Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:23][C:24]1[N:25]=[C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:49])=[C:37]([NH:39][C:40]([C:42]4[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=4)=[O:41])[CH:38]=3)=[N:28][N:27]2[CH:50]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[F:49][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:29]2[CH:30]=[CH:31][C:26]3[N:27]([CH:50]=[C:24]([NH:23][C:7]([CH:3]4[C:4]([CH3:5])([CH3:6])[C:2]4([CH3:1])[CH3:10])=[O:9])[N:25]=3)[N:28]=2)=[CH:38][C:37]=1[NH:39][C:40]([C:42]1[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=1)=[O:41]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5C(C)(C)C5(C)C)cn4n3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a solution of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (102 mg, 0.72 mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide (20 μL, 0.26 mmol) and oxalyl chloride (63 mL, 0.72 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1) and precipitated from hexane/ethyl acetate to give the title compound (46 mg, 19%) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][C:25]1[S:29][CH:28]=[N:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:30]([C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:39][C:40]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[N:37]=1)([CH3:32])[CH3:31].CO>ClCCl>[CH:30]([C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:39][C:40]([NH:42][C@H:43]([C:47]([NH:1][C@H:2]([CH2:24][C:25]2[S:29][CH:28]=[N:27][CH:26]=2)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]2[S:22][CH:21]=[N:20][CH:19]=2)=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[N:37]=1)([CH3:32])[CH3:31]
Reactant: N[C@H](Cc1cncs1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(COC(=O)N[C@H](C(=O)O)C(C)C)cs1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc(COC(=O)N[C@H](C(=O)N[C@H](Cc2cncs2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine provided, after silica gel chromatography using 10% methanol in dichloromethane, 25 mg (76%) of the desired compound (Rf 0.47, 10% methanol in dichloromethane). Mass spectrum: (M+H)+ =715.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][N:7]1[C:12](=O)[CH2:11][CH:10]([OH:14])[CH2:9][CH:8]1[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27]C(=O)C(C)CC)[CH:20]=[CH:19][CH:18]1[CH3:35]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([OH:14])[CH2:9][CH:8]1[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[OH:27])[CH:20]=[CH:19][CH:18]1[CH3:35]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(=O)N3Cc3ccc(OC)c(OC)c3)C21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCC(O)CC2CCC2C(C)C=CC3=CC(C)CC(O)C32)cc1OC
Reaction time: 3 h

Procedure:
To a solution of 600 mg (1.1 mmol) of 2-methyl-butyric acid 8-(2-[1-(3,4-dimethyoxy-benzyl)-4-hydroxy-6-oxopiperidin-2-yl]-ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 15 ml of THF at rt are added 2 ml of a 65% RedAl® solution in toluene. After 3 hours, the reaction is quenched by the addition of 1 ml of methanol. The organic phase is extracted twice with 15 ml of 2N HCl. The aqueous phases are combined, brought to pH 12 with 1N NaOH and extracted three times with ethyl acetate. The organic phases are combined, dried over sodium sulfate and the solvent evaporated. The residue is purified by silica gel chromatography (t-butyl methyl ether/methanol 9/1) to afford pure 1-(3,4-Dimethoxy-benzyl)-2-[2-(8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-naphthalen-1-yl)-ethyl]-piperidin-4-ol as a white foam.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>CCCCC.C(OCC)C>[F:23][C:4]([F:3])([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C@H:5]([O:6][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CSc1ccc(OC(F)(F)[C@H](O)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCC
Product: CSc1ccc(OC(F)(F)[C@H](OS(=O)(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
NaH (60% in oil, 1.54 g, 4.9 mmol) was washed several times with pentane, under nitrogen and then suspended in anhydrous ethyl ether (10 m) and cooled at 0° C. A solution of 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethanol in ethyl ether (10 ml) was added. After stirring the reaction mixture for 15 min, trifluoromethylsulfonyl chloride was added and the resulting mixture was stirred for 2 h at 0° C. The reaction mixture was diluted with hexanes (20 ml) and washed with saturated solution of NaHCO3 and brine. After drying over magnesium sulfate, the solution was concentrated to give trifluoromethanesulfonic acid 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethyl ester (1.70 g, 77%) as an oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])=[CH:9][N:8]=1.CN([CH:22]=[O:23])C.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH2:22][OH:23])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: CN1CCCC1c1ccc(Br)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCCC1c1ccc(CO)nc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of BuLi (3.0 mmol) in hexanes (1.6 M, 1.87 ml) was added to a stirred solution of 2-bromo-5-(1-methylpyrrolidin-2-yl)pyridine (480 mg, 2.0 mmol) in THF (50 ml) at −78° C. under N2. The reaction was stirred at −78° C. for 10 min, DMF (462 μl, 6.0 mmol) was added and the reaction allowed to warm slowly to room temperature and stirred at room temperature for a further 1 h. MeOH (50 ml) was added, followed by sodium borohydride (75 mg, 2.0 mmol) and then the reaction mixture was stirred at room temperature for 1 h. NH4Cl solution (10 ml) was added cautiously. The resulting mixture was concentrated under reduced pressure, then dissolved in MeOH/CH2Cl2 (1:1, 50 ml) and dry loaded onto silica. The crude residue was purified by column chromatography on silica using 5% MeOH/CH2Cl2 containing 1% NH3 to yield the desired hydroxymethylpyridine (100 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 8.46 (1H, d, J=2.0 Hz), 7.70 (1H, dd, J=8.0, 2.0 Hz), 7.25 (1H, d, J=8.0 Hz), 4.75 (2H, s), 4.18 (1H, broad s), 3.28-3.18 (1H, m), 3.09 (1H, J=8.3 Hz), 2.31 (1H, q, J=9.0 Hz), 2.22-2.16 (1H, m), 2.16 (3H, s), 2.05-1.65 (3H, m). m/z (ES+) 193 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH3:14]>CCO.O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[O:12])[CH:14]=[CH:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
Step A Add 10% aqueous NaOH (38 mL) to a solution of p-anisaldehyde (25 mL, 0.206 mol) and acetophenone (23.97 mL, 0.206 mol) in EtOH (500 mL). Stir the mixture at room temperature over night. Dilute the mixture with water and extract with ether. Combine the ethereal extracts, wash with water and brine, dry over Na2SO4 and concentrate to a solid. Recrystallize the solid from ether/hexanes to provide 27.51 g (56%) of 4'-methoxychalcone, mp 72°-74° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO.O1CCOCC1.CO>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: N#Cc1ccnc(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C#N)ccn1
Yield: 110.8 %

Procedure:
2-Chloro-4-cyanopyridine (115.53 g) in methanol/dioxan (1:1, 850 ml) was added to a solution of sodium methoxide (prepared from 20.8 g sodium) in methanol (285 ml) and the mixture was boiled under reflux for 2.5 hours and was allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by evaporation to 200 ml and water (400 ml) was added. The solid which precipitated out was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%) m.p. 93°-95.5°.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][C@H:7]([NH:30][C:31]([C:33]2[NH:42][C:36]3=[CH:37][N:38]=[C:39]([Cl:41])[CH:40]=[C:35]3[CH:34]=2)=[O:32])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]([CH3:29])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C1C=CC(S)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]([NH:30][C:31]([C:33]2[NH:42][C:36]3=[CH:37][N:38]=[C:39]([Cl:41])[CH:40]=[C:35]3[CH:34]=2)=[O:32])[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][CH3:29])[CH2:14][CH2:15]2)=[O:9])=[CH:43][CH:44]=1
Reactant: CN(C1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: CNC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1-(S)-(4-fluorobenzyl)-2-{4-[methyl-(2-nitrobenzenesulfonyl)amino]piperidin-1-yl}-2-oxoethyl)amide (Preparation 76, 82 mg, 0.13 mmol) in acetonitrile (6 mL) was added phenylthiol (145 μL, 1.4 mmol) followed by potassium carbonate (230 mg, 1.66 mmol) and the reaction heated to 50° C. for 24 h. To the mixture was added diethyl ether (10 mL) and 1M HCl (15 mL) and stirred for 5 min. The organic layer was separated and washed with 1M HCl (15 mL) before combining the aqueous layers. The solution was basified to pH9 with solid potassium carbonate and extracted with ethyl acetate (2×20 mL). Organic layers were combined, washed with brine (2×20 mL) and dried (MgSO4). Removal of the solvent in vacuo provided the desired product as an off-white powder. m/z (ES+)=458.40 [M+H]+; RT=2.67 min. A small portion of the product (10 mg) was dissolved in methanol (2 mL) and 1M HCl added to bring the solution to pH 1–2. After stirring for 20 min the solvent was removed in vacuo to give the title compound as the hydrochloride salt as a yellow powder. m/z (ES+)=458.38 [M+H]+; RT=2.64 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[O:10][C:11]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=2[C:13](=[O:15])[CH:14]=1)(=O)[NH2:7]>CN(C)C=O>[C:6]([C:9]1[O:10][C:11]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=2[C:13](=[O:15])[CH:14]=1)#[N:7]
Reactant: Cc1ccc2c(=O)cc(C(N)=O)oc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)cc(C#N)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
26.41 g (17.22 mmoles) of phosphorus oxychloride is added to 100 ml dimethylformamide at 0° C. and stirred at 0° C. for 15 minutes at room temperature for 30 minutes 7.0 g (34.45 mmoles) 2-carbamyl-7-methyl-4-oxo-4H-1-benzopyran is added and the mixture stirred at room temperature overnight, then poured into ice water and is allowed to stand for 1 hour at room temperature. The resulting precipitate is filtered off, redissolved in ethyl acetate, decolorized with carbon, filtered and the filtrate concentrated in vacuo to give 4.5 g of 2-cyano-7-methyl-4-oxo-4H1-benzopyran as a crystalline solid having an m.p. of 155°-56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][CH:12]([F:29])[C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:27][NH2:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH2:27][C:19]1([C:16]2[CH:15]=[N:14][C:13]([CH:12]([F:29])[F:11])=[N:18][CH:17]=2)[CH2:24][CH2:23][C:22]([F:25])([F:26])[CH2:21][CH2:20]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and (1-(2-(difluoro methyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine. LCMS (MH+): m/z=416.1, tR (minutes, Method F)=2.83
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[CH3:9][C:10]1[CH:11]=[C:12]([N:23]=[C:24]=[O:25])[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19]>CCOCC>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:24](=[O:25])[NH:23][C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])=[C:10]([CH3:9])[CH:11]=1
Reactant: OCC1CCCCN1
Reactant: Cc1cc(N=C=O)ccc1OC(F)(F)C(F)F
Solvent: CCOCC
Product: Cc1cc(NC(=O)N2CCCCC2CO)ccc1OC(F)(F)C(F)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
11.5 g (0.10 mol) of 2-hydroxymethylpiperidine are dissolved in 100 ml of ether, and 24.9 g (0.10 mol) of 3-methyl-4-(1,1,2,2-tetrafluoroethoxy)-phenyl isocyanate, dissolved in 70 ml of ether, are added dropwise at 20° C. The mixture is stirred for 2 hours at 20° C. and cooled in an ice bath, and the precipitate which has been deposited is filtered off with suction. 32.1 g (88% of theory) of 2-hydroxymethyl-1-{N-[3-methyl-4-(1,1,2,2,-tetrafluoroethoxy)-phenyl]-carbamoyl}-piperidine are obtained after drying, in the form of colorless crystals, melting point 122°-126° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][CH:8]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:42]2([C:46]([O:48][CH3:49])=[O:47])[CH2:45][CH2:44][CH2:43]2)[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:32]3[CH:31]=[CH:30][C:29]([C:42]4([C:46]([O:48][CH3:49])=[O:47])[CH2:45][CH2:44][CH2:43]4)=[CH:28][C:27]=3[Cl:26])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]
Reactant: COC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c2)CCC1
Reactant: Cc1nc(C)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: COC(=O)C1(c2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CCC1
Temperature: 90 °C
Yield: 69 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate (Intermediate 7-4; 289 mg, 0.77 mmol) and methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxylate (Intermediate 7-2; 270 mg, 0.77 mmol) and potassium phosphate, tri-basic (196 mg, 0.92 mmol) in DME (10 mL), MeOH (5 mL) and water (2.5 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (31.4 mg, 0.04 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours. The reaction mixture was allowed to cool, diluted with EtOAc (40 mL) and water (20 mL). This was passed through a silica pad washing with EtOAc. The filtrate was separated and washed with brine (20 mL) then evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclobutanecarboxylate (239 mg, 69.0%) as a colourless gum.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[C:15]#[N:16])=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CO>[NH2:16][C:15]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[C:4]2[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[C:3]=12
Reactant: N#Cc1ccncc1NC1=CC(=O)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1c2c(nc3cnccc13)CCCC2=O
Yield: 90.9 %

Procedure:
A mixture consisting of 3-(1-oxo-2-cyclohexen-3-yl)amino-4-cyanopyridine (3.3 g), potassium carbonate (2.35 g), cuprous chloride (153 mg) and 80 ml of tetrahydrofuran was refluxed for 1 hour. To the mixture was added 25 ml of methanol and the inorganics were removed by filtration. The filtrate liquid was then passed through a packed column and eluted with ethyl acetate to give 3.0 g of solid, mp 237°-242° C. This was recrystallized from n-butyl acetate to give 1.85 g of crystals, mp 242.5°-245° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:16]=[C:17]([C:27]3[CH:28]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=3[F:29])[CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CN1C(=O)C(c2ccncc2)(c2cccc(Br)c2)N=C1N
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: COCCOC
Product: CN1C(=O)C(c2ccncc2)(c2cccc(-c3cc(F)ccc3F)c2)N=C1N
Yield: 83.7 %

Procedure:
To a solution of 2-amino-5-(3-bromophenyl)-3-methyl-5-pyridin-4-yl-3,5-dihydro-4H-imidazol-4-one (104 mg, 0.3 mmol) in DME (5 mL) is added 2,5-difluorophenylboronic acid (96 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmo) and 2.0M aqueous sodium carbonate (0.6 mL, 1.2 mmol) at room temperature. The reaction mixture is refluxed for 1 hour and cooled. After evaporation of the solvent, the crude mixture is purified by chromatography (silica gel, EtOAc/2M methanolic NH3: 92/8) to give the title compound (95 mg, 84%) as a solid. mp: 200-202° C.; MS(+) ES: 379 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.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)C.C1(C)C=CC=CC=1>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:7]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2cccnc2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (230 mg, 0.94 mmol), 3-pyridinylboronic acid (Frontier Scientific) (139 mg, 1.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (Aldrich Chemical Company) (22 mg, 0.024 mmol) and triphenylphosphine (Aldrich Chemical Company) (49 mg, 0.19 mmol) in a mixture of solvents (1.2 mL of toluene, 0.3 mL of 1.0 M Na2CO3 and 0.3 mL of ethanol) was heated at reflux under N2 for 40 h. Upon cooling to the room temperature, the reaction mixture was diluted with H2O (20 mL), and the crude product was extracted with CHCl3 (3×40 mL). The organic extracts were washed with H2O (50 mL), saturated NaCl (50 mL), dried over Na2SO4 and concentrated with a rotary evaporator. Chromatography on silica gel with a gradient eluant of MeOH (0-4%):CH2Cl2 (100-96%) afforded 171 mg (64%) of the title compound as a yellow solid. Mp: 252-254 C. 1H NMR (CDCl3; 400 MHz): δ 2.89 (s, 3), 6.99 (s, 1), 7.46 (m, 4), 7.78 (d, 2, J=7.1), 8.37 (d, 1, J=7.7), 8.66 (d, 1, J=3.9), 9.31 (s, 1), 9.50 (s, 1). MS m/z: 287 (M+1), 285 (M−1). HRMS: Calcd for M+H: 287.1297. Found: 287.1288.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH3:12])[C:3]=1[NH2:4].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]2[C:3]=1[NH:4][N:13]=[CH:12]2
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-6-methyl-4-nitroaniline (5.49 g, 29.4 mmole) in acetic acid (150 mL) was added sodium nitrite (2.03 g, 29.4 mmole) pre-dissolved in water (5 mL). The resulting brown slurry was stirred overnight at room temperature, then at 60° C. for a further 4 hours. The bulk of the solvent was removed by evaporation in-vacuo and the resulting black residue re-dissolved in EtOAc (100 mL) and washed in brine (2×70 mL). The organic layer was dried (MgSO4), filtered and concentrated to give a mixture of starting material and product 91 mg(1.49 g). The crude mixture was taken through to the next step; 1H NMR (400 MHz, DMSO) δ 8.25(1H, s), 8.50(1H, s), 8.85(1H, s), 14.30(1H, br s).MS (ES+): m/e=198 (minus Boc).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:16]>>[NH2:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc([N+](=O)[O-])c(Cl)nc12
Reactant: N
Product: Cc1cccc2cc([N+](=O)[O-])c(N)nc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
1.6 g of 2-chloro-8-methyl-3-nitroquinoline (compound C1) is dissolved in 70 ml of ethanolic ammonia solution and stirred at 130° C. for 18 h in an autocave. After cooling to room temperature, the reaction mixture is concentrated in vacuo and the residue recrystallized from ethyl acetate. 1.2 g of the title compound are obtained as red solid.