Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:16]([OH:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:16]([OH:18])=[O:17])=[O:11]
Reactant: Cc1cc(CO)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(C=O)cc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
In a 1 liter 4-necked round-bottomed flask were placed 500 ml of methylene chloride and cooled down to -78° C. 41.3 g (0.33 mole) of oxalyl chloride were added slowly, followed by dropwise addition of 56.4 g (0.72 mole) of dry dimethylsulfoxide in 30 ml of methylene chloride, all the while keeping the temperature below -70° C. After the addition was completed the reaction mixture was stirred at -78° C. for 30 minutes and 60 g (0.36 mole) of the previously prepared 3-hydroxymethyl-5-methylbenzoic acid were added in 1 portion, followed by dropwise addition of 131.4 g (1.3 mole) of triethylamine, keeping the temperature below -65° C. during each of the additions. The reaction mixture was then warmed up slowly to room temperature, stirred for 90 minutes and then washed with 2% aqueous sodium hydroxide (3×500 ml). The combined basic layers were washed with hexane once and acidified with concentrated hydrochloric acid and then extracted with ethyl acetate (4×500 ml). The combined organic layers were washed with water (1×500 ml) and then with brine (1×300 ml) and dried over anhydrous magnesium sulfate. The solvent was then eliminated in a rotavap. The resulting oily product was triturated with hexane and filtered yielding 52 g (88%) 3-formyl-5-methylbenzoic acid as a tan solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].[C:15]1([CH3:35])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Si:23]([C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34])(Cl)Cl>C1COCC1>[C:15]1([CH3:35])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Si:23]([C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34])([CH:10]1[C:8]2[C:13](=[CH:3][CH:2]=[CH:1][CH:9]=2)[CH:12]=[CH:11]1)[CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [Li]CCCC
Reactant: Cc1cc(C)c([Si](Cl)(Cl)c2c(C)cc(C)cc2C)c(C)c1
Reactant: C1=Cc2ccccc2C1
Solvent: C1CCOC1
Product: Cc1cc(C)c([Si](c2c(C)cc(C)cc2C)(C2C=Cc3ccccc32)C2C=Cc3ccccc32)c(C)c1
Temperature: 25 °C

Procedure:
7 g of indene in 50 cm3of THF were reacted with 24 cm3 of butyllithium (2.5-molar in hexane) at 0° C. under inert conditions. The mixture was heated to room temperature, added dropwise to a solution of 10 g of dimesityldichlorosilane in 40 cm3 of THF, and the mixture was refluxed for 4 hours. Decomposition of the batch with water, extraction with diethyl ether and chromatography on SiO2 using 2:1 toluene/hexane gave 3.28 g of dimesitylbis(indenyl)silane as a solid. MS(m/e,I rel %): 496 (100, M+); 1H NMR in CDCl3 : 2.22 ppm (12 H, s), 2.27 ppm (6 H, s), 3.40 ppm (4 H, s), 6.8-7.4 ppm (14 H, m).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccncc1)N(c1ccccc1)c1ccccc1

Procedure:
Employing the general method of Example 1, 27.5 g (0.12 mol) of diphenylcarbamic chloride and 20 g (0.12 mol) of 4-aminopyridine were heated under reflux for two hours in 150 ml of chloroform containing 12.0 g (0.12 mol) of triethylamine to produce the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[C:4]=1[C:17]([OH:19])=O)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:53]=[CH:52][C:35]([O:36][C:37]2[CH:38]=[CH:39][C:40]3[N:41]([CH:43]=[C:44]([NH:46][C:47]([CH:49]4[CH2:51][CH2:50]4)=[O:48])[N:45]=3)[CH:42]=2)=[C:34]([F:54])[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:49]1([C:47]([NH:46][C:44]2[N:45]=[C:40]3[CH:39]=[CH:38][C:37]([O:36][C:35]4[CH:52]=[CH:53][C:32]([NH:31][C:17]([C:4]5[C:5](=[O:16])[N:6]([C:9]6[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=6)[N:7]([CH3:8])[C:3]=5[CH2:1][CH3:2])=[O:19])=[CH:33][C:34]=4[F:54])=[CH:42][N:41]3[CH:43]=2)=[O:48])[CH2:50][CH2:51]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: CCc1c(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCc1c(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n(-c2ccc(F)cc2)n1C
Yield: 47 %

Procedure:
In the same manner as in Example 77 and using 5-ethyl-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (250 mg, 0.94 mmol), tetrahydrofuran (9 mL), N,N-dimethylformamide (1 drop), oxalyl dichloride (160 μL, 1.9 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.78 mmol) and N,N-dimethylacetamide (12 mL) as starting materials, the title compound (210 mg, 47%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34].C(N(CC)CC)C>C(#N)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1/[CH:34]=[CH:33]/[C:32]([O:36][CH3:37])=[O:35]
Reactant: Nc1cc(F)ccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(F)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a mixture of 2-bromo-5-fluoroaniline (35.00 g, 184 mmol, Aldrich), palladium (II) acetate (2.06 g, 9.18 mmol, Strem) and tri(o-tolyl)phosphine (5.60 g, 18.40 mmol; Strem) in acetonitrile (350 ml) at RT was added methyl acrylate (33.00 ml, 365 mmol, Aldrich) and triethylamine (64.00 ml, 460 mmol, Aldrich). The reaction was heated at 80° C. for 24 h. The reaction mixture was diluted with EtOAc (500 mL) and the resulting colorless crystalline solid was filtered and washed with EtOAc. The organic solution was concentrated to dryness and the solids were slurried in 10% EtOAc/hexane at 60° C. for 1 h. The slurry was cooled to RT and filtered. The solid was washed with 10% EtOAc/hexane and sucked dry with air to give 18.30 g (51%) of a light-yellow crystalline solid. m/z=195.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCCl
Reactant: COc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(NC(=O)CCCl)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 139.2 %

Procedure:
p-Anisidine (12.3 g) was dissolved in CH2C 12(30 ml) and the solution was cooled to 5° C. Aqueous NaOH (6.6 g in 13 ml water) and 3-chloro-propionyl-chloride (19.05 g) were simultaneous added to the above solution over 40 minutes. The two phase mixture was stirred at 5° C. for another 30 min. Water (250 ml) and concentrated HCl (3 ml) were then added . The product was isolated by filtration, washed with water and dried to a constant weight to give N-(4-methoxyphenyl)-3-chloropropionamide (29.7 g, 94.6 %) in 99.3% purity by HPLC analysis.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1c(O)cccc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(O)cccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-6-hydroxybenzoic acid (5.00 g, 32.029 mmol) in dimethyl formamide (200 mL) were added N,O-dimethylhydroxylamine hydro-chloride (6.25 g, 64.057 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.82 g, 48.043 mmol), 1-hydroxybenzotriazole (5.19 g, 38.435 mmol), and triethylamine (8.93 mL, 64.057 mmol). The mixture was stirred at room temperature for 15 hrs. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to give 2-fluoro-6-hydroxy-N-methoxy-N-methylbenzamide as an orange solid (4.320 g, yield; 68%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.IC1C=CC=C([N+:51]([O-:53])=[O:52])C=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[N+:51]([C:3]1[CH:4]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:7][CH:2]=1)([O-:53])=[O:52]
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3cccc([N+](=O)[O-])c3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Compound TTT in Example 83 above). In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.64 mmol) (from Example 82) was coupled with 1-iodo-3-nitrobenzene (175 mg, 0.70 mmol) (Aldrich) using CuI (13 mg, 0.068 mmol) and (Ph3P)2PdCl2 (22 mg, 0.031 mmol) (Aldrich) as catalyst in 3 mL DMF and 3 mL triethylamine at 70° C. for 13 hours to give (Z)-1,3-dihydro-5-(3-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 148 mg, 65%)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][C:23]([OH:25])=O)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.O[NH:51][C:52](=[NH:54])[CH3:53]>CN(C=O)C.ClCCl>[Br:1][C:2]1[C:3]([CH2:22][C:23]2[O:25][N:54]=[C:52]([CH3:53])[N:51]=2)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Reactant: CC(=N)NO
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(Cc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
A vial was charged with 2-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yl)acetic acid (0.0863 g, 0.2063 mmol) in 5 ml of DMF and DIEA (0.03953 ml, 0.2269 mmol), and tetramethylfluoroformamidinium hexafluorophosphate (TFFH) (0.060 g, 0.227 mmol) were added consecutively. The mixture was stirred for 30 minutes and N-hydroxyacetamidine (0.0168 g, 0.227 mmol) was added. The mixture was heated at 100° C. overnight. The mixture was then cooled, diluted with dichloromethane, and washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate/hexane to provide N-(5-bromo-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)pyridin-2-yl)-4-phenethylthiazol-2-amine (11 mg, 11.58% yield) as a yellow solid. 1H NMR (CDCl3) δ 2.37 (s, 3H), 2.94-2.98 (m, 4H), 4.25 (s, 2H), 6.39 (s, 1H), 6.89 (s, 1H), 7.14-7.26 (m, 5H), 8.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)nnc1Cl

Procedure:
To a suspension of 3,6-dichloropyridazine-4-carboxylic acid (1.16 g, 6 mmol) in toluene (20 mL) were added DMF (2 drops) and SOCl2 (4 mL) and the mixture was heated at reflux temperature for 3 h. The volatiles were removed and the residue was stripped with toluene. The resulting brown oil (3,6-dichloropyridazine-4-carbonyl chloride) was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=[C:7]([Br:24])[CH:6]=2.[C:25](N1C=CN=C1)(N1C=CN=C1)=[S:26]>C1COCC1>[Br:24][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:25](=[S:26])[NH:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cc(Br)ccc12
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A solution of tert-butyl 3-[(3-amino-7-bromoquinolin-4-yl)amino]propylcarbamate (9.3 g, 23.5 mmol) and 1,1′-thiocarbonyldiimidazole (4.6 g, 26 mmol) in THF (250 mL), and the reaction mixture was heated at reflux for two hours. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the reaction was incomplete, and additional 1,1′-thiocarbonyldiimidazole (1 g) was added. The reaction was heated at reflux for an additional hour, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in water, and the resulting solution was extracted with tert-butyl methyl ether. The combined organic fractions were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with a gradient of 2% ammonium hydroxide/methanol in dichloromethane) to provide 4 g of tert-butyl 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][O:54][CH2:55][CH2:56][NH2:57]>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][NH:57][CH2:56][CH2:55][O:54][CH3:53])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCNCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 40 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (17 μl, 0.10 mmol) was added 2-methoxyethylamine (7.0 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(2-methoxyethylamino)acetamide (Example 11) as an off-white solid (6 mg, 11%): m/z 637 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.71 (2H, t), 3.24 (3H, s), 3.33 (2H, m (obscured by DHO)), 3.40 (2H, t), 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.36 (2H, d), 7.43 (2H, d), 7.64-7.57 (3H, m), 7.92 (1H, m), 8.36-8.30 (3H, m), 8.59 (1H, s), 8.79 (1H, s).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.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]>[CH:30]1([C@H:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]5([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)COCCOC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (244 mg, 0.459 mmol), 6-vinyl-[1,4]dioxepane-6-carboxylic acid 57d (79 mg, 0.459 mmol), triethylamine (140 mg, 192 μL, 1.38 mmol) and tri(o-tolyl)phosphine (28 mg, 0.092 mmol) in 1,4-dioxane (9 mL) was degassed with nitrogen for 5 min and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol) was added and the mixture was heated to 80° C. for 45 min and then allowed to cool. The suspension was filtered and evaporated to give crude title compound which was used in the next stage without further purification. LCMS (m/z) 624.2 [M+H], Tr=1.58 min.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:33][N:32]=4)=[O:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccc(F)cn1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCc1ccc(F)cn1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Yield: 502.6 %

Procedure:
Stir mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid (0.767 g, 0.21 m mol), C-(5-fluoro-pyridin-2yl)-methylamine (0.041 g, 0.25 mmol), and EDC (0.063 g, 0.33 mmol) in dry CH2Cl2 (15 mL) under N2 and add DMAP (0.061 g, 0.50 mmol.). Stir the resulting mixture at ambient temperature for 72 h. Dilute the reaction mixture to 50 mL with CH2Cl2, wash with H2O, 1N NaOH, and brine sequentially. Dry the organic layer (MgSO4), filter and evaporate to give 0.189 g of crude product. Chromatograph on the ISCO using a 12 g column and eluting with Hexane-EtOAc (0-100%) to gives the title compound 0.60 g as a foam:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Se](=O)=[O:22].O>O1CCOCC1>[CH:1]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1)=[O:22]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1SC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C=O)nc(-c2ccccc2)nc1SC
Yield: 58.9 %

Procedure:
To a solution of ethyl 4-methyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (5 g 17.4 mmol) in 1.4-dioxane (50 mL) was added selenium dioxide (9.6 g, 86.5 mmol) and water (1.5 mL) and the reaction mixture was refluxed for 12 hours. Dioxane was removed in a vacuum and the crude solid suspended in ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to give the desired product (3.1 g). 1H-NMR (400 Hz, CDCl3): δ 10.10 (s, 1H), 8.54 (d, J=7.2 Hz, 2H), 7.56-7.43 (m, 3H), 4.47 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.64 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); MS m/z 303.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[N:22]O)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:12])([F:14])[F:13])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=NO)c2OC1C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#N)c2OC1C(F)(F)F
Yield: 193.3 %

Procedure:
The oxime from Step 1 (0.61 g, 1.7 mmol) and acetic anhydride (6 mL) were stirred at 140 ° C. for 6.3 hours. The reaction was poured into water, extracted with ethyl acetate, washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (1.09 g). The oil was purified by flash chromatography (10:1; hexanes: ethyl acetate) yielding upon concentration the title compound as a white solid (0.51 g, 88%): mp 114.6–115.6° C. 1H NMR (CDCl3/300 MHz) 7.65 (s, 1H), 7.53 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.87 (q, 1H, J=6.4 Hz), 4.36 (m, 2H), 1.37 (t, 3H, J=6.5 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[C:7]=2[CH:24]=1)#[N:2].C[Sn](C)(C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>CCOCC.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][F:13])([CH2:14][F:15])[CH:9]=[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:7]=2[CH:24]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CC(CF)(CF)O2
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [Cl-]
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Yield: 82.5 %

Procedure:
A mixture of 120 mg of 6-cyano-4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-2H-1-benzopyran, 87 mg of 2-trimethylstannylpyridine, 25.4 mg of tris-dibenzylidene acetone chloroform dipalladium (0), 12.8 mg of triphenylphosphine, 110 mg of lithium chloride and 6 ml of dry tetrahydrofuran was refluxed for 6.5 hours. After cooling, ether was added and the mixture was filtered using Celite. After the organic layer of the mother liquor was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2) to obtain 80 mg of oily 6-cyano-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.