O-]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(C)[nH]c(=O)n(C[C@H](NC(=O)C(C)(C)C)c3ccccc3)c2=O)c1F
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
DMF (anhydrous, 70 mL) was added to carbamate residue 3a (7.5 g, 19.7 mmol) and the mixture was cooled to 0° C. t-BOC-(1R)-amino-2-amino-1-phenylethane acetate salt (6.41 g, 21.6 mmol) was added followed by K2CO3 (4.08 g, 29.6 mmol). The mixture was stirred for ˜3 hours (all carbamate 3a (tR=11.5 minute in HPLC method 1) was converted to urea intermediate (tR=10.5 minute in HPLC method 1)). The temperature was raised to 60° C. to control the CO2 release. The mixture was heated for 2-3 hours then 210 mL of water was slowly added over 30-60 minutes maintaining the temperature at 60° C. The slurry was stirred for 30-60 minutes at 50-60° C. and was cooled down to 25° C. over 30-60 minutes. The slurry was filtered and the cake was washed with 210 mL water to remove the residual base. The cake was dried at 10 mm/50° C. to give 6.5 g (70% yield) of off-white fine needle crystal 3b. Alternately, the cake may be washed with acetonitrile/water 2:1 before drying.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:25]=[CH:24][C:10]2[S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Cl)=[CH:14][C:13]=3[C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>O1CCCC1>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:25]=[CH:24][C:10]3[S:11][C:12]4[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2sc3ccc(C(=O)CCCCl)cc3c2c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCCCC1)c1ccc2sc3ccc(C(=O)CCCN4CCCCC4)cc3c2c1
Temperature: 125 °C
Reaction time: 24 h

Procedure:
A mixture of 28.0 g (0.072 mole) of 2,8-bis(4-chlorobutyryl)dibenzothiophene, 49.4 g (0.58 mole) of piperidine and 2.0 g of potassium iodide in 200 ml of tetrahydrofuran is heated at 125°C with stirring for 24 hours in a Parr general purpose bomb. The reaction mixture is cooled, filtered, and the filtrate is evaporated in vacuo leaving a residue which is washed with water and recrystallized twice from acetone to give 2,8-bis(4-piperidinobutyryl)dibenzothiophene, M.P. 93°-95°C.