Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cncc(Cl)n2)cc1
Reaction time: 12 h
Yield: 74.7 %

Procedure:
To a solution of 2,6-dichloropyrazine (4.00 g, 26.8 mmol) and 4-methoxybenzylamine (7.02 mL, 53.7 mmol) in DMF (30 mL) was added K2CO3 (7.42 g, 53.7 mmol) at RT and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with cold water (100 mL) and extracted into ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a residue that was purified by CombiFlash (REDISEP®, silica gel, 24 g, 25% EtOAc/petroleum ether) to give 6-chloro-N-(4-methoxybenzyl)pyrazin-2-amine (5.00 g, 74.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.31 (s, 3H), 4.37 (d, J=6.0 Hz, 2H), 6.87-6.93 (m, 2H), 7.24-7.31 (m, 2H), 7.70 (s, 1H), 7.90 (s, 1H), 7.95 (t, J=5.5 Hz, 1H).
Reaction SMILES: [S:1]1[C:9]2[C:8](=[O:10])[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)CC.CCOCC>[N+:11]([C:7]1[C:8](=[O:10])[C:9]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=c1cc[nH]c2ccsc12
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CCC(=O)O
Product: O=c1c([N+](=O)[O-])c[nH]c2ccsc12
Yield: 78 %

Procedure:
To a solution of 3.1 g of thieno[3,2-b]pyridin-7(4H)-one 13 in 90 ml of propionic acid is added 1.5 ml of fuming nitric acid at 110° C. with stirring and the mixture is refluxed for 1 hour. The cooled mixture is diluted with 50 ml of ether and the resulting crystals are collected by filtration, washed with water and ether-methanol, and dried to give 3.13 g (78%) of Compound 14. Recrystallization from dimethyl sulfoxide-methanol affords colorless crystals melting at 328°-331° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>>[CH3:12][CH:8]1[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:14](=[O:15])[CH3:13])[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)c2sc(N)nc2C1
Product: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (25.0 g, 0.137 mol) in Ac2O (300 mL) is heated at reflux temperature for 3 h. The reaction mixture is then cooled to RT and the precipitate is filtered off to afford N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide. Yield: 26 g.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:32])=[C:24]([C:28]([F:31])=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:32])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[C:28]([F:31])=[CH:29][CH:30]=1
Reactant: O=C(O)c1c(F)ccc(Cl)c1F
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3c(F)ccc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2,6-difluorobenzoic acid: MS (APCI) m/z 440 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([NH:30][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: NC1CCCCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)NC3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and cyclohexanamine. MS (ESI): mass calcd. for C23H23FN4O, 390.19; m/z found, 391.4 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.60-8.53 (m, 1H), 8.11 (d, J=1.5, 1H), 8.03-7.93 (m, 1H), 7.74-7.62 (m, 1H), 7.54-7.37 (m, 3H), 7.32 (dd, J=8.0, 1.7, 1H), 7.30-7.20 (m, 1H), 5.24 (d, J=8.3, 1H), 4.72 (s, 2H), 3.93-3.73 (m, 1H), 1.78-1.67 (m, 2H), 1.61-1.44 (m, 3H), 1.39-1.27 (m, 2H), 1.14-0.98 (m, 1H), 0.97-0.81 (m, 2H).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9](Br)[CH:8]=1.B(OC)(OC)[O:19]C>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([OH:19])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 34 mL of 1.6 M n-BuLi in hexanes in 20 mL of THF at −78° C. was added 8.15 g of 1,3-dibromo-5-tert-butylbenzene in 80 mL of THF dropwise over a period of 1 h. After 1 h at −78° C., 4.6 mL of B(OMe)3 was added, and after 20 min. the cold bath was removed and stirring continued with warming to r.t. After 1 h, EtOAc and 70 mL of 1 N HCl were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. To a stirring mixture of the crude product in 105 mL of 1 N NaOH at 0° C. was added 22 mL of H2O2 (30 wt % in H2O) dropwise. After 25 min. 5 N HCl was added to a pH=1. Ethyl acetate was added, and the organic layer was washed with 80 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (hexanes to 10% EtOAc/hexanes) provided 6.54 g of 3-bromo-5-tert-butylphenol as an orange oil with some impurity.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][NH:3]1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O.C(O)C>[CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][N:3]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1NCCN[C@@H]1C
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H]1NCCN(C(=O)OCc2ccccc2)[C@H]1C
Temperature: 20 °C
Yield: 48.2 %

Procedure:
A 100 mL, three-necked round-bottom flask was charged with cis-2,3-dimethylpiperazine (Helvetica Chimica Acta, 1994, 77, 1057-64) (1.781 g, 15.6 mmol). The flask was cooled in an ice bath, and a solution of methanesulfonic acid (2.02 mL, 31.2 mmol) in 1.4 mL of water was added slowly, maintaining the temperature below 40° C. The solution was cooled to 20° C., and 2 mL of ethanol was added. The pH was adjusted to 4 with 60% aqueous potassium acetate, and then benzyl chloroformate (2.08 mL, 14.8 mmol in 1 mL of THF) and potassium acetate solutions were simultaneously added dropwise with adjustment of the rate to maintain the reaction solution at pH 4, with cooling to maintain the temperature at 25° C. After the mixture was stirred an additional hour, the organic solvents were removed and the remaining aqueous solution was washed with ethyl acetate. The ethyl acetate wash was extracted with 1 M HCl twice to recover the desired product. The acid extracts were combined with the original aqueous solution, and the pH was adjusted to 11 by the addition of 6 N NaOH, with cooling to maintain temperature below 40° C. The aqueous solution was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo to provide phenylmethyl cis-2,3-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) as a yellow oil (1.77 g, 46%). LCMS: (M+H)+: 249.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=1[NH2:14].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:3]=1[N:14]=[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])[N:9]2[CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCNc1nc(C)nc(Cl)c1N
Reactant: O=Cc1ccccc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCn1c(-c2ccccc2Cl)nc2c(Cl)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
Heat a solution of 6-chloro-N4-(2-methoxyethyl)-2-methylpyrimidine-4,5-diamine (5.0 g, 0.023 mol), 2-chlorobenzaldehyde (4.8 g, 0.03 mol), 15% FeCl3 on SiO2 (20 g) in 1,4-dioxane (150 mL) to 100° C. for 16 h. Remove the silica by filtration through diatomaceous earth, and concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (150 mL) and add DDQ (5.2 g, 0.022 mol) at 0° C., and stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with ethyl acetate:n-hexane (40:60) to give the title compound (2.9 g). ES/MS m/z 337 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[Cl:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(-c2ccc(Cl)c(Cl)c2)cn1
Yield: 49 %

Procedure:
The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 3,4-dichloro-phenyl boronic acid (57 mg, 0.3 mmol) as described in example 208 to afford 25 mg (45%) of the title compound. LC/MS (m/z): 510 (M+1)+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].B(Br)(Br)Br.CO>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:4]3[C:3]([C:8](=[O:20])[CH:9]=2)=[CH:2][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ccccc2O)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (200 mg, 0.74 mmol) in dichloromethane (15 mL) was added BBr3 (185 mg, 0.74 mmol, 1M solution in dichloromethane) slowly at 0° C., and then stirred for overnight at rt. Then MeOH was added at 0° C. to quench the unreacted BBr3. The organic layer was washed with water, dried and concentrated to give a crude product, which was purified by column chromatography using 30% EtOAc in hexane to afford 50 mg (26%) of 2-(4-methoxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 253.08 (M+1), and 149.00.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH2:6])=[O:5])[NH2:3].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1>>[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25](/[C:28](=[N:3]/[N:2]([CH3:1])[C:4]([NH2:6])=[O:5])/[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: CN(N)C(N)=O
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\N(C)C(N)=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 21 %

Procedure:
The title compound was prepared from 1-methylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 21% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (dd, 1H), 8.31 (d, 1H), 8.05 (s, 2H), 7.97 (d, 1H), 7.77 (d, 1H), 7.72 (s, 1H), 7.47 (q, 1H), 6.54 (s, 2H), 4.58 (s, 2H), 3.19 (s, 3H), 2.37 (s, 3H). LCMS (method A): [MH]+=392, tR=4.76 min.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.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>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:16]=[N:15][C:5]4[NH:6][C:7]5[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=5[C:4]=4[CH:3]=3)=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: OCc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(CO)cc5c4c3)cc2)CC1
Temperature: 150 °C

Procedure:
A suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-methanol (40.7 mg, 0.146 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester (46.4 mg, 0.154 mmol) and bis(triphenylphosphine)palladium(II) dichloride (5.1 mg, 7.3 μmol) in acetonitrile (0.73 mL) and 2N aqueous sodium carbonate solution (0.73 mL) was heated at 150° C. under microwave irradiation for 20 minutes. The cooled reaction mixture was diluted with THF, the solid removed by filtration, and washed with THF and DCM. The combined filtrate was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 1-15% (2N ammonia methanol) in DCM) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.46 (s, 1H), 9.76 (s, 1H), 9.07 (d, J=1.8 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 4.13 (s, 2H), 3.38-3.30 (m, 8H), 2.89 (s, 3H). LCMS (Method D): RT=5.24 min, M+H+=374.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O=P(Cl)(Cl)Cl.O.CN([CH:26]=[O:27])C>>[CH:26]([C:5]1[CH:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2](=[O:1])[N:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2)=[O:27]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reaction time: 1 h
Yield: 93 %

Procedure:
Ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (1 g, 4.0 mmol) was dissolved in 2 ml DMF followed by the addition of POCl3 (1.0 ml, 11 mmol). The reaction mixture was stirred for 1 h, poured into 100 ml water and extracted three times with 100 ml dichloromethane. Evaporation of the organic solvent gave a sticky yellow solid, which was further purified by flash chromatography (ethyl acetate), followed by overnight stirring with 10 ml ether to remove the last traces of DMF. Filtration of the suspension and drying in vacuo gave a bright yellow powder (920 mg, 93%). M.p. 179-181° C. 1H NMR (δ, CDCl3): 1.43 (t, J=7 Hz), 4.42 (q, J=7 Hz), 7.51 (dd, J=7 Hz, J=7 Hz, 1H), 8.06 (dd, J=7, J=7 Hz, 1H), 8.80 (s, 1H), 9.57 (d, J=7 Hz), 9.90 (s, 1H). MS: m/z 245.0683; required for C13H11NO4: 245.0688.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:22][CH:23]=1)[N:21]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(F)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-fluoro-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-fluoro-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([N:16](C(C)C)[CH2:17]C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl.O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:13])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(I)cc(F)c1F
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1cc(I)cc(F)c1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
2,3 Difluoro-5-iodobenzoic acid (10.8 g, 38 mmol) was suspended in 80 mL of dry dichloromethane under nitrogen. Di-iso-propylethylamine (6.6 mL, 38 mmol) was added and the mixture was cooled to 0° C. Pivaloyl chloride (4.7 mL, 38 mmol) was added and the solution was stirred at 0° C. for 1.5 hrs. Dimethylamine was added (40% wt solution in water, 10.6 mL, 83 mmol) and the reaction mixture was stirred for 5 hrs. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane (50 mL). The layers were separated, the organic phase was washed with 1 N hydrochloric acid and brine. The organic phase was dried over magnesium sulfate and concentrated to give 10.3 g (33 mmol, 87%) of 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (ddd, J1=10 Hz, J2=7.5 Hz, J3=2 Hz, 1H), 7.57 (dt, J1=10 Hz, J2=2 Hz, 1H), 2.98 (s, 3H), 2.84 (s, 3H); MS: m/z 312 [MH+]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:31])[C:28](O)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:31])[C:28]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1COCCN1
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)O
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCOCC1
Yield: 26 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (400 mg, 0.87 mmol) was reacted with morpholine to give the title compound as a white solid (120 mg, 26%); NMR Spectrum 1.58 (d, 3H), 3.46-3.73 (m, 8H), 5.70 (s, 2H), 5.88 (q, 1H), 7.04-7.12 (m, 3H), 7.29 (d, 1H), 7.34-7.37 (m, 2H), 7.72-7.75 (m, 2H), 7.86 (d, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.54 (s, 1H), 11.13 (br s, 1H); Mass spectrum MH+ 527.
Reaction SMILES: [C:1]1([P:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=O)[CH2:9][C:8]2([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20].[B-]C#N.[Na+].Cl>CO>[CH2:18]([NH:21][CH:10]1[CH2:11][C:12]([CH3:14])([CH3:13])[P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([CH3:17])([CH3:16])[CH2:9]1)[CH2:19][CH3:20]
Reactant: CCCN
Reactant: CC1(C)CC(=O)CC(C)(C)P1c1ccccc1
Agent: Cl
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNC1CC(C)(C)P(c2ccccc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.9 %

Procedure:
A flask, under nitrogen, was charged with a mixture of 12.4 grams (0.05 mole) of 1-phenyl-2,2,6,6-tetra methyl-4-phosphorinanone, 17.7 grams (0.30 mole) of n-propylamine, 1.89 grams (0.03 mole) of sodium cyanotrihydroborate, 20 mls of 5N methanolic hydrochloric acid and 150 mls of methanol. The mixture was stirred at ambient temperature for three days and then treated with 20 mls of conc. hydrochloric acid. The reaction mixture was concentrated in vacuo and 30 mls of water and 25 mls of diethylether were added. The layers were separated and to the aqueous layer was added 8 grams of solid sodium hydroxide. The resultant basic mixture was extracted sequentially with five 25 ml portions of diethylether. The combined extracts were dried over anhydrous sodium sulfate, the solvent removed in vacuo and the residue distilled under reduced pressure to give 11.2 grams (77% yield) of colorless liquid, b.p. 140°-144° C. (0.1 mm Hg)
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([NH2:32])[C:21]([NH2:31])=[CH:22][C:23]=1[N:24]1[CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[F:17][C:18]1[C:23]([N:24]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][C:21]2[NH:31][C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:6]=3)=[N:32][C:20]=2[CH:19]=1
Reactant: Nc1cc(F)c(N2CCCOCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
3 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde and 43 mg of ferric chloride are added to a solution of 3 g of 4-fluoro-5-perhydro-1,4-oxazepin-4-ylbenzene-1,2-diamine in 60 mL of DMF. The reaction medium is stirred at 22° C. for 16 hours. After evaporation, the reaction crude is purified by flash chromatography. The elution is carried out in a 1/1 mixture of cyclohexane/ethyl acetate. 3 g of 5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazoleare isolated in the form of a red oil. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.40 to 2.25 (m, 8H); from 3.25 to 3.39 (m partially masked, 4H); 3.70 (m, 1H); 3.78 (m, 4H); 3.99 (m, 1H); 5.59 (dd, J=2.5 and 9.5 Hz, 1H); 7.16 (broad m, 1H); 7.39 (broad d, J=11.5 Hz, 1H); 9.17 (s, 1H); 12.75 (broad m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[C:11]([O:17][CH3:18])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[CH:3]=2)=[N:10][C:11]=1[O:17][CH3:18])#[N:16]
Reactant: COc1nc(Nc2cc(Cl)ncn2)cnc1C#N
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc(Nc2cc(NCC3CCN(C(=O)OC(C)(C)C)CC3)ncn2)cnc1C#N
Yield: 40.1 %

Procedure:
A solution of 5-(6-chloropyrimidin-4-ylamino)-3-methoxypyrazine-2-carbonitrile (4.5 mg, 0.017 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (4 mg, 0.034 mmol) and triethylamine (12 uL, 0.085 mmol) in acetonitrile (1.5 mL) was heated at 145° C. for 90 min using microwave irradiation. The solvent was removed in vacuo and the crude mixture was purified by preparative thin layer chromatography, eluting with dichloromethane/MeOH (10/1), to give the title compound as a yellow oil (3 mg, 40%).
Reaction SMILES: C([C:3]1[CH:11]=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[N:15]=[C:14]([CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)[CH:13]=2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])C.C(Cl)(=O)C([Cl:38])=O>C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[C:12]([C:10]2[CH:11]=[CH:3][C:4]([C:5]([Cl:38])=[O:6])=[CH:8][CH:9]=2)=[CH:13][C:14]([CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[O:28][C:27]([CH3:33])([CH3:34])[CH2:26]2)=[N:15]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc(-c2cc(C3CC(C)(C)OC(C)(C)C3)nn2-c2ccccc2OC)ccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-benzoic acid (Example 46) (177 mg, 0.41 mmol) in 4 mL of DCM was added oxalyl chloride (0.043 mL, 0.49 mmol) and 1 drop of DMF and the mixture stirred for 3 hrs at RT The mixture was concentrated and used without further purification in the next step.