Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 96 h
Yield: 60.4 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (10.5 g. 30 mmols), ethyl 5-bromovalerate (10.2 ml, 60 mmols), potassium carbonate (4.2 g, 30 mmols) and N,N-dimethylformamide (100 ml) was stirred at 60° C. for 96 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 5-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminovalerate (8.65 g, 60.4%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)#[N:16]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Cl)n2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Temperature: 25 °C

Procedure:
A mixture of 3-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (from example 308 step 3, 140 mg, 0.00044 mol), p-aminobenzoic acid (90.6 mg, 0.000661 mol), and p-toluenesulfonic acid (64 mg, 0.00037 mol) in dry 1,4-dioxane (3 mL, 0.04 mol) was refluxed overnight, cooled to room temperature. The desired product crashed out and was collected by filtration (180 mg, 97.64%). LCMS (M+H) 419.3.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH2:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1

Procedure:
5.7 g of benzoguanamine and 4.0 g of nicotinic acid are dissolved in 300 ml of pyridine, and this solution is stirred with 5.0 g of phosphoryl chloride at room temperature. After continuing agitation at 60° C for 2 hours, the pyridine is removed by evaporation to dryness under vacuum. The residue is washed with water and fractionated and recrystallized from a mixed solution of methanol and dioxane, to yield 2-amino-4-nicotinamido-6-phenyl-s-triazine [mononicotinoylbenzoguanamine], melting point, 240° - 242° C in a yield of 2.8 g, and 2,4-bis(nicotinamido)-6-phenyl-s-triazine [dinicotinoylbenzoguanamine], melting point, 131° - 133° C in a yield of 0.7 g.
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][CH:23]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:17].FC(F)(F)C(O[C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42])=O.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O>CC(N(C)C)=O.N1C=CC=CC=1>[CH3:1][N:2]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([O:26][C:32]2[C:33]([F:42])=[C:34]([F:41])[C:35]([F:40])=[C:36]([F:39])[C:37]=2[F:38])=[O:25])=[N:22][CH:23]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:17]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)O)nc1)CC3
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)nc1)CC3
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]pyridine-2-carboxylic acid (0.01 g), pentafluorophenyl trifluoroacetate (0.16 g; prepared by the reaction of pentafluorophenol and trifluoroacetic acid), pyridine (0.045 g) and DMA (5 ml) was stirred at ambient temperature for 5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and methanol as eluant. There was thus obtained pentafluorophenyl 5-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-pyridine-2-carboxylate as a foam (0.1 g);
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.O>CN(C=O)C.[Cu](I)I>[CH3:15][C:4]1[N:5]=[C:6]([S:13][CH3:14])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)[N:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1SC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Oc2cccc(C(F)(F)F)c2)nc(C)nc1SC

Procedure:
A solution of methyl 2-(4-chloro-2-methyl-6-methylthio-pyrimidin-5-yl)-acetate (4.9 g) in DMF is added to a suspension of anhydrous potassium carbonate 5.6 g), copper iodide (1.0 g) and 3-trifluoromethylphenol (3.3 g) in DMF (50 ml) at room temperature. The mixture is heated to +120° C. for 90 minutes and then cooled. The cooled mixture is poured into water and extracted successively with ethyl acetate (2×50 ml) and then the organic phase is dried over anhydrous sodium sulfate. Evaporation and drying under high vacuum gives the methyl 2-[2-methyl-4-methylthio-6-(3-trifluoromethyl-phenoxy)-pyrimidin-5-yl]-acetate in form of a dark oil. NMR (CDCl3): 7.25-7.55 (m, 4H); 3.78 (s, 3H); 3.70 (s, 3H); 2.62 (s, 3H); 2.46 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([O:12][CH2:13][CH2:14][CH3:15])[C:4](=[O:16])[C:3]=1[C:17]([O:19]CC)=O.C(N1C2C(=CC=CN=2)C(O)=C(C(OCC)=O)C1=O)C1C=CC=CC=1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50](Br)=[CH:49][C:48]=1[S:54]([NH2:57])(=[O:56])=[O:55]>>[NH2:57][S:54]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[NH:46][C:17]([C:3]1[C:4](=[O:16])[N:5]([O:12][CH2:13][CH2:14][CH3:15])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19])(=[O:55])=[O:56]
Reactant: CCCOn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Reactant: Nc1ccc(Br)cc1S(N)(=O)=O
Agent: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: CCCOn1c(=O)c(C(=O)Nc2ccccc2S(N)(=O)=O)c(O)c2ccccc21

Procedure:
The title compound is prepared according to the procedure of Example 84C substituting the product of Example 172D for the product of Example 84B and substituting 2-aminosulfonamide for the product of Example 84A.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:17]C(N)=O>O>[NH:10]=[C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:7][C:6]2[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:13][CH2:12]1
Reactant: NC(N)=O
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Product: N#Cc1ccc(N=NC2=CCC(=N)C=C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
8.6 g 4-cyanoaniline were diazotised, analogously to 1.1.2. The reaction mixture was slowly added at 5 to 10° C. to a solution of 6.5 g aniline and 3 g urea in 60 ml water and was stirred at room temperature overnight. The precipitate was filtered off under suction, washed with water and dried. 6.9 g of the orange-coloured 4-imino-4′-cyano-azobenzene were obtained, and were used further without purification. The further synthesis of the monomer was effected analogously to 1.1.1. Monomer 1.1.10 had an f.p. of 174° C., and exhibited a liquid crystalline phase up to 204° C.; λmax=380 nm (DMF). 1.1.11
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([CH3:13])=[CH:4][C:3]1=[O:14].[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29]Cl)[CH2:23][CH2:22]2)=[CH:18][CH:17]=1>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][N:21]([CH2:20][C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:32][CH:31]=4)[CH2:22][CH2:23]3)=[CH:9][CH:10]=2)[C:5]([CH3:13])=[CH:4][C:3]1=[O:14].[ClH:15]
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: Cc1cc(=O)n(C)c2ccc(O)cc12
Product: Cc1cc(=O)n(C)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc12
Product: Cl

Procedure:
1,4-Dimethyl-6-hydroxy-2-oxo-1,2-dihydroquinoline is reacted with 3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propyl chloride in a manner analogous to that described in Example 3. There is obtained 1,4-dimethyl-6-{3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline in the form of a hydrochloride which melts, with decomposition, at 215°-220° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[CH:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)=[O:36].O1CCOCC1>C(OCC)(=O)C.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.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([CH:35]=[O:36])[CH:42]=4)=[CH:32][C:17]=3[C:18]=2[C:28]([NH:29][CH3:30])=[O:31])=[CH:26][CH:25]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: O=Cc1cccc(B(O)O)c1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C=O)c3)cc12
Temperature: 90 °C
Yield: 41 %

Procedure:
Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)4 (20 mg, 0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.359 mmol), 3-formylphenylboronic acid (59 mg, 0.395 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was heated to 90° C. overnight. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the titled compound (55 mg, 41%). LC-MS retention time: 1.49 min; m/z (MH+): 374. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([O:17][C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)=[O:24])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1cccc(C(=O)OCc2ccccc2)c1
Product: O=C(OCc1ccccc1)c1cccc(C(=O)Oc2cc(=O)[nH]cc2Cl)c1
Yield: 29.8 %

Procedure:
The general procedure of Example 1 was followed using 2.20 g of 5-chloro-4-hydroxy-2-pyridone and 5.31 g of 3-benzyloxycarbonylbenzoyl chloride, thereby giving 1.73 g of the title compound in a yield of 29%.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:13])=[N:6][C:7]=1[C:8]1[O:9][CH:10]=[CH:11][CH:12]=1.[CH3:14][S:15][C:16]1[N:21]=[C:20]([Sn](C)(C)C)[CH:19]=[CH:18][N:17]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C)C=O>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:7]1[N:6]=[C:5]([NH2:13])[CH:4]=[N:3][C:2]=1[C:18]1[CH:19]=[CH:20][N:21]=[C:16]([S:15][CH3:14])[N:17]=1
Reactant: Nc1cnc(Br)c(-c2ccco2)n1
Reactant: CSc1nccc([Sn](C)(C)C)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nccc(-c2ncc(N)nc2-c2ccco2)n1
Temperature: 150 °C
Yield: 47 %

Procedure:
A microwave oven reactor was charged with 5-bromo-6-furan-2-ylpyrazin-2-ylamine (Preparation 2, 220 mg, 0.91 mmol), 2-methylsulfanyl-4-trimethylstannanylpyrimidine* (500 mg, 1.74 mmol), bis-(triphenylphosphin)palladium (II) chloride (60 mg, 0.08 mmol) and dimethylformamide (2.5 mL). The mixture was heated at 150° C. for 10 min in the microwave oven, then cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (dichloromethane to dichloromethane/methanol 95:5) gave the title compound as a yellowish solid (123 mg, 47%). *Prepared according to Sandosham J.; Undheim, K. Tetrahedron 1994, 50 (1), 275-284.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18]C)=[O:17])=[CH:7][CH:6]=1>C1COCC1>[CH3:3][O:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OC)c2c1OCCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c2c1OCCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A NaOH solution (500 ml, 2N) was added to a solution of intermediate (7) in THF (250 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated partially. The residue was extrated with DCM. The mixture was separated into its layers. The aqueous layer was acidified with a concentrated HCl solution until pH=1 to 2. The solid was filtered off, washed with water and dried, yielding 35.5 g of 9-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid (intermediate 8).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(C3CCCOC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 11.9 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (29 mg, 0.197 mmol). The mixture was heated under microwave at 120° C. for 30 minutes. Then the reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-(tetrahydro-2H-pyran-3-yl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (2.51 mg, 10%). 1H-NMR (MeOD): 1.69 (t, 2H), 1.91 (m, 2H), 2.18 (t, 1H), 2.41 (d, 1H), 3.08 (t, 2H), 3.24 (s, 3H), 3.49 (m, 2H), 3.88 (dd, 2H), 4.40 (m, 1H), 7.05 (d, 1H), 7.50 (m, 1H), 7.61 (m, 3H), 7.86 (t, 1H), 7.94 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])=[N:8][C:9](O)=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:17]>O>[Cl:17][C:9]1[N:8]=[C:7]([CH3:14])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(C)nc(O)nc2c1
Solvent: O
Product: COc1ccc2c(C)nc(Cl)nc2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
To 7-methoxy-4-methylquinazolin-2-ol was added POCl3 and the mixture was added heated to 100° C. for 16 h when the reaction went to completion. To the reaction mixture was added ice and water and the precipitated solid was filtered and dried on the high vacuum overnight to give 2-chloro-7-methoxy-4-methylquinazoline in 60% yield. ES/MS m/z 209 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(OCC)(=O)C>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:27])=[O:26]
Reactant: CCOC(=O)COc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)-phenoxy]acetate (7.3 g) in ethyl acetate (22 mL) was added triethylamine (5.9 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred. Methanesulfonyl chloride (2.8 mL) was added dropwise to the mixture at 0-15° C. of internal temperature, and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, ethyl acetate (8.6 mL) and 2-propanol (23 mL) were added to the residue, and the mixture was heated to dissolve. After cooling to room temperature, the resulting crystals were collected by filtration to give ethyl 2-[4-(2-methanesulfonyloxyethyl)-phenoxy]acetate (7.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH3:23][C:16]([O:15][C:14]1[CH:24]=[CH:25][C:11]([CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:7][N:6]=2)[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)=[CH:12][CH:13]=1)([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:44][S:45]([N:1]([S:45]([CH3:44])(=[O:47])=[O:46])[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:22])([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(N)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cn2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(NS(C)(=O)=O)cn2)cc1
Reaction time: 0.5 h
Yield: 13 %
Yield: 46 %

Procedure:
A solution of ethyl 2-[4-(2-{(5-aminopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (65 mg; 0.13 mmol) in 3 ml of dichloromethane was treated with Et3N (0.019 ml; 0.14 mmol) and methanesulfonyl chloride (0.011 ml; 0.14 mmol). After 30 minutes, additional amounts of Et3N (0.019 ml) and methanesulfonyl chloride (0.011 ml) were added and stirred for another 30 minutes. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCl and brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using an ethyl acetate-hexane gradient (10–70%) provided two main products: ethyl 2-methyl-2-[4-(2-{{5-[(methylsulfonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (10 mg; 13% yield; MS: m/z 580 (M+1)) and ethyl 2-[4-(2-{{5-[bis(methylsulfonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (39 mg; 46% yield; MS: m/z 658 (M+1)). (Both of these products can be hydrolyzed to the title compound).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#N.[OH:14]S(O)(=O)=O.[C:19](=O)([O-])[O-:20].[Na+].[Na+]>CO>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]([O:20][CH3:19])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(COCCO)c1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(COCCO)c1
Temperature: 25 °C

Procedure:
A solution of 3-[(2-hydroxyethoxy)methyl]benzonitrile (1 g) in MeOH (20 ml) was treated with conc. H2SO4 (10 ml) at 0° C. The solution was then allowed to warm to room temperature before heating at reflux for 10 h. Aqueous sodium carbonate was added to neutralise the cooled solution before extracting with EtOAc. The combined organic layers were then washed with water, dried (MgSO4) and concentrated in vacuo. The residue was then purified by chromatography (Biotage, 90 g) eluting with 40°C.-60° C. petroleum ether-EtOAc (3:2) to give the title compound (650 mg). LCMS RT=2.33 min.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>C1COCC1.[Cl-].[Na+].O>[C:3]([CH:2]([CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)C(F)(F)F)C(C)=O
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl acetoacetate (3.98 mL) in THF (dry) (50 mL) was added NaH (1.571 g) at 0° C., and the mixture was stirred for 30 min at the same temperature. To the mixture was added 3-bromo-1,1,1-trifluoroacetone (5 g) 0° C., and the mixture was stirred for 3 h. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.570 g).