Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](B(O)O)=[N:12][N:11]3[CH:19]=2)=[CH:4][C:3]=1[NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].Br[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[C:36]([F:39])([F:38])[F:37].C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)C.O>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([CH:19]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:4]=4)[N:9]=3)[N:12]=2)=[C:29]([C:36]([F:37])([F:38])[F:39])[CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: Cc1ccc(-c2cn3nc(B(O)O)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2cn3nc(-c4ccc(C#N)cc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 48.3 %

Procedure:
A 200 mL flask is charged with 2-(4-methyl-3-pivalamidophenyl)imidazo[1,2-b]pyridazin-6-ylboronic acid (11.4 g, 0.0325 mol), 4-bromo-3-(trifluoromethyl)benzonitrile (10.16 g, 0.04 mol), K2CO3 (8.98 g, 0.065 mol), palladium acetate (0.510 g, 2.28 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (1.868 g, 4.55 mmol) and a solution of isopropanol-water (3:1, 80 mL). The mixture is degassed by bubbling N2 through and heated at 90° C. for 5 hours. The mixture is then cooled and filtered through celite, concentrated and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2). The desired fractions are combined and stirred for 24 hours with QuadraSil MP (a mercaptopropyl bound silica gel, 20 g) to scavenge the palladium, filtered and concentrated to give desired title compound (7.5 g). LCMS (m/z)=478.6 [M+H]+, tR=2.97 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([NH2:21])=[CH:10][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]#[C:23]Br>CO.C(#N)C.O>[CH:1]1([N:7]2[C:8]3[CH:13]=[CH:12][C:11]([CH2:14][N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)=[CH:10][C:9]=3[N:21]=[C:23]2[NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cc(CN2CCCCC2)ccc1NC1CCCCC1
Reactant: N#CBr
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Nc1nc2cc(CN3CCCCC3)ccc2n1C1CCCCC1
Reaction time: 4.5 h

Procedure:
N1-cyclohexyl-4-(piperidin-1-ylmethyl)benzene-1,2-diamine from step3 in methanol (200 mL) was added to a mixture of 5 M cyanogen bromide in acetonitrile (3.2 mL) and water (100 mL) dropwise over 1 hr with stirring. After 4.5 hr total reaction time, the mixture was evaporated to dryness. The residue was purified by preparative HPLC chromatography to yield 2.23 g of the title compound as the bis-TFA salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[OH-].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>O1CCOCC1>[C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Nc1cc2c(c(C(=O)O)c1)NCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc2c(c(C(=O)O)c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A solution of 6-amino-1,2,3,4-tetrahydroquinoline-8-carboxylic acid (4.80 g) in dioxane (60 ml) was added 1N aqueous sodium hydroxide solution (60 ml) and acetyl chloride (2.5 ml), the mixture was stirred for 8 hours at room temperature. After salting out, extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution successively and dried over anhydrous sodium sulfate. After solvent was distilled away and the resulting residue was purified by silica gel column chromatography eluting with dichloromethane-ethanol (9:1) to yield 0.98 g (16.8%) of the title compound. This compound was recrystallized from ethanol to give yellow crystals, mp 258°-259° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@@H](Cc2ccccc2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (5.0 g) in dimethyl sulfoxide (100 mL) were added phenylalanine (6.37 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted 3 times with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 9.67 g, 100%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[NH2:52][C:53]1[CH:58]=[C:57]([O:59][C@H:60]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH3:61])[C:56]([N+:68]([O-:70])=[O:69])=[CH:55][C:54]=1[C:71]1[CH:87]=[CH:86][C:74]([C:75]([O:77][C:78]2[CH:83]=[CH:82][C:81]([CH2:84]O)=[CH:80][CH:79]=2)=[O:76])=[CH:73][CH:72]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:84][C:81]2[CH:82]=[CH:83][C:78]([O:77][C:75](=[O:76])[C:74]3[CH:73]=[CH:72][C:71]([C:54]4[CH:55]=[C:56]([N+:68]([O-:70])=[O:69])[C:57]([O:59][C@H:60]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH3:61])=[CH:58][C:53]=4[NH2:52])=[CH:87][CH:86]=3)=[CH:79][CH:80]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(CO)cc3)cc2)cc1[N+](=O)[O-]
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCc3ccc(OC(=O)c4ccc(-c5cc([N+](=O)[O-])c(O[C@@H](C)CCCCCC)cc5N)cc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
0.2 g of N,N'-dicyclodicyclohexylcarbodiimide was added at room temperature while stirring to a solution of 0.6 g of 2,5-bis(4-[6-acryloyloxyhexyloxy]phenylcarboxy)benzoic acid, 0.4 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]-phenyl)benzoyloxy]phenylmethanol and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from acetone of the fractions which were pure according to thin-layer chromatography gave 0.4 g of (4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]phenyl)-methyl 2,5-bis(4-[6-acryloyloxyhexyloxy]phenylcarboxy)benzoate; m.p. (C-I) 100° C., Sc* -N*, 96° C., cl.p. (N* -I) 100° C.
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[C:6]([Br:12])=[N:5]1)(=O)C.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.CCOC(C)=O>[Br:12][C:6]1[C:7](=[O:11])[N:8]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[C:9](=[O:10])[NH:4][N:5]=1
Reactant: CC(=O)n1nc(Br)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1c(=O)[nH]nc(Br)c1=O
Temperature: 5 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
2-acetyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (P6, 2.47 g, 10.56 mmol) was dissolved in 1,4-Dioxane (18 ml) and pyridine (2.56 ml, 31.7 mmol). The solution was cooled to 5° C. then benzoyl chloride (1.470 ml, 12.67 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The day after the reaction mixture was diluted with AcOEt and washed with 0.5N HCl aq solution. Organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. Crude product (brown oil) was purified by flash chromatography (SiO2, eluent: Cy to Cy/AcOEt 6:4) affording 6-bromo-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.46 g, 4.93 mmol, 46.7% yield) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.BrC1[CH:18]=[N:19][CH:20]=[N:21]C=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:1]2[CH:2]=[N:21][CH:20]=[N:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Brc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(Oc2cncnc2)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To 1.00 g (4.99 mmol) 4-(benzyloxy)phenol and 794 mg (4.99 mmol) 5-bromo-pyrimidine in 5 mL DMF are added 3.25 g (9.99 mmol) Cs2CO3 and the reaction mixture is stirred at 120° C. for 6 h in a microwave oven. Then the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCC(F)(F)F)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 1.8 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (740 mg, 6.0 mmol) and (3,3,3-trifluoro)-1-iodopropane (2.67 g, 12.0 mmol) in 10 mL dimethylformamide was added cesium carbonate (4.0 g, 12.3 mmol) and the resulting slurry stirred vigorously at 85° C. for 24 h. After cooling to room temperature the reaction mixture was poured into 100 mL water. Organics were extracted with ether (3×75 mL), dried over magnesium sulfate, filtered and concentrated. The residue was subjected to chromatography on silica gel (30% ethyl acetate in hexanes) to give 4-(3,3,3-trifluoropropoxyl)benzaldehyde (24 mg, 2%). Used without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23])=[CH:16]2>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:28]2[CH2:29][CH2:30][N:25]([S:22]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][C:13]([Cl:12])=[CH:21][CH:20]=4)(=[O:23])=[O:24])[CH2:26][CH2:27]2)=[O:10])=[N:4][CH:3]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: Cl
Product: O=C(c1ncc(Br)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
In the same manner as in Referential Example 12, a reaction was effected using 5-bromo-2-pyrimidinecarboxylic acid and 1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Br[C:25]1[C:26]2[N:27]([CH:32]=[CH:33][N:34]=2)[N:28]=[C:29]([Cl:31])[CH:30]=1>C1COCC1>[Cl:31][C:29]1[CH:30]=[C:25]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[C:26]2[N:27]([CH:32]=[CH:33][N:34]=2)[N:28]=1
Reactant: COc1ccc(CNc2ccc(C)cn2)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3ccnc23)cc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a flask was added N-(4-methoxybenzyl)-5-methylpyridin-2-amine (147 g, 645 mmol) in THF (5 mL) at 25° C. The solution was stirred at 25° C. and potassium t-butoxide (1936 mL, 1936 mmol) was added. The reaction solution was stirred at 25° C. for 30 minutes. Next, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (150 g, 645 mmol, Example 1 from WO 2007/038314) was added and the reaction solution was stirred at room temperature for 1 hour. The reaction was quenched with ethyl acetate and the solvent was removed in vacuo. The residue was redissolved in ethyl acetate, washed with sat NaHCO3, and sat. NaCl and dried (Na2SO4), filt and concentrated in vacuo to give the crude product. The residue was purified via ISCO (5% EtOAC/DCM; 12 g column) to give pure product 6-chloro-N-(4-methoxybenzyl)-N-(5-methylpyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.1367 g, 0.360 mmol, 0.056% yield).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1>>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid at ambient temperature in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate is obtained after conventional workup.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:14](=[O:18])[CH2:15][C:16]#[N:17])C.C(O)(=O)C.C([O-])(=O)C.[NH4+].C(N)(=O)C>C1C=CC=CC=1>[OH:18][C:14]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[C:8]([CH3:9])[C:15]=1[C:16]#[N:17]
Reactant: CC(=O)Cc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: CC(N)=O
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2ccccc2c(O)c1C#N
Temperature: 160 °C
Yield: 40.5 %

Procedure:
Phenyl-2-propanone (24.93 g, 0.178 mol) was combined with ethylcyanoacetate (19.8 mL, 0.180 mol), acetic acid (8.0 mL, 0.14 mol), ammonium acetate (2.82 g, 0.0370 mol) and 80 mL of benzene in a round bottom flask equipped with a Dean-Stark trap and condenser cooled by a chiller. The reaction was heated to 160° C. for 4 h. The mixture was removed from heat and the trap drained so that the mixture could be concentrated by distilling off excess (˜50 mL) benzene. The solution contained crude (E)-ethyl 2-cyano-3-methyl-4-phenylbut-2-enoate. The concentrated mixture was removed from heat and heat adjusted to 240° C. Acetamide (50.9483 g, 0.862 mol) was added, and a Claisen head attached to distill any ethanol resulting while the mixture was heated at 240° C. for 60-90 minutes. The mixture was cooled to ˜100° C., and poured into room temperature water to quench the reaction. A clumpy orange solid was formed, removed by filtration and triturated with ice cold absolute EtOH. The solid was filtered off and the process repeated 4 times to harvest additional material. The resulting product was a pale yellow fine powder (13.20 g, 36% yield). 1H-NMR: (300 MHz, DMSO-d6): δ 11.28 (s, 1H); 8.24 (d, J=8.4 Hz, 1H); 7.80 (d, J=8.0 Hz, 1H); 7.62-7.58 (m, 1H); 7.52-7.48 (m, 1H); 7.34 (s, 1H); 2.47 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>CS(C)=O.O>[C:4]1(=[CH:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Reactant: COc1ccccc1C=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C=C1CCCC1
Temperature: 60 °C
Yield: 67 %

Procedure:
A suspension of sodium hydride (608 mmol, 24.3 g; 60% dispersion in oil) in dry DMSO (3L) was heated to 60° C. for one hour and cooled to an internal temperature of 42° C. Cyclopentyltriphenylphosphonium bromide (608 mmol, 250 g) was added in one portion and to the resulting red solution was added 2-methoxybenzaldehyde (669 mmol, 91.0 g; 80.7 mL) dropwise over a few minutes. The dark reaction mixture was heated to 60° C. for 18 hours and cooled to room temperature. The reaction was diluted with water (4L), extracted with CH2Cl2 (2×3L) and concentrated in vacuo. The residue was partitioned between 15:1 hexane/EtOAc (1.3L) and water (1.6L), the organics washed with water (3×600 mL), dried (Na2SO4) and concentrated in vacuo. Upon concentration, triphenylphosphine oxide crystallized out of solution. The suspension was diluted with hexane, the solids removed by filtration, and the filtrate concentrated in vacuo to afford a dark oil. This material was vacuum distilled to afford the title compound as a light yellow oil (76.7 g, 67%). The desired material comes over at 90°-97° C. at 0.05 mm Hg and is used as such in the subsequent transformation.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14]SC.ClC(OC1C=CC=CC=1)=O.C[Mg]Br.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.[Cu]I>[O:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC
Reactant: c1ccc(Oc2cccnc2)cc1
Agent: [Cu]I
Agent: C[Mg]Br
Agent: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccncc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-phenoxypyridine (10.26 g, 0.06 mol) in dry THF (500 ml) under nitrogen was added copper(I) iodide and methyl sulphide (30 ml). The mixture was stirred at room temperature for 15 minutes and then cooled to -25° C. Phenyl chloroformate (8.0 ml, 0.066 mol) was then added dropwise to produce a dark-brown solution. After 10 minutes methylmagnesium bromide (20 mls of 3M solution, 0.066 mol) was added dropwise at -25° C. After stirring at -25° C. for 15 minutes the solution was warmed to room temperature over 1 hour, during which time the solution had become a clear light yellow colour. The reaction was quenched with 20% aqueous ammonium chloride solution (150 ml) and then partitioned with ether (250 ml). The organic layer was washed with 20 ml portions of 20% aqueous ammonium chloride--ammonium hydroxide (1:1) solution, 10% hydrochloric acid, water and brine. After drying the ether was evaporated to give a yellow oil which was redissolved in dry toluene (250 ml). A suspension of o-chloranil (15 g) in toluene (100 ml) was added portionwise at room temperature. The resulting dark solution was stirred overnight and then 10% aqueous sodium hydroxide solution (200 ml) was added and stirring continued for 10 minutes at room temperature. The reaction mixture was partitioned with ether (200 ml) and the organic layer washed with 200 ml portions of 10% aqueous sodium hydroxide solution and water and then 10% hydrochloric acid (4×250 ml). The acidic extracts were basified with 25% aqueous sodium hydroxide solution and then extracted with methylene chloride (X4). The combined methylene chloride extracts were dried and evaporated to give a yellow oil. Bulb-to-bulb distillation (100° C. at 0.05 mBar) afforded 3-phenoxy-4-methylpyridine (6.5 g) as a clear liquid, 1H NMR delta (CDCl13) 2.25 (3H,s); 6.9-7.4 (6H,m); 8.2 (1H,s); 8.3 (1H,d).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[C:13]1(=[O:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>CCCCCC.CCOCC>[N:10]1[CH:11]=[CH:12][C:7]([C:13]2([OH:23])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:8][CH:9]=1
Reactant: O=C1CCCc2ccccc21
Reactant: Brc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2ccncc2)CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
85 ml of a 1.5M solution of n-butyllithium in hexane are added, dropwise, to a solution of 20 g of 4-bromopyridine in 73 ml of ether, cooled to −78° C. Stirring is carried out for 30 minutes at that temperature, a solution of 1-tetralone in 73 ml of ether is then poured in and, at the end of the addition, the mixture is allowed to return to ambient temperature. After stirring overnight, a saturated aqueous solution of ammonium chloride is poured in. After separation, extraction with ether is carried out. The ethereal phases are combined and extracted with 1N hydrochloric acid. The combined acid phases are adjusted to pH=8 using 20% sodium hydroxide solution and extracted with dichloromethane. After drying, the expected product is isolated, which is purified by high-speed chromatography on silica (eluant: dichloromethane/methanol 95/5) to yield the expected product.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]1[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]4[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Cn1ccc(Cl)cc1=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ccn(C)c(=O)c2)C3)cc1

Procedure:
The compound was prepared following the general procedure in Example 308, substituting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea for (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea and substituting 1-methylpyridin-2(1H)-one for 4-chloro-1-methylpyridin-2(1H)-one: LC-MS m/z=504 (M+H).