Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[CH2:11].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:19])[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH2:11][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(C)cc1
Reactant: c1c[nH]cn1
Solvent: CCO
Product: Cc1ccc(C(Cn2ccnc2)C(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)-2-(4-methylphenyl)propen-1-one (660 mg) and imidazole (770 mg) in ethanol (10 ml) were stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a gum. The gum was chromatographed on silica gel in methanol: dichloromethane (1:24) to yield 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-(4-methylphenyl)propan-1-one (450 mg) (Found: C, 78.25; H, 5.88; N, 9.53; C19H18N2O requires C, 78.62; H, 6.21; N, 9.66) which was treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-(4-methylphenyl)propan-1-one m.p. 92°-96° C. (Found: C, 54.79; H, 4.33; N, 6.59; C19H17Cl3N2O.H2O requires C, 55.16; H, 4.38; N, 6.77) having the formula: ##STR25##
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
2-Fluorobenzoyl chloride (10.5 g, 66.5 mmol) was added to a stirred solution of 4-piperidone hydrochloride (6.0 g, 60.5 mmol) and DIPEA (3.0 mL, 17.1 mmol) in DCM (150 mL). The mixture was stirred at room temperature for 2 hours and extracted with a 10% solution of citric acid, a saturated solution of Na2CO3 and H2O. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 1-(2-fluorobenzoyl)-4-piperidinone (5.5 g, 41% yield) that was used in the next step without further purification.
Reaction SMILES: Cl.[N:2]1([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:36][CH3:37])=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[C:20](Cl)[N:19]=1.C(N(CC)CC)C.C(OCC)C>C(O)CCC>[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:36][CH3:37])=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[C:20]([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)=[O:9])[CH2:11][CH2:12]2)[N:19]=1
Reactant: O=C(N1CCCNCC1)N1CCOCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OCc1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1OCc1ccccc1
Yield: 69.2 %

Procedure:
1-(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride (16 g, 0.075 mol) and 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline (15 g, 0.048 mol) were added to a solution of triethylamine (20 ml, 0.144 mol) in n-butanol (200 ml) and the reaction stirred at reflux for 1 hour. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (400 ml) and water (400 ml). The phases were separated and the organic layer dried (MgSO4), filtered and evaporated under reduced pressure to give a cream coloured solid. Trituration with diethyl ether gave the title compound as a solid (16.35 g, 70%). Rf 0.50 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 493 (MH)+. 1H-NMR (CDCl3): δ=2.03 (2H, m), 3.18 (4H, m), 3.34 (2H, t), 3.56 (2H, m), 3.65 (5H, m), 3.85 (2H, m), 4.00 (4H, m), 5.00 (1H, bs), 5.18 (2H, s), 6.87 (1H, bs), 7.37 (4H, m), 7.47 (3H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[NH2:22][C:17]1[N:18]=[C:19]([NH:21][C:31]2[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=2)[CH:20]=[C:15]([C:13]2[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=2[O:23][CH2:24][CH3:25])[CH:16]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(C=O)cc2)c1
Yield: 22 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-ethoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and 4-formyl-phenylboronic acid provided the title compound (22% yield). 1H NMR (acetone-d6) δ1.36 (t, 3H, J=6.9 Hz, CH3), 4.11 (q, 2H, J=7.0 Hz, CH2), 5.51 (bs, 2H, NH2), 6.33 (d, 1H, J=1.1 Hz, Ar), 6.44 (d, 1H, J=1.0 Hz, Ar), 7.12 (d, 1H, J=8.5 Hz, Ar), 7.31-7.37 (m, 2H, Ar), 7.78 (d, 2H, J=8.8 Hz, Ar), 7.88-7.97 (m, 2H, Ar), 8.57 (s, 1H, NH), 9.84 (s, 1H, CH).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]N3C(=O)CCC3=O)=O)=[CH:11][CH:10]=2)=[N:4][N:3]=1.[CH3:25][NH:26][CH3:27].CO.CNC>CO>[CH3:25][N:26]([CH3:27])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][S:7][C:5]2[S:6][C:2]([CH3:1])=[N:3][N:4]=2)=[CH:24][CH:23]=1
Reactant: Cc1nnc(SCc2ccc(C(=O)ON3C(=O)CCC3=O)cc2)s1
Reactant: CNC
Solvent: CO
Product: Cc1nnc(SCc2ccc(C(=O)N(C)C)cc2)s1

Procedure:
A slurry of 3.0 grams of 1-((4-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)benzoyl)oxy)-2,5-pyrrolidinedione (0.0083 mole) was treated with 50 ml of methanol saturated with dimethylamine. After the mixture of methanol-dimethylamine went into solution, the reaction mixture was concentrated and a viscous oil obtained. Crystals formed upon drying the viscous oil in vacuo. Further purification gave the product N,N-dimethyl-4-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)benzamide, confirmed by nuclear magnetic resonance, as a white solid having a melting point of 75°-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][OH:12])[CH2:9][CH2:10]1
Reactant: O=C(O)C1CCC(Cc2ccccc2Cl)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(Cc2ccccc2Cl)CC1
Yield: 63.7 %

Procedure:
4-(2-Chlorobenzyl)cyclohexanecarboxylic acid (115 mg; 0.48 mmol) and lithium aluminum hydride (100 mg; 2.64 mmol) was carried out using Method H in 5 mL tetrahydrofuran. Material was purified by flash chromatography using 10-50% ethyl acetate in hexanes gradient to give 73 mgs of title compound. (67% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:39][C:40]1[N:41]=[N:42][C:43](Cl)=[CH:44][CH:45]=1>CN1C(=O)CCC1.C(OCC)(=O)C.O>[Cl:39][C:40]1[N:41]=[N:42][C:43]([N:14]2[CH2:13][C:12]3[CH2:8][N:9]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=3[CH2:15]2)=[CH:44][CH:45]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: Clc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(Cl)nn1)C2
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (1 g, 2.52 mmol, example 1b) was dissolved in 18 ml of NMP and admixed with potassium tert-butoxide (849 mg, 7.57 mmol). tert-Butanol formed was drawn off on a rotary evaporator, and 3,6-dichloropyridazine (376 mg, 2.52 mmol) was added. The reaction mixture was stirred in a microwave reactor at 100° C. for 10 min. After adding 0.5 eq of 3,6-dichloropyridazine each time, the mixture was stirred twice more at 100° C. for 15 min in the microwave reactor. The residue was admixed with water and ethyl acetate, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 669 mg (67%), M+H+: 395.08.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[N:13]=[C:12]([C:15](=[O:26])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:5])C.[Cl:33][C:34]1[S:38][C:37]([C:39]2[O:43][N:42]=[C:41]([CH2:44]OS(C)(=O)=O)[CH:40]=2)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[S:38][C:37]([C:39]2[O:43][N:42]=[C:41]([CH2:44][N:11]3[C:10]4[CH:9]=[CH:8][C:7]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:6]([C:4]([OH:3])=[O:5])[C:14]=4[N:13]=[C:12]3[C:15](=[O:26])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:19][CH2:18]3)[CH:40]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1c(OCC(F)(F)F)ccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(Cl)s2)on1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)c(OCC(F)(F)F)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-4-carboxylic acid was prepared by a procedure according to example 81 starting from 299.0 mg (0.66 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-4-carboxylic acid ethyl ester and 192.4 mg (0.66 mmol) methanesulfonic acid 5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl ester. Hydrolysis of the resulting ethyl ester by treatment with LiOH in MeOH and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compound as its formiate in form of a white amorphous solid. Yield: 90 mg MS (ES+): m/e=626, chloro pattern.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]1=[O:16])(=O)[CH2:2][CH2:3][CH3:4].[CH2:17]([O:20][NH2:21])[CH:18]=[CH2:19]>C(O)C>[CH2:17]([O:20][NH:21][C:1](=[C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]1=[O:16])[CH2:2][CH2:3][CH3:4])[CH:18]=[CH2:19]
Reactant: C=CCON
Reactant: CCCC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)N(C)C(=O)N(C)C1=O
Reaction time: 2 h

Procedure:
2.3 g of 5-butyryl-1,3-dimethylbarbituric acid was dissolved in 30 ml of ethanol and 1 g of allyloxyamine was added to it at a temperature of 30° C. After stirring during 2 hours, said ethanol was distilled off and thereby 2.6 g of white crystals was separated. The purified compound was obtained as needles by recrystallization from methanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[CH:8]=[C:9]([N:11]3[C:15]([CH3:16])=[N:14][N:13]=[N:12]3)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C)c2)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a stirred solution of 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl ester (1 mmol, 308 mg) in 10 ml of THF was added a solution of LiOH.H2O (5 mmol, 210 mg) in 2 mL of water. The reaction mixture was heated to reflux for 3.5 hours and then cooled to room temperature. Solvent was removed under reduced pressure and the liquid residue was pH adjusted to 2.0 by addition of 2N aqueous HCl solution. The mixture was extracted with ethyl acetate and the combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid as white solid (279 mg, 95% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][S:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]([OH:24])[N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:36]1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=C[CH:41]=1)C.S(=O)(=O)(O)O.[OH-].[K+]>C(O)C.CCOC(C)=O.CCCCCC>[CH2:1]([N:8]1[CH:12]([CH2:13][S:14][CH2:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:11]([O:24][CH2:36][CH3:41])[N:10]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CSCC1C(O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1)c1ccccc1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC1C(CSCC(=O)c2ccccc2)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 2.12 g (4 RS, 5 R)-1,3-dibenzyl-2-oxo-5-(4-oxo-4-phenyl-2-thiabutyl)imidazolidin-4-ol (prepared according to Example 3) and 100 ml of ethanol is brought to pH 3.1 (against Methyl Orange) at 0°-5° C. using 2 normal sulfuric acid in ethanol. After stirring at 0°-5° C. for two hours, the mixture is brought to pH 5 to 6 using 2% potassium hydroxide in ethanol. After customary working-up and flash chromatography, 2.043 g (91% of theory) of (4 RS, 5 R)-1,3-dibenzyl-2-oxo-5-(4-oxo-4-phenyl-2-thiabutyl)-4-ethoxyimidazolidine, Rf =0.69 (EtOAc/hexane 3:7), are obtained. The following are oxo-7-(methoxycarbonyl)-2-thiaheptyl)-4-ethoxyimidazolidine, yield 85% of theory, Rf =0.62 (EtOAc/hexane 1:1),
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:3](=[O:4])[CH:2]([Cl:1])[CH3:6])=[N:9][CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(Cl)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.14 mL (22.0 mmol) 2-chloropropionic acid chloride in 5 mL DCM is added dropwise to a solution of 3.46 g (20.0 mmol) 2-amino-5-bromopyridine and 6.12 mL (44.0 mmol) triethylamine in 80 mL DCM at 0° C. The ice bath is removed and the reaction solution is stirred for a further 1.5 h at RT. Another 0.40 mL (4.12 mmol) 2-chloropropionic acid chloride is added and the solution is stirred for a further hour at RT. The reaction mixture is combined with 80 mL water, washed once with 80 mL saturated NaCl solution and dried over MgSO4. The solvent is eliminated i.vac. and the residue is triturated with a little EtOAc, suction filtered and dried.
Reaction SMILES: [CH2:1]1[CH:3]2[C:4]([O:6][C:7](=[O:8])[CH:2]12)=O.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:7](=[O:8])[CH:2]2[CH:3]([CH2:1]2)[C:4]1=[O:6]
Reactant: NCCCO
Reactant: O=C1OC(=O)C2CC12
Product: O=C1C2CC2C(=O)N1CCCO
Temperature: 180 °C
Yield: 49 %

Procedure:
A mixture of cyclopropane-2,3-dicarboxylic acid anhydride (purchased at Acros, Ref 37012-0010, 500 mg, 1.0 eq.) and 3-amino-1-propanol (340 mL, 1.0 eq.) was heated 6 h at 180° C. The reaction mixture was purified on silica, eluting with a 98:2 to 19:1 gradient of dichloromethane/methanol, to yield 360 mg (49%) of the desired product as light yellow solid. MS (m/e): 168.1 (M−H−, 100%)
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3](B(O)O)[CH:2]=1.I[C:21]1[CH:22]=[C:23]([Br:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:27][C:23]1[CH:22]=[C:21]([C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14]([C:15]5[C:16]=3[C:4]=2[CH:3]=[CH:2][CH:1]=5)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1ccc2c3c(cccc13)-c1ccccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3c4c(cccc24)-c2ccccc2-3)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A flask was charged with 9.1 g of fluoranthene-3-boronic acid, 10.5 g of 3-iodobromobenzene, 2.1 g of tetrakis(triphenylphosphine)palladium(0), 186 mL of toluene, and 74 mL of a 2 M sodium carbonate aqueous solution in an argon atmosphere. The mixture was stirred at 100° C. for 8 hours. After cooling the reaction solution to room temperature, the reaction solution was extracted with toluene. After removing the aqueous phase, the organic phase was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering the organic phase, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.2 g of the target 3-(3-bromophenyl)fluoranthene (yield: 70%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.I[C:16]1[CH:28]=[CH:27][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O)(CC)(C)C>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]>[N:21]1([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([NH:1][C:2]3[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:3]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Ic1ccc(CN2CCOCC2)cc1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: N#Cc1cn(-c2ccccc2)nc1Nc1ccc(CN2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (100 mg, 0.543 mmol), 4-(4-iodobenzyl)morpholine (165 mg, 0.543 mmol), Pd2dba3 (24.86 mg, 0.027 mmol), K2CO3 (83 mg, 0.597 mmol) and X-Phos (64.7 mg, 0.136 mmol) were added to a 5 mL microwave vial. Degassed tert-amyl alcohol (0.8 mL) was added and the vial was evacuated and back-filled with N2 (×3). The resulting mixture was stirred at 100° C. for 24 hours. Room temperature was attained, MeOH was added and the solvent removed in vacuo while loading onto silica. Purification of the residue by MPLC (0-15% MeOH—CHCl3) gave 3-{[4-(morpholin-4-ylmethyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carbonitrile as a beige solid.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][CH2:11][CH:12]([CH3:43])[C:13]#[C:14][C@@H:15]([N:22]1[CH2:27][CH2:26][C@@H:25]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:24][C@H:23]1[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C([O-])(O)=O.[Na+]>O.C1COCC1>[CH2:3]([O:10][CH2:11][C@H:12]([CH3:43])[C:13]#[C:14][C@@H:15]([N:22]1[CH2:27][CH2:26][C@@H:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][C@H:23]1[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=1)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C[C@@H]1CCN([C@H](C#CC(C)COCc2ccccc2)CCC(F)(F)F)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C#C[C@H](CCC(F)(F)F)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1)COCc1ccccc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A solution of lithium hydroxide (19.7 mg, 0.822 mmol) in water (1 ml) was added to a stirred solution of the ester (Step 3, 96 mg, 0.164 mmol) in THF (2 ml) at RT. The mixture was stirred at RT o/n. 2N HCl (1 ml) was added The pH of the aqueous layer was adjusted to 7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 2-5% MeOH/DCM) to give the acid (91 mg) as a colourless oil. M/Z 570 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12].[NH2:16][C:17]1[N:22]=[C:21](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:20]([CH2:36][C:37]2[CH:58]=[CH:57][C:40]([O:41][CH2:42][CH2:43][CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][C@@H:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:39][C:38]=2[O:59][CH3:60])=[C:19]([CH3:61])[N:18]=1>C(#N)CC.C(OC([O-])=O)(O)=O.[Na+]>[NH2:16][C:17]1[N:22]=[C:21]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:20]([CH2:36][C:37]2[CH:58]=[CH:57][C:40]([O:41][CH2:42][CH2:43][CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][C@@H:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:39][C:38]=2[O:59][CH3:60])=[C:19]([CH3:61])[N:18]=1
Reactant: COc1cc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCC[C@H](N)CCO
Agent: O=C([O-])OC(=O)O
Agent: [Na+]
Solvent: CCC#N
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Temperature: 120 °C
Yield: 76.8 %

Procedure:
Trifluoroacetic acid (0.091 mL) was added to the mixture of (S)-3-aminohexan-1-ol (416 mg) and the product from step (ix) (775 mg) in propionitrile (8 mL). After the mixture was heated at 120° C. for 16 h, the reaction mixture was cooled to RT, diluted with sat. sodium hydrogen dicarbonate and extracted with EtOAc. The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (520 mg) as a white gum; 1H NMR (CDCl3); 6.81 (1H, d), 6.44 (1H, d), 6.38 (1H, dd), 4.80 (2H, br s), 4.13-4.03 (1H, m), 4.03-3.90 (2H, m), 3.84 (3H, s), 3.59 (2H, s), 3.49-3.37 (1H, m), 3.34-3.22 (1H, m), 3.18-3.08 (1H, m), 3.08-3.00 (1H, m), 2.91-2.80 (1H, m), 2.62-2.49 (1H, m), 2.41-2.30 (1H, m), 2.35 (3H, s), 2.10-1.70 (8H, m), 1.44-1.34 (1H, m), 1.42 (9H, s), 1.28-0.89 (4H, m), 0.75 (3H, t); LC-MS: m/z 573.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=O)[CH:4]([CH3:13])[O:3]2.[NH2:14][NH2:15]>C(O)C>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([C:6](=[N:9][OH:10])[C:7]1=[N:14][NH2:15])[CH:4]([CH3:13])[O:3]2
Reactant: NN
Reactant: CC1OC2(C)CCC1C(=NO)C2=O
Solvent: CCO
Product: CC1OC2(C)CCC1C(=NO)C2=NN

Procedure:
A mixture of 1.83 g. (0.01 mole) 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime and 0.35 ml. (0.011 mole) anhydrous hydrazine (98%) in 25 ml. absolute ethanol is refluxed under nitrogen at a bath temperature of 80° C. for 1 hour. Evaporation of the solvent gives 1,3-dimethyl-2-oxa-bicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone.