Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].CC([O-])(C)C.[K+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1F.[Cl-].[Na+]>O.C1(C)C=CC=CC=1.CS(C)=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: Fc1cc(F)c(F)cc1F
Reactant: OCCCO
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: OCCCOc1cc(F)c(F)cc1F
Reaction time: 18 h

Procedure:
To a mixture of 1,3-propanediol (15 g, 0.20 mol) and t-BuOK (8.0 g, 0.071 mol) were added 1,2,4,5-tetrafluorobenzene (5.0 g, 33 mol) and DMSO (50 g) at 60° C. After being stirred at this temperature for 18 h, toluene (200 mL), water (50 mL) and sodium chloride (10 g) were added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo to the title compound that was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:9]2[C:10]([CH3:20])=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:7][N:8]=1.C1C(=O)N([Cl:28])C(=O)C1>C(Cl)(Cl)Cl>[Cl:28][C:7]1[N:8]=[C:4]([CH2:3][O:2][CH3:1])[NH:5][C:6]=1[C:9]1[C:10]([CH3:20])=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1ncc(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Solvent: ClC(Cl)Cl
Product: COCc1nc(Cl)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 5-(2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 230.5, 70 mg, 0.26 mmol) in chloroform (6 mL). NCS (35 mg, 0.26 mmol) was added to the reaction. The reaction mixture was stirred overnight at room temperature, then quenched with 1 mL of water. The aqueous phase was extracted with 2×5 mL of dichloromethane and the combined organic layers were concentrated under reduced pressure. The residue was applied onto a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to yield 30 mg (38%) of the title compound as a white crude solid.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:52]=[CH:51][C:16]2[N:17]([CH2:21][C:22]([O:24][C@H:25]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]4[CH2:50][CH2:49]4)[CH:37]=3)[CH2:26][C:27]3[C:32]([Cl:33])=[CH:31][N+:30]([O-:34])=[CH:29][C:28]=3[Cl:35])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl.C1COCC1>C(Cl)Cl>[Cl:33][C:32]1[CH:31]=[N+:30]([O-:34])[CH:29]=[C:28]([Cl:35])[C:27]=1[CH2:26][C@@H:25]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:24][C:22](=[O:23])[CH2:21][N:17]1[C:16]2[CH:51]=[CH:52][C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:14][C:15]=2[O:19][C:18]1=[O:20]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
To a solution of (S)-4-(2-(2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.200 g, 0.254 mmol) in DCM (10 ml) cooled to 0° C., HCl 4M in THF (0.634 ml, 2.54 mmol) was added, and the mixture was warmed to room temperature and stirred for 48 hours. A white solid precipitated. The precipitate was collected by filtration and washed with DCM affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)ethyl)pyridine 1-oxide (0.140 g, 0.203 mmol, 80% yield). MS/ESI+ 688.1 [MH]+; [αD]=−31.04, c=0.46, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.66 (br. s., 1H), 8.43 (s, 2H), 7.25 (d, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 7.08 (d, 1H), 7.05 (dd, 1H), 6.96 (dd, 1H), 7.07 (t, 1H), 6.04 (dd, 1H), 4.82 (d, 1H), 4.70 (d, 1H), 3.92 (d, 2H), 3.40 (dd, 1H), 3.22 (dd, 1H), 2.99 (s, 3H), 1.07-1.41 (m, 1H), 0.48-0.70 (m, 2H), 0.25-0.44 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a 0° C. solution of 1-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethanone (3.0 g, 0.01 mol) in acetonitrile (60 mL) under an inert atmosphere was added potassium carbonate (3.4 g, 0.02 mol) followed by benzyl chloride (1.8 mL, 0.014 mol). The reaction mixture was brought to 80° C. and stirred for 2 h. The reaction was quenched with cold water, filtered and the filtrate was extracted with DCM (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 1-(4-(benzyloxy)phenyl)-2-(4-methoxyphenyl)ethanone (1.0 g, 24%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:29]#[C:28][C:30]2[N:31]=[C:32]([CH3:42])[N:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:34]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodopyridine (1.39 g, 5.8 mmol) was dissolved in 50 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (39 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) chloride (170 mg, 0.24 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper (I) iodide (28 mg, 0.15 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (970 mg, 4.84 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/triethyl amine 1:0:0->10:10:1 gradient) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545 mg, 36%), MS: m/e=312.1 (M+H+).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([OH:24])[CH:12]=[C:13]([Cl:23])[C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:12]=[C:13]([Cl:23])[C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.5 %

Procedure:
To a mixture of 1.028 g (2.65 mmol) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenol, 0.600 g (4.00 mmol) of t-butyldimethylsilyl chloride, and 0.048 g (0.40 mmol) of 4-dimethylaminopyridine in 10 mL of dichloromethane under argon at 25° C. was added 1.30 mL (9.26 mmol) of triethylamine. After stirring at 25° C. for 10 h, the mixture was diluted with 30 mL of water and extracted three times with diethyl ether (50 mL each). The combined extracts were washed with 30 mL of brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and diethyl ether as eluent to give 1.100 g (83% yield) of 14. 1H NMR (CDCl3) d 6.49 (d, J=2.8 Hz, 1H, Ar, C4-H), 6.30 (d, J=2.8 Hz, 1H, C6-H), 1.04˜0.97 (broad s, 27H, t-Bu), 0.18 (s, 6H, Me), 0.175 (s, 12H, Me); 13C NMR (CDCl3) d 149.3 (s), 148.6 (s), 138.6 (s), 126.8 (s), 114.6 (d), 112.1 (d), 26.3 (q, t-Bu), 25.9 (q, t-Bu), 18.9 (s), 8.8 (s), −3.5 (q, 2C, Me), −3.4 (q, 2C, Me), −4.3 (q, 2C, Me). Anal. Calcd for C24H47ClO3Si3: C, 57.27; H, 9.41. Found: C, 57.37; H, 9.55.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[N:28]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([F:39])[CH:33]=2)[CH:29]=[CH:30][N:31]=1)[CH3:25].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:25][N:24]([CH2:26][C:27]1[N:28]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[C:34]([F:39])[CH:33]=2)[CH:29]=[CH:30][N:31]=1)[CH3:23]
Reactant: CN(C)Cc1nccn1-c1ccc(N)c(F)c1
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)Cc1nccn1-c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 55, 62 mg, 0.19 mmol) and 4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluorophenylamine (45 mg, 0.19 mmol) in pyridine (3 mL) cooled in an ice-bath, POCl3 (0.035 mL, 0.38 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (19 mg). MS 539.1 and 541.1 (M+H, Cl pattern).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.[Cu]Br.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][N:19]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[C:16]2=[N:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu+2]
Agent: [Cu]Br
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-n2ccc3cc(Br)cnc32)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
1-Iodo-4-(trifluoromethyl)benzene (1.657 g, 6.09 mmol) was added to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.08 mmol) and Copper(I) bromide (0.073 g, 0.508 mmol) in DMF (10 mL) followed by potassium carbonate (1.75 g, 12.69 mmol), and the mixture was stirred at 100° C. for 10 min. NaOH (150 mg, 3.75 mmol) and copper(II) acetate (4.61 mg, 0.025 mmol) were added to the reaction mixture at 110° C., and the mixture was stirred for 16 h. Insoluble solids were filtered off, and the filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 10% ethyl acetate in pet ether to afford title compound (0.4 g, 22%) as a off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.4 (d, J=2.0 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.56 (d, J=4.0 Hz, 1H), 6.63 (d, J=3.6 Hz, 1H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(Cl)(Cl)Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1(O)[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1.O>C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([F:7])[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2Cl)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC(F)(c2ccccc2Cl)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 5.26 mL of diethylaminosulfur trifluoride was added to chloroform (160 mL) solution of 5.51 g of benzyl 4-(2-chlorophenyl)-4-hydroxypiperidine-1-carboxylate at −78° C., and stirred for 1 hour at −78° C. Water was added to the reaction liquid, and extracted with chloroform. The chloroform layer was dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was dissolved in 150 mL of acetone/water (2:1) mixture. 15.9 mL of aqueous 0.05 M osmium tetroxide solution and 3.73 g of N-methylmorpholine N-oxide were added thereto, and stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 2.11 g of the entitled compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.C(OP(OCC)OCC)C.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1
Agent: CCOP(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Brc1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Yield: 47.1 %

Procedure:
4′-bromo-2-nitrobiphenyl (9.8 g, 35.4 mmol) was refluxed with 30 mL triethylphosphite overnight. After cooling down the solution to room temperature, 40 mL 6(N)HCl was added to it slowly and heated to 80° C. for 3 h. Acidic solution was halfway neutralized with conc. NaOH, rest of the acidic solution was neutralized with solid Na2CO3. Cloudy solution was extracted three times with ethylacetate (500 mL). Combined organic layer was evaporated under vacuum and crude was flashed on silica gel (15% to 30% ethylacetate/hexane). 4.1 g final compound was isolated as off white solid.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]([NH:19][NH2:20])=[O:18])[C:13]=1[CH2:14][CH3:15]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]2[O:18][C:2]([NH2:1])=[N:20][N:19]=2)[C:13]=1[CH2:14][CH3:15]
Reactant: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: N#CBr
Solvent: CCO
Product: CCc1nn(Cc2nnc(N)o2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 44.2 %

Procedure:
Cyanogen bromide (49 mg, 0.462 mmol) was added to a stirred solution of the hydrazide of Example 11 (150 mg, 0.420 mmol) in ethanol (30 ml), at room temperature, under nitrogen and the resulting solution was heated to reflux for 2.5 hours. After cooling, the mixture was concentrated under reduced pressure to leave a brown oil. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:1.75:0.25, by volume) to provide the title compound (71 mg) as a white powder, m.p. 226-228° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](Cl)=[O:17])=[N:14][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.C(Cl)Cl.O1CCOCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:17][C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)=[N:14][CH:15]=1
Reactant: Nc1ccccc1Br
Reactant: O=C(Cl)c1ccc(Br)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Brc1ccc(-c2nc3ccccc3o2)nc1
Temperature: 120 °C
Yield: 29.8 %

Procedure:
A mixture of 2-bromoaniline (3.90 g, 22.7 mmol), 5-bromopyridine-2-carbonyl chloride (5.00 g, 22.7 mmol), Cs2CO3 (14.78 g, 45.36 mmol), 1,10-phenanthroline (0.409 g, 2.27 mmol), CuI (0.216 g, 1.13 mmol) and anhydrous 1,4-dioxane (40 mL) was degassed with argon for about 40 min while stirring. The stirring reaction mixture was then maintained under argon at about 120° C. for about 40 h. Upon completion, the reaction was cooled to RT and poured over CH2Cl2 (300 mL). The organics were then washed with sat. NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 4:1 dichloromethane-hexanes) and subsequent recrystallization from hexanes afforded compound 11 (1.86 g, 30% yield) as colorless fibers.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>CCCCCC>[C:1]([C:5]1[O:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:19])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)O)o1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C2CC2C(=O)Cl)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of 2-(5-t-butylfuran-2-yl)-cyclopropanecarboxylic acid (3.6 g, 0.017 mol) and oxalyl chloride (4.4 g, 0.035 mol) in hexane (40 ml) was stirred at room temperature for 2 hours and then warmed at 60° C. for 3 hours. The hexane and excess oxalyl chloride were removed in vacuo to give 2-(5-t-butylfuran-2-yl)-cyclopropanecarbonyl chloride (3.9 g, 100%) as a pale yellow liquid which was used in the next stage without further purification.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1.Cl.[CH:30]1([C:33]2([F:37])[CH2:36][NH:35][CH2:34]2)[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11]([N:35]3[CH2:36][C:33]([CH:30]4[CH2:32][CH2:31]4)([F:37])[CH2:34]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Nc3ncns3)cc(N3CC(F)(C4CC4)C3)n2)cc1
Yield: 20.6 %

Procedure:
To a microwave tube was added N-(4-(4-(1,2,4-thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)-3,3,3-trifluoropropanamide (100 mg, 0.25 mmol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (100 mg, 0.7 mmol), DIPEA (0.1 ml) and dioxane. The mixture was microwaved at 130 C for 20 mins, partitioned between ethylacetate and bicarbonate and organic layer concentrated to an oil. The product was purified by HPLC to afford the product as a white solid (27 mg, 20%) 1H NMR d6 DMSO 0.42-0.48 (2H, m), 0.6-0.63 (2H, m), 1.38-1.43 (1H, m), 3.55-3.65 (2H, m), 3.8-4.0 (4H, m), 5.65 (1H,s), 7.65 (2H, d), 7.75 (2H, d), 8.2 (1H,s), 10.7 (1H,s), 12.1 (1H,s); MS ESI+ve 526 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15](Br)=[CH:14][C:13]=1[CH3:20])([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl>CN(C)C=O.O>[N+:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[CH:14][C:13]=1[CH3:20])([O-:11])=[O:10]
Reactant: Oc1cccc(S)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 18.9 g of 3-mercaptophenol (0.150 moles), 32.9 g of 2-nitro-5-bromo-p-xylene (0.143 moles) and K2CO3 (0.143 moles) in 95 ml of N,N-dimethylformamide is stirred at room temperature for 2 hours. A solution of HCl at 10% is added under stirring; the mixture is diluted with H2O and extracted with ethyl acetate. The organic phase is washed again with water, anhydrified on sodium sulfate, filtered and evaporated. 20 g of solid product are obtained, which is used as such for the subsequent reaction.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].Cl.[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[CH2:1]([NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)C1CCC(CN)CC1)C2
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNCC1CCC(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydro-chloride from Example E10.2 (1.88 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=396.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[NH2:43][C:44]1[CH:56]=[C:55]([CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][C:45]=1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:43][C:44]1[CH:56]=[C:55]([CH2:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:54]=[CH:53][C:45]=1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Fc1ccccc1I
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccccc1F
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To 1-fluoro-2-iodobenzene 0.11 g were added 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 0.90 mg, tert-butyl 2-amino-4-phenethylbenzoate 59 mg, cesium carbonate 0.13 g and toluene 1.0 mL at room temperature, and it was heated and refluxed for 9 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=200:1] to give tert-butyl 2-(2-fluoroanilino)-4-phenethylbenzoate 62 mg of a colorless oil.