Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:20][C:21]1[CH:22]=C([CH:25]=[CH:26][C:27]=1[F:28])N>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[C:9](=[CH:15][NH:16][C:18]1[CH:25]=[CH:26][C:27]([F:28])=[C:21]([Cl:20])[CH:22]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of ethyl 2-chloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanoate (50 mg, 0.177 mmol) in 1 mL of EtOH was treated with neat 3-chloro-4-fluoroaniline (25.8 mg, 0.177 mmol). After stirring at rt until complete by TLC, the reaction was concentrated in vacuo. The residue was subjected to flash chromatography (1:1 EtOAc/hexanes), affording 42.6 mg (63%) of the product as a white solid, mp 96-102° C. 1H NMR (400 MHz, CDCl3 9:1 ratio of alkene isomers, major isomer NMR given) δ12.66 (d, 1H, J=12.8 Hz), 8.50 (d, 1H, J=13.2 Hz), 7.37-7.16 (m, 7H), 4.01 (q, 2H, J=7.1 Hz), 0.93 (t, 2H, J=7.1 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[S:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:20]([N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[S:10][CH:9]=1)[CH2:21][CH3:22]
Reactant: c1cc(Nc2csc3cnccc23)ccn1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(c1ccncc1)c1csc2cnccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
3-(4-Pyridinylamino)thieno[2,3-c]pyridine (4 g) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 0.8 g washed with heptane) in 50 mL of dimethylformamide. After anion formation was completed 1-bromopropane (2.2 g) was added. After stirring one hour the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water saturated sodium chloride, and then was dried (anhydrous magnesium sulfate), filtered and evaporated to 5 g of a dark oil. Elution through silica with 5% methanol in ethyl acetate via flash column chromatography afforded 3.5 g of a yellow solid. Elution through alumina with ether via column chromatography afforded 2.8 g of a yellow solid. Recrystallization from heptane afforded 2.6 g (54.8%) of yellowish crystals, m.p. 119°-120° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCCNCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCN(CCCCO)c1ccc(C=O)cc1
Temperature: 95 °C

Procedure:
To a three neck flask fitted with a mechanical stirrer, a thermometer, and a condenser, is added 124 g (1 mole) of 4-fluorobenzaldehyde, 145.3 g (1 mole) of N-butyl-N-4-hydroxybutylamine, 138.2 g (1 mole) of anhydrous potassium carbonate, and dimethylsulfoxide. The mixture is then heated at 95° C. until the reaction is complete. After cooling to room temperature, the solution is poured into a four-fold excess of ice water, and the solid product is collected by filtration and purified by recrystallization from tetrahydrofuran/benzene.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)[N:13]=1>O.CO>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=[N:2][OH:3])[N:13]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
3.5 g of hydroxylamine hydrochloride were added to 100 ml of a 1:1 mixed solution of water and methanol containing 3.5 g of potassium carbonate at 0° C. The solution was stirred at 0° C. for 10 minutes. At 0° C., 13.0 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour and then warmed at 60° C. for 1 hour. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=5:1) to obtain 7.7 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][C:9]=1[OH:17].[OH:20]S(O)(=O)=O.O=S(=O)=O.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[C:18]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[C:9]([OH:17])[C:8]=3[C:7](=[O:20])[C:6]=2[C:5]([F:19])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cncc(O)c1Cc1cc(Cl)ccc1F
Agent: O=C([O-])O
Agent: O=S(=O)=O
Agent: [Na+]
Product: O=C1c2c(O)cncc2C(=O)c2c(Cl)ccc(F)c21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4-(5'-chloro-2'-fluorobenzyl) -5-hydroxynicotinic acid of Preparative Example 27 (0.15 g) and 20% oleum (2 mL) is stirred for 45 minutes at 125°-130° C. (external bath temperature). The reaction mixture is then allowed to cool at room temperature and poured over 20 g of crushed ice and the resultant mixture neutralized with solid sodium bicarbonate to pH=7. The dione is extracted with dichloromethane (4×20 mL) and the combined organic phases are dried over MgSO4 and concentrated to dryness. The product is obtained as a yellow-tan solid (0.12 g) which darkens on standing in air.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11](OCC)[O:12]CC)=[CH:8][C:9]=1[CH3:10])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: CCOC(OCC)c1cc(C)c(C(=O)OC)s1
Solvent: C1COCCO1
Solvent: O=CO
Product: COC(=O)c1sc(C=O)cc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 5-diethoxymethyl-3-methyl-thiophene-2-carboxylic acid methyl ester (4.41 g, 17.1 mmol) in dioxane (20 ml) was cooled to 0° C. (ice bath). 88% formic acid (40 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 30 min. The mixture was concentrated under reduced pressure to afford the desired product which was not further purified (3.2 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[N:35]1([C:16]([C:15]2[CH:19]=[CH:20][C:12]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:21])([F:22])[F:1])=[N:4]3)=[CH:13][CH:14]=2)=[O:18])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A solution of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (87 mg, 0.28 mmol) in dichloromethane (3 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (46 mg, 0.28 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Pyrrolidine (23 mg, 0.32 mmol) was then added and the stirring continued for 1 hour at room temperature. The reaction mixture was then added to a 5 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (51 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 2,4,6-trimethylphenol (161 mg, 1.16 mmol) in 1-methyl-2-pyrridone (2 mL) in a sealed tube was added NaH (46 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (100 mg, 0.39 mmol) in 1-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 107 mg (77%) of 7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a stirred solution of 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (0.69 g), ethyl 2-butynoate (0.43 mL), tetrahydrofuran (15 mL) and toluene (25 mL) was added tributylphosphine (0.54 mL) at room temperature under argon atmosphere. After the mixture was stirred at 40° C. for 4 h, ethyl 2-butynoate (0.22 mL) and tributylphosphine (0.27 mL) were added thereto. After stirring at 40° C. for 2 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=30:70 to 75:25, volume ratio) to give the title compound (684 mg, 72%) as a light yellow oil. MS 489 (MH+).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1>>[C:4]12[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2]3[C:3]1=[C:12]([C:19]1[C:18]([CH:22]=3)=[CH:17][N:16]=[CH:21][CH:20]=1)[CH:11]=[CH:10][CH:9]=2
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: O=Cc1cccnc1
Product: O=C1OC(=O)c2cc3cnccc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and pyridine-3-carboxaldehyde:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:11]([OH:13])=O)=[C:6]([C:14]([OH:16])=[O:15])[N:5]=2>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]1[C:11]([O:16][C:14](=[O:15])[C:6]=1[N:5]=2)=[O:13]
Reactant: Cc1nc2cc(C(=O)O)c(C(=O)O)nc2o1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cc3c(nc2o1)C(=O)OC3=O
Temperature: 70 °C
Yield: 97 %

Procedure:
A suspension of 2-methyloxazolo[5,4-b]pyridine-5,6-dicarboxylic acid (4.84 g, 0.0218 mol) in acetic anhydride (150 mL) is slowly heated to 70° C. at which point all the solids dissolve forming a yellow solution. The reaction mixture is heated at 70° C. overnight, cooled to room temperature, and concentrated in vacuo. Xylene is added to remove excess acetic anhydride by codistillation. 2-Methyloxazolo[5,4-b]pyridine-5,6-dicarboxylic anhydride is obtained as a pale yellow solid in 97% yield melting point 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14](O)=[O:15].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:32][NH2:33]>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([NH:32][NH2:33])=[O:15]
Reactant: NN
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)NN)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
To a solution of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.050 g, 0.175 mmol) in anhydrous THF (2 mL), under N2, was added CDI (0.030 g, 0.184 mmol). The mixture was stirred at rt for 4 h and additional CDI (0.030 g, 0.184 mmol) was added. After 45 min, additional CDI (0.079 g, 0.49 mmol) was added. After 5 min, hydrazine (0.112 g, 3.5 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was partitioned between EtOAc and 0.2N NaOH. The organic phase was washed with 0.2N NaOH and sat'd brine. The combined aqueous phases were extracted with EtOAc (×2). The second EtOAc phases were washed with sat'd NaHCO3 solution and brine. The organic phases were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-10% MeOH—CH2Cl2 gradient) to afford the title compound (0.027 g, 52% yield): MS (ES) m/z 299 (M+1).
Reaction SMILES: C([O:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13](Br)[C:8]=2[O:7][C:6]1([CH3:16])[CH3:15])(=O)C.C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C>O1CCCC1>[OH:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([B:22]([OH:25])[OH:23])[C:8]=2[O:7][C:6]1([CH3:16])[CH3:15]
Reactant: COB(OC)OC
Reactant: CC(=O)OC1c2cccc(Br)c2OC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2c(B(O)O)cccc2C1O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
A stirring solution of 5.7 grams (0.020 mole) of 3-acetoxy-7-bromo-2,3-dihydro-2,2-dimethylbenzofuran in 150 mL of tetrahydrofuran is cooled to -80° C., and 18.2 mL of n-butyllithium in hexanes (2.5 Molar-0.046 mole) is added dropwise during a 15 minute period, while maintaining the reaction mixture temperature at about -80° C. Upon completion of the addition, the reaction mixture is stirred at -80° C. for 15 minutes. After this time, 6.9 mL (0.061 mole) of trimethyl borate is added during a 1 minute period. The reaction mixture is then allowed to warm slowly to ambient temperature during a 3 hour period, where it is stirred for an additional 1 hour. After this time, the reaction mixture is concentrated under reduced pressure to a volume of about 50 mL. The concentrate is then poured into 500 mL of ice-water. The mixture is then made acidic with about 26 mL of aqueous 2N hydrochloric acid. The mixture is filtered, yielding 2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-ylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13](Cl)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:37]=[CH:36][C:27]([O:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13]([O:35][C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:36]=[CH:37][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=4)=[CH:34][CH:33]=3)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 82 %

Procedure:
2-(4-(4-Chlorophenoxy)phenoxy)propionic acid chloride (0.6 g) and 4-(4-nitrophenoxy)phenol (0.5 g) were dissolved in dry tetrahydrofuran (10 ml), and the solution was stirred with an addition of triethylamine (0.3 ml) at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, the residue was dissolved in methylene chloride (20 ml), and washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water, saturated aqueous sodium hydrogen carbonate, water, and aqueous saturated sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue obtained was purified by medium pressure column chromatography to obtain 4-(4-nitrophenoxy)phenyl 2-(4-(4-chlorophenoxy)phenoxy)propionate (0.8 g)
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[CH:26]=[N:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:24]([CH3:23])[N:25]=[CH:26]4)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: Cn1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc5c(cnn5C)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (from Combi-Blocks). LCMS calculated for C24H24N5O2(M+H)+: m/z=414.2. Found 414.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6](/[CH:7]=[N:8]/[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[H][H]>[Pd].CC(=O)OCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNNC(=O)OC(C)(C)C)cc1
Yield: 104.3 %

Procedure:
Add 10% palladium on carbon (water wet, 20 g) slurried in EA (100 mL) to a sealed pressure reactor via vacuum transfer. Rinse transfer line with a minimal amount of EA. Charge (E)-tert-butyl 2-(4-methoxybenzylidene)hydrazinecarboxylate (320 g, 1.28 mol) dissolved in tetrahydrofuran (THF, 1000 mL) via vacuum transfer and rinse line with a minimal amount of THF. Pressurize the reactor to 50 PSI with H2 and mix the contents of the reactor at 20±10° C. Continue the reaction, maintaining the hydrogen pressure at 50 PSI, until no further hydrogen uptake is observed. Filter the reaction solution to remove the catalyst and wash the catalyst filter-cake with THF (500 mL). Add the wash to the reaction filtrate. Concentrate the solution in vacuo to obtain the title compound (337 g, 86%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.1-8.3 (s, 1H), 7.1-7.3 (d, 2H), 6.8-6.9 (d, 2H), 4.4-4.6 (bs, 1H), 3.7-3.8 (s, 2H), 3.6-3.7 (s, 3H), 1.3-1.5 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([O:20]C)=O.O.[NH2:23][NH2:24]>C(O)C>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:23][NH2:24])=[O:20]
Reactant: NN
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (1.019 g, 3.42 mmol) and hydrazine monohydrate (0.3 mL, 6.19 mmol) in ethanol (10 mL) was heated under microwave conditions for 10 min at 120° C. After that time, the reaction was cooled to room temperature and the product was collected by filtration and washed with cold ethanol to give 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbohydrazide (0.607 g, 60%) as bright orange crystals.
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[O:5])[CH2:3][CH2:2]1.[Br:7][CH2:8][C:9](Br)=[O:10]>O1CCOCC1>[Br:7][CH2:8][C:9]([NH:6][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[O:10]
Reactant: O=C(Br)CBr
Reactant: NC(=O)C1CC1
Solvent: C1COCCO1
Product: O=C(CBr)NC(=O)C1CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
Cyclopropanecarboxamide (58.7 g, 690 mmol) in 1,4-Dioxane (1600 ml) was added 2-bromoacetyl bromide (59.9 ml, 690 mmol) at room temperature and stirred for 4 h at 60° C. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and carefully washed with satd. NaHCO3, water then with brine solution, dried over Na2SO4 and concentrated to get N-(2-bromoacetyl)cyclopropanecarboxamide (138 g, 670 mmol, 97% yield) as an off white solid. This material was used without purification. ESI-MS:m/z 208.0 (M+2H)+.
Reaction SMILES: [Br: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])=[C:6]([OH:17])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:17][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][Br:1])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COc1ccc(CCBr)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(CCBr)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a solution of ethyl 2-[4-(2-bromoethyl)-2-hydroxyphenoxy]acetate (400 mg) in N,N-dimethylformamide (4 ml) were added potassium carbonate (200 mg) and benzyl bromide (0.17 ml) and the mixture was stirred for 13.5 hours at room temperature. The reaction mixture was poured into water and extracted with a mixed solution of diethyl ether and ethyl acetate (3/1). The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=17/3) gave ethyl 2-[2-benzyloxy-4-(2-bromoethyl)phenoxy]acetate (252 mg).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]2[C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl>>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]2[C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Agent: Cl
Product: O=C(NOCCO)c1cc2ccncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (54 mg, 0.11 mmol) in IMS (3 mL) was added aqueous hydrochloric acid (0.5 mL, 1M, 0.5 mmol). The reaction was stirred at room temperature for 1 hour then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The product was triturated with MeOH/diethylether to yield the title compound as a light brown solid (20 mg, 39%). 1H NMR (d6-DMSO, 400 MHz) 11.32 (1H, s), 8.69 (1H, s), 7.98 (1H, s), 7.49 (1H, dd, J=11.0, 2.0 Hz), 7.40 (2H, s), 7.18-7.14 (1H, m), 6.74 (1H, s), 5.92 (1H, t, J=8.8 Hz), 4.65 (1H, t, J=5.6 Hz), 3.75 (2H, t, J=5.0 Hz), 3.46 (2H, q, J=5.0 Hz). LCMS (Method A): RT=8.14 min, M+H+=457.