Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:6]([CH2:14][OH:15])[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:6]([CH2:14][OH:15])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)O)cc1
Yield: 53.5 %

Procedure:
A solution of 0.75 g (1.72 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionic acid, tert-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of CH2Cl2 was stirred at room temperature for 3 hours and then concentrated to dryness under vacuum. To the residue was added H2O, CH2Cl2 and 1N NaOH until the aqueous layer reached pH 8. The aqueous layer was then separated, acidified with 2 N citric acid and extracted with ethyl acetate. The extract was washed with H2O, brine and dried Na2SO4. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Anal. for C17H20N2O6S: Calc'd: C, 53.7; H, 5.3; N, 7.4; Found: C, 53.0; H, 5.3; N, 6.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: Cc1cccc(CC(=O)O)c1
Product: Cc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure I above, and using 3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tl c on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[N:13]([CH2:24][C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36][CH2:35]4)[CH:28]=[CH:29][CH:30]=3)[C:12](=[O:45])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Li+].[CH3:47]C([N-]C(C)C)C.CN(P(N(C)C)(N(C)C)=O)C.CI>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[N:13]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]([CH3:47])[C:32](=[O:44])[CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36][CH2:35]4)[CH:28]=[CH:29][CH:30]=3)[C:12](=[O:45])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(NC(=O)CN2CCN(CCOC)CC2)c1
Agent: [Li+]
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(N(C)C(=O)CN2CCN(CCOC)CC2)c1
Temperature: -78 °C

Procedure:
A solution of 1.20 g (2 mmol) of N-{3-[4-(4-isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1-ylmethyl]-phenyl}-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-acetamide is treated with 4.1 ml 0.5 M LDA-solution (in THF) and 0.35 ml (2.0 mmol) HMPT at −78° C. The cooling bath is removed and stirring continued for half an hour while the solution turns slowly red. The reaction mixture is cooled down again to −78° C., 284 μl methyl iodide (2 mmol; diluted with 5 ml THF) is added. After stirring overnight at rt, the orange solution is concentrated in vacuo The yellow foamy residue is purified by chromatography (CH2Cl2/MeOH 9:1). Yield: 480 mg (13%) yellow foam.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[F:13][C:14]1([C:33](O)=[O:34])[C:23]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[CH:22][C:17]2=[N:18][CH2:19][N:20]([CH3:21])[C:16]2=[CH:15]1.C1(N=C=NC2CCCCC2)CCCCC1.CCOC(C)=O>C1COCC1>[F:1][C:2]1[C:7]([O:8][C:33]([C:14]2([F:13])[C:23]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])=[CH:22][C:17]3=[N:18][CH2:19][N:20]([CH3:21])[C:16]3=[CH:15]2)=[O:34])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(=O)O)C=C21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)C=C21

Procedure:
A solution of pentafluorophenol (21.6 g, 0.113 mol) DMF (100 ml) at room temperature was slowly added to a suspension of 5-fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid (40.0 g , 0.093 mol) in 165 ml of THF, followed by dicyclohexylcarbodiimide (24.14 g, 0.118 mol). The mixture was stirred overnight at room temperature (TLC-EtOAc), evaporated under vacuum and is added 200 g of crushed ice to the residual DMF solution. The light yellow compound separated was filtered and vacuum dried to give the title compound (crude), which is directly proceeded to next step without purification. Yield: 55 g (99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30]C(=O)C)[CH:10]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:30])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)cn1
Temperature: 85 °C
Yield: 66 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo-[d]imidazol-1-yl)biphenyl-3-yl)acetamide of Example 1 (1.0 g, 2.26 mmol) in ethanol (10 ml) was added aqueous solution of NaOH (800 mg, 20 mmol, 8.9 eq.) and the mixture was heated at 85° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off under reduced pressure to afford the product in 66% yield (0.6 g). LC-MS (ESI): Calculated mass: 401.41; Observed mass: 402.1 [M+H]+ (rt: 1.198 min).
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C@:7]23[CH2:14][C@@H:13]([NH:15][C:16](=[O:30])[C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=4)[CH2:12][N:11]2[C:10](=[O:31])[N:9]([C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)[C:8]3=[O:40])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C@:7]23[CH2:14][C@@H:13]([NH:15][C:16](=[O:30])[C:17]4[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=4)[CH2:12][N:11]2[C:10](=[O:31])[N:9]([C:32]2[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=2)[C:8]3=[O:40])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N[C@H]2CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(Cc3ccc(Br)cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C(=O)N[C@H]2CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(Cc3ccc(Br)cc3)C2)cc1
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of Example 80 (0.161 g) in CH2Cl2 (4 mL) was added TFA (1 mL). After 3 hours at room temperature, the reaction mixture was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel: 80:20 CH2Cl2:MeOH, Chromatotron) to afford the titled compound (0.133 g). MS (m/z) 614 [M—H]−.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([N:33]3[CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: CCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Product: CCN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CC1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.17 mmol) was used in general procedure 3 with 1-ethylpiperazin (0.868 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide. MS (Q1) 482.3 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH:21]=O)[CH:4]=1.[NH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5](/[CH:21]=[N:23]/[N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:4]=1
Reactant: COCn1c(=O)c2c(c3c(OC)cc(C=O)cc31)NCCC2
Reactant: NN1CCOCC1
Solvent: Cc1ccccc1
Product: COCn1c(=O)c2c(c3c(OC)cc(/C=N/N4CCOCC4)cc31)NCCC2
Temperature: 25 °C
Yield: 91 %

Procedure:
The compound (95 mg, 0.31 mmol) prepared in step 1 was dissolved in toluene (10 ml), added with 4-aminomorpholine (0.031 ml, 0.31 mmol) at room temperature. The resulting mixture was then heated and allowed to reflux under dean-stark condenser for 5 hours. After cooling to room temperature, the solivent was removed under reduced pressure and the residue was purified by flash column chromatography (dichloromethane:methanol=20:1) to obtain the title compound (109 mg, yield: 89%, yellow solid).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([NH:5][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(N)cccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)cccc1NN
Yield: 110.5 %

Procedure:
To a stirred suspension of 3-chloro-2-methoxyaniline (5 g, 31.7 mmol, 1.0 eq) in conc. HCl (25 mL) was added a solution of NaNO2 (3.28 g, 47.55 mmol, 1.5 eq.) in water (5 mL) dropwise at −5 to 0° C. until the reaction mixture formed a clear solution. The reaction mixture was added drop wise to a stirred solution of SnCl2 (13.24 g, 69.74 mmol, 2.2 eq) in conc. HCl (50 mL) at −5° C. for 30 min. A solid precipitate obtained was filtered out and washed with excess of ice cold water to get (3-chloro-2-methoxyphenyl)hydrazine (6.049 g, 94%, brown solid; TLC system: EtOAc/PE (3:7) Rf: 0.4).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH3:13][O:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:18]
Reactant: COc1cc(OC)c(C(=O)Cl)cc1OC
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1OC

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,4,5-trimethoxybenzoyl chloride according to the procedure of Example 19 to yield 5-(2,4,5-trimethoxybenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 159°-160.5° C. after purification from ethanol.
Reaction SMILES: [C:1]([N:4]1[C:18]2[C:19]3[CH:6]([CH2:7][C@@H:8]4[C:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:12][C@H:11]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:10][N:9]4[CH3:28])[CH2:5]1)(=[O:3])[CH3:2].[Br:29]Br>C(O)(=O)C>[C:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C:13]([C:14]=3[C:15]([Br:29])=[CH:16][CH:17]=2)=[CH:12][C@H:11]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:10][N:9]4[CH3:28])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3C(C[C@H]2N(C)C1)CN4C(C)=O
Solvent: CC(=O)O
Product: CCN(CC)C(=O)N[C@H]1C=C2c3c(Br)ccc4c3c(cn4C(C)=O)C[C@H]2N(C)C1

Procedure:
The compound is produced by reacting 3-(1-acetyl-9,10-didehydro-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea with elemental bromine in 5% acetic acid, analogously to Example 6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To 3-(4-bromophenyl)-1H-pyrazole (2.0 g, 9.0 mmol) in DMF was added sodium hydride (0.54 g, 13 mmol) (60% in oil) and the reaction was stirred at ambient temperature for 30 minutes. (2-(Chloromethoxy)ethyl)trimethylsilane (4.5 g, 27 mmol) was added and the reaction was stirred overnight. Water was added and the aqueous phase extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated. The crude material was purified by reverse phase chromatography (SP4, 25M, water/CH3CN 60:40 to 0:100, 20 column volumes) to yield 3-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.4 g, 76% yield) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])/[CH:11]=[CH:28]/[C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(/C=C/C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(/C=C/C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
A suspension of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one (600 mg, 3.1 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (863 mg, 6.2 mmol) in H2O (5 mL) was added and the reaction mixture was stirred for further 10 min at 0° C. After the dropwise addition of 4-(trifluoromethoxy)-benzaldehyde (473 μl, 3.3 mmol), the orange suspension was heated to reflux for 4 d at 40° C. The solvent was evaporated in vacuo and the resulting residue was purified by flash-chromatography on silica gel (Hexane/EtOAc 2:1) and dried in vacuo to obtain NW351 as a yellow solid (191 mg, 17%). mp: 93-95° C. 1H NMR (300 MHz, CD3OD) δ (ppm): 7.72 (d, 3J=8.4 Hz, 2H, HAr), 7.71 (d, 3J=15.9 Hz, 1H, Hvin), 7.68 (d, 3J=15.6 Hz, 1H, Hvin), 7.27 (d, 3J=8.3 Hz, 2H, HAr), 7.24 (d, 4J=1.9 Hz, 1H, HAr), 7.19 (d, 3J=16.0 Hz, 1H, Hvin), 7.15 (dd, 3J=8.4 Hz, 4J=2.0 Hz, 1H, HAr), 7.02 (dd, 3J=15.9 Hz, 5J=0.99, Hz, 1H, Hvin), 6.83 (dd, 3J=8.2 Hz, 5J=0.9 Hz, 1H, HAr), 3.89 (d, 5J=0.9, 3H, OCH3). 13C NMR (75 MHz, CD3OD) δ (ppm): 191.1 (C), 151.7 (q, 4J (C, F)=1.7 Hz), 151.2 (C), 149.4 (C), 146.4 (CH), 142.4 (CH), 135.4 (C), 131.3 (CH), 128.1 (C), 127.6 (CH), 125.0 (CH), 123.6 (CH), 122.3 (CH), 120.2 (C), 116.7 (CH), 112.2 (CH), 56.5 (OCH3). MS (FAB) m/z: 365.2 (M+). Anal. calcd for C19H15F3O4: C, 62.64; H, 4.15. Found: C, 62.45; H, 4.39%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([O:8][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)cnc1Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cc(Cl)cnc1Cl
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To an acetonitrile solution (400 ml) of 2,5-dichloropyridin-3-ol (20.0 g) (Synthesis, 1990, 6, 499-501) and tert-butyl 2-bromo-2-methylpropionate (54.4 g) was added at room temperature potassium carbonate (30.3 g), followed by stirring for 12 hours under heating at reflux. The insolubles were filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography to afford tert-butyl 2-[(2,5-dichloropyridin-3-yl)oxy]-2-methylpropionate (31.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6]([CH3:9])=[CH:7][O:8][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(N(C(C)C)C(C)C)C>C(O)C>[CH3:9][C:6]1[C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([N:1]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: BrCCCCCBr
Reactant: Cc1cc2c(C)coc2cc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(C)coc2cc1N1CCCCC1

Procedure:
A mixture of 8 g (49.6 mmole) of 6-amino-3,5-dimethylbenzofuran, 23 g (0.1 mole) of 1,5-dibromopentane, 12.9 g (0.1 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 18 hours. The residue obtained after concentration by evaporation in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is chromatographed with petroleum ether/methylene chloride over silica gel. Distillation of the pure fractions in a bulb tube (130°/10-1 torr) yields 3,5-dimethyl-6-piperidinobenzofuran having a melting point of 64°-66°.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[CH2:12]([O:19][CH2:20][CH2:21][SH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C=O)C.O>[CH2:12]([O:19][CH2:20][CH2:21][S:22][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: SCCOCc1ccccc1
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1SCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 2-nitrobenzonitrile (5.85 g) in DMF (20 mL) was treated with 2-(benzyloxy)ethanethiol (Example 320a, 6.64 g) and a solution of potassium hydroxide (3.76 g) in water (5 mL) was added dropwise under nitrogen. The resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified (SiO2 chromatography eluting with 50% diethyl ether in iso-hexane) to afford the subtitle compound as a solid (7.08 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:17])[CH:5]=2.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:2]([CH3:1])[N:3]2[CH2:18][CH2:19][CH3:20])=[CH:8][CH:7]=1)[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(-c2ccncc2)c2ccc(O)cc21
Product: CCCn1c(C)c(-c2ccncc2)c2ccc(OC(C)(C)C(=O)OCC)cc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-6-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)\[O-])[CH3:2].[Li+].Cl.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>>[CH3:31][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])=[N:30]2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(C)cc2)n1
Yield: 67 %

Procedure:
Starting from 631.5 mg (2.15 mmol) of lithium (1Z)-4-ethoxy-3,4-dioxo-1-[3-(trifluoromethyl)phenyl]but-1-en-1-olate from example 1A and 463.2 mg (2.92 mmol) of 4-tolylhydrazine hydrochloride, 535.8 mg (1.4 mmol, 67% yield of theory) of product are obtained according the method described in example 4A.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C-:32]#[N:33].[Na+]>CS(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([C:32]#[N:33])=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: [C-]#N
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cnc2c(Sc3ccc(Nc4nnc(C#N)c5ccccc45)cc3)ccnc2c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
In a 15 ml sealed pressure tube, was dissolved 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (150 mg, 490 μmol) in 0.8 ml of DMSO. Sodium cyanide (72 mg, 1469 μmol) was added and the reaction was capped and stirred at 130° C. for 3 hours. The reaction was cooled to RT and purified via Gilson Reverse Phase HPLC eluting with a 12-75% gradient of ACN in water with 0.1% TFA. The product fractions were basified with saturated sodium bicarbonate and extracted into DCM. The DCM layers were dried over Na2SO4, filtered and concentrated in vacuo to afford 4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazine 1-carbonitrile. MS: [M+H]=437.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]([C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:30](Cl)CCl.CN(C1C=CC=CN=1)C>ClCCl>[C:21]([O:20][C:18]([NH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]([C:25]([O:27][CH3:30])=[O:26])[CH2:14]1)=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Reactant: ClCCCl
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis (+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (1.0 eq), methanol (20 eq.) and EDC (1.3 eq) in dichloromethane at a concentration of 0.25 M at 0*C was added dimethylaminopyridine (0.1 eq). After stirring for 48 hours as the reaction was allowed to warm to rt the volatiles were removed in vacuo. Upon addition of ethyl actetate and washing with H2O (3×), 1N HCl, NaHCO3(sat.) and brine, the solution was dried over MgSO4, filtered, concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to yield cis (+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)piperidine-1,3-dicarboxylate. LCMS (m/z): 293.1 (MH-Boc+); LC Rt=4.09 min
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:26]#[C:25][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[CH:3][N:4]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Product: Nc1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nn23)cn1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 11) (229 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (101 mg, 0.85 mmol) according to general procedure II. Obtained as a bright orange solid (180 mg, 80%). MS (ISP) 448.2 [(M+H)+]; mp 267° C.