Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[O:21][CH3:22])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(P([Ni-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH3:22][O:21][C:11]1[CH:12]=[CH:13][C:14]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1Cl
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Ni-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 51.1 %

Procedure:
To a 250mL 3 neck round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were charged 98.1 mL of tetrahydrofuran, 3.27 grams (9.83 mmoles) of the 2-chloro-3-(2-methoxy-5trifluoromethoxybenzylamino) pyridine and 1.93 grams (2.95 mmoles) of bis(triphenylphosphino)nickel(II) chloride. The black reaction mixture was stirred at 25 degree celsius for 40 minutes. Phenylmagnesium bromide (1M/THF, 38.4 mL, 38.4 mmoles) was added over a 25 minute period and the resulting black slurry was stirred for 2 hours at 25 degree celsius. During this time, the reaction was monitored by thin layer chromatography assay. The reaction mixture was cooled to 4° C., and quenched with 5.89 mL acetic acid. The reaction mixture was vacuum concentrated to a low volume and partitioned between 100 mL each of toluene and water. The organic layer was washed several times with water and concentrated to an oil. The oil was purifid by column chromatography to yield 1.88 grams (51.1%) of the desired material (as an oil). The structure of this compound was assigned on the basis of high resolution NMR. 1H NMR (CDCl3) 8.05 (d, 1H), 7.63 (d, 2H), 7.45 (m, 3H), 7.12 (bs, 1H), 7.08 (m, 2H), 6.93 (dd, 1H), 6.85 (d, 1H), 4.71 (t, 1H), 4.26 (d, 2H), 3.78 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[F:21].O.[OH-].[Li+]>CO.C1COCC1.O>[F:21][C:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][C:4]=1[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Nc2ccccc2)c(C(=O)OC)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1F
Temperature: 75 °C

Procedure:
A mixture of 174C (30.0 g, 9.89 mmol) and lithium hydroxide monohydrate (12.5 g, 29.7 mmol) in MeOH (200 mL), THF (200 mL) and water (100 mL) was heated at 75° C. for 0.5 h. HPLC indicated that the reaction was complete. The organic solvents were removed under reduced pressure, and the aqueous residue was diluted with water. The pH was adjusted to 3.0 with 6N aqueous hydrochloric acid which resulted in a precipitate. The solid was collected by vacuum filtration and dried under reduced pressure to provide a quantitative yeild of compound 174D as an orange-yellow solid. HPLC retention time=3.02 min. (Condition B). 1H-NMR (400 MHz, DMSO) δ7.11 (m, 1H), 7.25 (m, 2H), 7.39 (m, 2H), 7.60 (m, 1H), 7.68 (m, 1H), 9.32 (br s, 1H), and 13.55 (br s, 2H).
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:21].[CH3:22][C:23]1[C:28]([OH:29])=[C:27]([CH:30]=O)[C:26]([CH2:32][OH:33])=[CH:25][N:24]=1.Cl.[OH-].[NH4+:36]>CS(C)=O>[C:1]1([C:7]2[N:21]=[C:30]([C:27]3[C:26]([CH2:32][OH:33])=[CH:25][N:24]=[C:23]([CH3:22])[C:28]=3[OH:29])[NH:36][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ncc(CO)c(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c1O
Temperature: 100 °C
Reaction time: 1.67 h

Procedure:
Benzil (2.10 g, 10 mmol), ammonium acetate (11.5 g, 150 mmol) were dissolved in DMSO (60 mL) and heated to 100° C. Pyridoxal hydrochloride (4.1 g, 20 mmol) in DMSO (50 mL) was added drop wise and after 100 min stirring at 100° C. the reaction mixture was poured into icewater (300 mL) and aq. ammonium hydroxide solution (50 mL). The precipitate was filtered off, washed with water (100 mL), dissolved in ethyl acetate (150 mL) and extracted with water (2×50 mL). The organic layer was dried over MgSO4 (10 g) and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with toluene/acetone 7/3. Fractions containing product were evaporated to a volume of 50 mL and cooled to 0° C. The precipitate was filtered off and dried to give (250 mg) the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=[O:40])[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:20]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(O)(C)(C)C>[C:30]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=[C:28]([C:27]2[C:26](=[O:40])[C:25]([C:21]3[CH:20]=[C:19]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:24]=[CH:23][CH:22]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH:29]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: O=C(Cc1cccc(-c2ccccc2)c1)Cc1cccc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1C(c2cccc(-c3ccccc3)c2)=C(c2ccc(Br)cc2)C(c2ccc(Br)cc2)=C1c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a degassed solution of 2.84 g of 4,4′-dibromobenzil (7.73 mmol) and 2.80 g of 1,3-di(biphenyl-3-yl)propan-2-one (7, 7.73 mmol) in 30 ml of tert-butanol was added, at 80° C., a methanolic tetrabutylammonium hydroxide solution (1 M, 2.84 ml, 2.84 mmol). The reaction solution was stirred at 80° C. for 20 minutes and then stopped by adding water. Extraction was effected three times with dichloromethane, and the collected organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate before the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: hexane with 20% DCM) and gave 2.85 g of the tetraarylcyclopentadienone 8a as a violet wax (53%, 4.10 mmol). Elemental analysis measured: C 70.5; H 3.3% (calculated for C41H26Br2O: C, 70.9; H, 3.8%); 1H NMR (700 MHz, d8-THF) δ=7.51-7.49 (m, 4H, CH), 7.49-7.46 (m, 4H, CH), 7.41 (dd, J=8.2, 1.1 Hz, 4H, CH), 7.36 (t, J=7.8 Hz, 4H, CH), 7.32 (t, J=8.0 Hz, 2H, CH), 7.29-7.25 (m, 2H, CH), 7.25-7.22 (m, 2H, CH), 7.01-6.99 (m, 4H, CH); 13C NMR (175 MHz, d8-THF) δ=154.28, 141.92, 141.83, 133.58, 132.72, 132.34, 132.30, 132.12, 129.99, 129.89, 129.71, 129.53, 128.26, 127.80, 127.21, 126.74, 123.92; MS (FD, 8 kV): m/z (%): 693.8 (100) [M+] (calculated for C41H26Br2O: 694.0); Rf (hexane with 6% ethyl acetate)=0.47.
Reaction SMILES: O.O.[Na].[Na].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1)(O)=[O:6].[NH3:25]>S(Cl)(Cl)=O>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1)(=[O:6])[NH2:25]
Reactant: N
Reactant: O=C(O)c1ccc(-c2ccc3[nH]c(=O)ccc3c2)cc1
Agent: [Na]
Solvent: O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(-c2ccc3[nH]c(=O)ccc3c2)cc1

Procedure:
A suspension of 6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt dihydrate (0.5 g) (see Example 13B) in thionyl chloride (10 cm3) was heated under reflux for 10 minutes. The cooled solution was evaporated in vacuo to afford a yellow solid which was treated without purification with aqueous ammonia solution (5 cm3, S.G. 0.88) with stirring. The solid material was filtered off and warmed with chloroform:methanol, 4:1, to remove soluble impurities and the remaining solid was filtered to afford the title compound, m.p. >320°, (0.3 g).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:11](Br)[C:12]#[CH:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:13]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[C:12]#[CH:11]
Reactant: O=C1NCc2ccccc21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCN1Cc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To 2,3-dihydro-isoindol-1-one (250.0 mg, 1.85 mmol) in acetonitrile (9 mL) was added propargyl bromide (308.6 uL, 2.77 mmol) and cesium carbonate (2.4 g, 7.39 mmol) and the mixture was allowed to stir at 80° C. for two hours. An aqueous workup was done to provide the title compound (303.3 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Br)cc1
Yield: 84.8 %

Procedure:
Using 3.86 g of (4-bromobenzyl)malononitrile, 25 ml of N,N-dimethylformamide, 0.72 g of sodium hydride (60% in oil), and 3.20 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 4.61 g of 2-(4-bromobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (9)).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:20])C>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:20])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 80 °C
Yield: 66 %

Procedure:
4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9 mmol) was heated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15 mL). The resulting black solution was concentrated to a volume of 15 mL, and the solid was filtered off, rinsed with CH2Cl2 and dried under vacuum to provide the title compound (1.26 g, 66%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 7.80-7.74 (br m, 5H), 6.85-6.66 (br m, 2H).
Reaction SMILES: [N+](=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[O:5][CH2:4]1)=[N-].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][CH:3]([O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]2=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Reactant: Oc1ccccc1
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1c2cc(OCc3ccccc3)ccc2OCC1Oc1ccccc1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
A solution of 17 g of 3-diazo-6-benzyloxy-4-chromanone and 17 g of phenol in 100 ml of toluene was heated to 110° C. in an oil bath. Rhodium (II) acetate dimer (50 mg) was added in one portion. After nitrogen evolution ceased (5 minutes), the reaction was allowed to cool to room temperature, diluted with ethyl acetate and washed with 10% sodium hydroxide to remove excess phenol. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel elutinq with dichloromethane to give 2.6 g of product, m.p. 100-102° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li][CH2:15]CCC.C(O[B:24]([O:30][CH2:31][CH2:32][CH2:33]C)[O:25][CH2:26]CCC)CCC.CC(C)(CO)CO>C1COCC1>[CH3:15][C:32]1([CH3:33])[CH2:26][O:25][B:24]([C:12]2[S:11][CH:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:13]=2)[O:30][CH2:31]1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CCCCCCCCc1ccsc1
Reactant: [Li]CCCC
Agent: CC(C)(CO)CO
Solvent: C1CCOC1
Product: CCCCCCCCc1csc(B2OCC(C)(C)CO2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Under argon atmosphere, in a three necked flask 3 g (15.28 mmol, 1 eq.) of 3-octylthiophene are dissolved in 30 mL of THF. After having cooled the medium to −78° C., 12 mL (18.34 mmol, 1.2 eq., C=1.6 mol/L) of BuLi are added drop by drop. The reaction is stirred for 1 h at −50° C. Then 8 mL (30.56 mmol, 2 eq.) of tributylborate are added to the medium cooled beforehand to −78° C. The reaction remains under stirring for the following 2 h where the temperature rises to ambient temperature. The mixture is then hydrolysed with a 2 mol·L−1 HCl solution and extracted with 2×50 mL of ethyl ether. During the drying of the organic phase collected on Na2SO4, 4.8 g (45.84 mmol, 3 eq.) of 2,2-dimethyl-1,3-propanediol are added. After 45 min of stirring, the mixture is filtered and concentrated in a rotary evaporator. The purification is carried out on silica column with an eluent [hexane/Et2O: 9/1]. 3.40 g of a yellow oil (yield of 72.0%) are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)#N.[PH2]([O-])=[O:18].[Na+]>N1C=CC=CC=1.C(O)(=O)C.O.[Ni]>[CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=[O:18]
Reactant: N#Cc1ccc(CN2C(=O)CNC2=O)cc1
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(CN2C(=O)CNC2=O)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
The 3-(4-cyanobenzyl)hydantoin derivative obtained in step F (about 14 mmol) was dissolved in 360 ml of a mixture of pyridine/acetic acid/water (2/1/1), cooled to 0° C. and treated with 25.1 g of sodium hypophosphite (monohydrate) and 4.17 g of moist Raney nickel. After stirring at 60° C. for 6 h, the solvents were removed in vacuo and the residue was taken up in ethyl acetate. The solvent was washed with 10% strength citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. After filtration and concentration, the 3-(4-formylbenzyl)hydantoin derivative obtained was employed in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48]([C:50]1(Br)[CH2:53][CH2:52][CH2:51]1)=[O:49])[CH3:46]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:50]3([C:48]([O:47][CH2:45][CH3:46])=[O:49])[CH2:53][CH2:52][CH2:51]3)[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 1.5 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 1.8 g of cesium carbonate and 1.2 g of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 860 mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1.O.I([O-])(=O)(=O)=[O:30].[Na+]>CC(C)=O.CC(O)(C)C.[Os]>[Cl:1][C:2]1[C:7]([CH:8]=[O:30])=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1
Reactant: C=Cc1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Os]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1cc(C=O)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A suspension of 2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (210 mg, 0.557 mmol) in acetone (50 mL) was heated to give a cloudy solution. After cooling to RT, water (5 mL), osmium tertroxide (0.350 mL, 2.5 wt % in t-BuOH, 0.028 mmol) and sodium periodate (262 mg, 1.23 mmol) were added. This was stirred overnight. Additional water (20 mL) was added and the reaction was left stirring for 1 day. Most of the acetone was removed and the suspended solid was collected by filtration, washed with water, and air dried to leave 2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (188 mg) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.07 mmol) in CH2Cl2 (3 mL) was added triethylamine (22 mg, 0.22 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (16 mg, 0.11 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (40 mg, 100% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 3.40 (m, 1H), 1.71 (m, 2H), 0.91-0.85 (m, 2H).
Reaction SMILES: C[N:2](C(ON1N=[N:16][C:11]2C=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25](N(C(C)C)CC)(C)C.[F:34][CH:35]([F:60])[N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[C:45]1[CH:46]=[C:47]([N:51]2[CH2:56][CH2:55][CH:54]([C:57](O)=[O:58])[CH2:53][CH2:52]2)[CH:48]=[CH:49][CH:50]=1>ClCCl>[NH3:2].[F:34][CH:35]([F:60])[N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[C:45]1[CH:46]=[C:47]([N:51]2[CH2:52][CH2:53][CH:54]([C:57]([N:15]3[CH2:10][CH2:11][N:16]([CH3:25])[CH2:13][CH2:14]3)=[O:58])[CH2:55][CH2:56]2)[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)C1CCN(c2cccc(-c3nc4ccccc4n3C(F)F)c2)CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)C2CCN(c3cccc(-c4nc5ccccc5n4C(F)F)c3)CC2)CC1
Product: N
Temperature: 35 °C
Yield: 20.4 %

Procedure:
HATU (0.11 g, 0.30 mmol) and diisopropylethylamine (DIPEA) (0.09 mL, 0.54 mmol) were added to a suspension of 1-[3-(1-Difluoromethyl-1H-benzoimidazol-2-yl)-phenyl]piperidine-4-carboxylic acid (0.10 g, 0.27 mmol) in dichloromethane at room temperature. Reaction was heated at 35° C. overnight. Reaction was cooled to room temperature and washed with saturated Na2CO3 solution (2×4 mL) and with water (1×3 mL) The organic layer was concentrated under reduced pressure and crude was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from cyclohexane 1:AcOEt 1 to 100% AcOEt and finally with AcOEt: 2.0 N ammonia in methanol 5:1) to afford 0.025 g of the title compound (20%).
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=1[F:29].[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:33]2[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34]2)=[O:26])=[CH:22][C:21]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Reaction time: 2 h
Yield: 100.2 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (9.67 mmol, 5.76 mL, 50% solution in ethyl acetate) was added to a solution of 4-amino-3-fluorobenzoic acid (6.45 mmol, 1 g), tert-butyl piperazine-1-carboxylate (6.45 mmol, 1.2 g) and triethylamine (12.89 mmol, 1.74 mL) in dichloromethane (20 mL) and stirred for 2 hours. The reaction mixture was washed with sodium bicarbonate solution and concentrated under vacuum to give the title compound (2.09 g). MS (ESI) m/z 324.5 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:32][C:20]1[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[C:27]2[C:22]([C:21]=1[CH3:31])=[CH:23][C:24]([C:28](=[O:29])[NH:42][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH3:41])=[CH:25][CH:26]=2
Reactant: CCC(N)c1ccccc1
Reactant: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)NC(CC)c4ccccc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.