Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[N:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[N:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc(Oc3ccccc3)nn2)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(-c2ccc(Oc3ccccc3)nn2)cc1F
Temperature: 170 °C

Procedure:
A mixture of 3-(3-fluoro-4-methoxy-phenyl)-6-phenoxy-pyridazine (Step 1, 0.60 g, 2.0 mmol) and pyridine hydrochloride (3 g) was heated in an oil bath at 170° C. for 8 h. The sublimed pyridine hydrochloride on the top of the reaction flask was removed, and the residue (0.65 g) was used in the next step without further purification. MS (ESI pos. ion) m/z: 283.1 (M+H). Calc'd Exact Mass for C16H11FN2O2: 282.27.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].C(=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N>C([O-])(O)=O.[Na+].O>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: O=C([O-])O
Solvent: O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A suspension of (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester hydrochloride salt (500 mg, 1.43 mmol, Intermediate 3) in aqueous 10% NaHCO3 solution was extracted with DCM (3 times 10 ml). The organic phase was dried over Na2SO4 and evaporated. The resulting oil was dissolved in DCM (15 ml), treated with benzaldehyde (0.174 ml, 1.71 mmol) and NaBH(OAc)3 (455 mg, 2.14 mmol), and the resulting clear solution was stirred at RT for 2 h. Water was added to the mixture and the pH was adjusted to a basic pH value with NH3. The mixture was extracted with DCM (3 times 10 ml). The organic layer was dried, evaporated, and the crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 7:3) to give (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (490 mg) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[CH:4][N:3]=1.OP([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Cl:1][C:2]1[N:7]=[C:6](/[CH:18]=[CH:17]/[O:20][CH2:21][CH3:22])[C:5]([NH2:9])=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: Nc1cnc(Cl)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: O
Product: CCO/C=C/c1nc(Cl)ncc1N
Temperature: 80 °C
Yield: 12.32 %

Procedure:
A mixture of 2,4-dichloropyrimidin-5-amine (2.0 g, 12.2 mmol), product of Example 100G (6.04 g, 30.5 mmol), potassium phosphate dibasic (5.31 g, 30.5 mmol), palladium(II) acetate (0.027 g, 0.122 mmol) and dicyclohexyl-(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.050 g, 0.122 mmol) in acetonitrile (30 mL) and water (20 mL) under argon was refluxed at 80° C. for 16 h. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water (2×30 mL) and saturated aqueous brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by flash chromatography using 30% ethyl acetate in hexane to afford title compound (0.3 g, 12.32%) as an oil. 1H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.85 (d, J=11.7 Hz, 1H), 5.69 (d, J=11.7 Hz, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.49 (bs, 2H), 1.37 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23](Cl)[CH:22]=[CH:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([N+](CCCC)(CCCC)CCCC)CCC>O.C1(C)C=CC=CC=1>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:22]=[CH:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc2cc(OCc3ccccc3)ccc2n1
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(COc2ccc3nc(Oc4ccccc4)ccc3c2)cc1
Reaction time: 0.83 h

Procedure:
To a 50% (w/w) NaOH solution (10.2 ml) is added phenol (0.697 g). After 50 minutes at room temperature, toluene (10.21 ml) and 6-(benzyloxy)-2-chloroquinoline 12 (2 g) and tetrabutyl ammonium (2.062 g) are added. The solution is stirred under argon at reflux for 24 h. Water (5 ml) is added and the solution is extracted with toluene (3×10 ml). The organic phases are dried over MgSO4 and evaporated under vacuum. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 20/80 as eluent. The obtained solid is dissolved in AcOEt and pentane is added; 6-(benzyloxy)-2-phenoxyquinoline 13 precipitates as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH:16][C:17](=O)[CH3:18])=[C:4]([N+:20]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[N:16]=[C:17]([CH3:18])[NH:20][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.4 %

Procedure:
A mixture of N-{4-bromo-2-nitro-6-[(phenylmethyl)oxy]phenyl}acetamide (120 g, 329 mmol, STEP 1 in Example 1) and iron powder (55.1 g, 986 mmol) in acetic acid (500 mL) was refluxed with stirring for 6 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate (1.5 L). The resulted precipitates were filtered through a pad of Celite, and washed with ethyl acetate (500 mL). The filterate was concentrated in vacuum, and the residue was diluted with ethyl acetate (200 mL). The brine (800 mL) was added to the organic mixture, the resulted white precipitates were collected by filtration, and washed with water (200 mL) and diethyl ether (200 mL). The white solid was dissolved with dichloromethane/methanol (10:1, 1.0 L), dried over magnesium sulfate, and concentrated. The solid was triturated with diethyl ether (300 mL), collected by filtration, and dried in vacuum to afford the title compound as a white solid (54.7 g, 53%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1/[CH:6]=[N:7]/[S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9].[CH3:14][Mg]Br>ClCCl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH3:14]
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ncco1
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1ncco1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
In a round-bottomed flask, 2-methyl-propane-2-sulfinic acid 1-oxazol-2-yl-meth-(E)-ylideneamide (414 mg, 2.07 mmol) was dissolved in dichloromethane (7 ml). The reaction mixture was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether, 0.76 ml, 2.28 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 453 mg (96%) of 2-methyl-propane-2-sulfinic acid (1-oxazol-2-yl-ethyl)-amide as a yellow oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:15]=2[N:16]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>O1CCCC1>[CH3:9][C:10]([CH3:27])([CH3:28])[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]([F:39])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:15]=2[N:16]=1
Reactant: COC(=O)C(C)c1ccc2oc(CC(C)(C)C)nc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(F)c1ccc2oc(CC(C)(C)C)nc2c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethylbenzene/heptane, 4.55 ml, 0.009 mol) was added, dropwise, to a solution of methyl 2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propionate (2.5 g, 0.009 mol) in tetrahydrofran (65 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of N-fluorobenzensulfonimide (2.9 g. 0.009 mol) in tetrahydrofuran (15 ml) was added and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature, with stirring over 1½ hours. The mixture was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 1:99, to give methyl 2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]-2-fluoropropionate (2.06 g).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14])=[N:8][N:7]=1)(=[O:5])=[O:4].C(=O)(O[C:20]1[CH:25]=[CH:24]C=CC=1)N.Cl.C(NCC)C>>[CH3:15][N:13]([CH3:14])[C:12]([NH:11][C:9]1[S:10][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[CH2:24][CH2:25][CH3:20])=[N:7][N:8]=1)=[O:16]
Reactant: CNS(=O)(=O)c1nnc(NC(=O)N(C)C)s1
Reactant: NC(=O)Oc1ccccc1
Agent: Cl
Solvent: CCNCC
Product: CCCN(C)S(=O)(=O)c1nnc(NC(=O)N(C)C)s1

Procedure:
3-[5-(N-methylsulfamoyl)-1,3,4-thiadiazol-2-yl]-1,1-dimethylurea, from 4 g. of the carbamic acid, phenyl ester, above, and 3 g. of diethylamine hydrochloride. The product had a melting point of about 152°-153° C. and weighed 1.5 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:26])[N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:47])(=O)=O)=CC=1>O1CCCC1>[F:47][C:14]1([N:7]2[C:6](=[O:26])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[C:8]2=[O:13])[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25]
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl]-3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (2.0 g, 4.3 mmol) in tetrahydrofuran (20 mL) is added sodium bis(trimethylsilyl)amide (4.3 mL, 4.3 mmol, 1.0 M) in tetrahydrofuran at −78° C. After 10-30 minutes, N-fluorobenzenesulfonimide (1.1 g, 4.3 mmol) is added to the mixture. The mixture is warmed to room temperature and the solvent is removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and hydrochloric acid (10 mL, 1N) for 1 hour, the organic layer is separated, and the solvent is removed in vacuo to give 3-fluoro-3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br-].[Li+].[CH3:8][O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1.C(N(CC)CC)C>CC(C)=O.C1(C)C=CC=CC=1.ClCCl.CO>[CH3:8][O:9][C:10]1[C:3]([CH3:4])=[CH:2][N:12]2[C:11]=1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13]2
Reactant: COCc1ccc(C(=O)OC)cn1
Reactant: CC(=O)CCl
Agent: [Br-]
Agent: [Li+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(OC)c(C)cn2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.46 mL (0.0174 mol) of chloroacetone are added to 1.5 g (0.0174 mol) of lithium bromide in 10 mL of acetone and the medium is stirred at room temperature for 15 minutes and then 1.5 g (0.00828 mol) of methyl 6-(methoxymethyl)nicotinate are added and the medium is heated under reflux overnight. 1.5 g (0.0174 mol) of lithium bromide and 1.46 mL (0.0174 mol) of chloroacetone are added to the reaction medium and the medium is kept under reflux for 5 hours. The medium is evaporated to dryness and the residue obtained is taken up in a dichloromethane-methanol (9-1) mixture. The insoluble material obtained is filtered and then 4.62 mL (0.033 mol) of triethylamine are added to the filtrate and the medium is stirred at room temperature for one hour. The reaction medium is concentrated. The residue obtained is taken up in toluene and the product is purified by filtration on a silica bed, eluting with toluene. After evaporation, 450 mg of a yellow solid are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[C:7]([N:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH3:22][N:23]=[C:24]=[O:25].C(Cl)Cl>C(N(CC)CC)C>[CH3:22][NH:23][C:24](=[O:25])[O:11][C:10]1[C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:6][C:5]=2[C:7]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])=[CH:8][CH:9]=1
Reactant: CN=C=O
Reactant: CC1(C)Cc2c(N=Cc3ccccc3O)ccc(O)c2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Oc1ccc(N=Cc2ccccc2O)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 66 h
Yield: 92.9 %

Procedure:
To a 350 milliliter glass pressure bottle equipped with a magnetic stirrer was added 6.00 grams (0.021 moles) of 2,3-dihydro-2,2-dimethyl-4-(2-hydroxybenzylideneamino)benzofuran-7-ol prepared in part A, 1.4 grams (0.024 moles) of methyl isocyanate, 100 milliliters of methylene chloride and 0.1 milliliters of triethylamine. The resulting reaction mixture was stirred for 66 hours at room temperature and then concentrated under reduced pressure to give a yellow solid material. The yellow solid material was washed with hexane and dried to yield 6.64 grams (0.0195 moles) of 2,3-dihydro-2,2-dimethyl-4-(2-hydroxybenzylideneamino)benzofuran-7-yl methylcarbamate in the form of a yellow solid having a melting point of 201°-203° C. and the following structural formula: ##STR18##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:32]#[N:33])[CH2:23][C:22](=[O:34])[NH:21][C:9]=3[CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccc(F)c4)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K65) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (57 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)C>[CH:37]1([CH2:40][N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)[CH2:39][CH2:38]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(CC6CC6)CC5)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (20.0 mg, 0.0414 mmol) in 1,2-dichloroethane (2 mL) and ethanol (0.5 mL) was added cyclopropanecarboxaldehyde (4.6 μL, 0.062 mmol) and triethylamine (17 μL, 0.12 mmol). The suspension was stirred at r.t. for 1 h then sodium triacetoxyborohydride (18 mg, 0.083 mmol) was added. The reaction solution was stirred at r.t. overnight. The reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=538.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:57](O)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(Cl)Cl.O.C(OCC)(=O)C>[C:57]([NH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:8])(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
A mixture of (E)-tert-butyl 2-(6-aminohex-3-enamido)phenylcarbamate (100 mg, 0.3134 mmol), HATU (119.1 mg, 0.3134 mmol), DIEA (0.25 ml), benzoic acid (38 mg, 03134 mmol) in DCM was stirred at RT for 5 hours, The reaction mixture was poured onto 50 mL of ethyl acetate and 20 mL of water. The organic layers were washed with water (20 mL×3) and brine (3×20 mL), dried over Na2SO4 and concentrated to give the desired compound of (E)-tert-butyl 2-(6-benzamidohex-3-enamido)phenylcarbamate (86.16 mg, yield 65%) as a white solid after purification by column chromatography on silica gel (eluent: DCM:MeOH=200:1). LC-MS found 424 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CCO>[CH2:16]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: CCCCCCCCBr
Solvent: CCO
Product: CCCCCCCCSc1nnc(-c2ccc3[nH]cnc3c2)o1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and octylbromide (0.258 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:13]=O)[CH:8]=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH2:3][CH3:4])[CH3:2].[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[CH:1]([C:5]1[CH:12]=[C:9]([CH:10]=[O:11])[CH:8]=[C:7]2[C:6]=1[O:15][C:16](=[O:23])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(C=O)cc(C=O)c1O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C=O)cc(C(C)CC)c2oc1=O

Procedure:
A solution of 5-sec-butyl-4-hydroxyisophthalaldehyde of formula I (0.5 g, 2.42 mmol), diethyl malonate (0.38 g, 2.42 mmol) in ethanol (20 mL) was treated with piperidine (0.3 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with acetic acid. To this residue water (20 mL) was added and extracted 3-fold with 20 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides ethyl 8-sec-butyl-6-formyl-2-oxo-2H-chromene-3-carboxylate (General Formula II). (0.47 g, 65% yield). White solid, m. p. 89-90° C.; 1H NMR (CDCl3, 300 MHz): δ 10.05 (s, 1H), 8.60 (s, 1H), 8.05 (brs, 1H), 8.01 (brs, 1H) 4.44 (q, 2H, J=7.1 Hz), 3.51-3.40 (m, 1H), 1.78-1.69 (m, 2H), 1.43 (t, 3H, J=7.1 Hz), 1.33 (d, 3H, J=7 Hz), 0.88 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz): δ 190.2, 162.7, 156.5, 155.8, 148.5, 137.3, 132.9, 131.7, 129.9, 119.2, 118.0, 62.2, 33.4, 29.6, 20.4, 14.2, 12.0; ESI-MS (m/z): 303 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(O)c1CNc1cccn2c(C)c(C)nc12
Temperature: -73 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
8-(2-methoxy-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.14 g, 0.48 mmol) was solved in methylene chloride (9 ml) and the mixture was cooled to −73° C. Boron tribromide in methylene chloride (1M) (2.37 ml, 2.37 mmol) was added dropwise and the mixture was stirred for 20 h. in a nitrogen atmosphere and the temperature was allowed to raise to room temperature. The reaction mixture was cooled on ice and ice, water and methylene chloride were added. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure to give 0.077 g (57%) of the title compound
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:3]1=[O:33].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.Cl.C(OCC)(=O)C>C(#N)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)[N:12]=[CH:11][C:10]=2[F:35])=[C:5]([CH3:22])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:3]1=[O:33]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(-c2c(F)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a solution of 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 1) (1.0 g) in acetonitrile (20 ml) was added Selectfluor (trade mark) (1.2 g) and the resulting mixture was stirred at 80° C. for four hours. To the reaction mixture was added 10% hydrochloric acid followed by an addition of ethyl acetate (20 ml×2) such the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-fluoro-1H-pyrazol-1-yl)benzonitrile (238 mg). UPLC/MS 470 (M+H)/1.023 min. (measurement condition 9)