Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:4][C:3]=1[O:15][CH3:16].Br.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH2:23].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH:23][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:15][CH3:16])[CH:4]=1
Reactant: COc1cc(/C=C/C=C/C(=O)O)ccc1O
Reactant: NCc1ccc(O)c(O)c1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C=C/C(=O)NCc2ccc(O)c(O)c2)ccc1O

Procedure:
The compound was prepared as described in Example 5 using 11 mg (0.05 mmol) of 5-(4-hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid [Example 3], 22 mg (0.10 mmol) of 3,4 dihydroxybenzylamine hydrobromide, 50 g (0.50 mmol) of triethylamine, and 33 mg (0.075 mmol) of BOP reagent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[Cl:27][CH2:23][CH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:12]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)N2C(CO)CCC2c2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2C(CCl)CCC2c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
A stirred mixture of (2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol (1.25 g, 3.58 mmol) and thionyl chloride (2 ml) was heated for 4 h at 80° C. aqueous work-up and crystallization from ethyl acetate/hexane yielded the title compound as an off-white solid (1.12 g, yield 85%), m.p. 130° C. and MS: m/e=367 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@@H:10]2[O:19][C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]2[CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[CH3:40].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:34]1[CH:35]=[C:36]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]3[O:19][C@@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@@H:12]4[C@@H:11]3[CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:6][CH:7]=2)[CH:37]=[CH:38][C:39]=1[CH3:40]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: CC1(C)O[C@H]2O[C@@H](/C=C/c3ccc(Br)cc3)[C@@H](CCN3C(=O)c4ccccc4C3=O)[C@H]2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2ccc(/C=C/[C@@H]3O[C@@H]4OC(C)(C)O[C@@H]4[C@@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cc1F
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step k above (0.5 g), 3-fluoro-4-methylphenylboronic acid (0.314 g), tetrakistriphenylphosphinepalladium (0) (0.057 g), and potassium carbonate (0.414 g) was dried under high vacuum for 10 minutes. The vacuum was released under nitrogen atmosphere and dry dimethylformamide (5 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane as eluant to afford the title compound (0.37 g).
Reaction SMILES: [Na].COS([O-])(=O)=O.CN(C)[C:10]1[CH2:14][CH2:13][CH2:12][N+:11]=1[CH3:15].[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:19]>C(O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:18](=[O:19])[CH:17]=[C:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: CN(C)C1=[N+](C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1cccc(C(=O)C=C2CCCN2C)c1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution of 10.35 g of sodium in 225 ml of ethanol is added dropwise at 90° (with stirring) in the course of one hour to a mixture of 107 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate and 45.1 g of 3-methoxyacetophenone; stirring is effected for a further 2 hours at this temperature, and the solvent is then largely distilled off under a vacuum. 300 ml of water and 300 ml of diethyl ether are added to the cooled residue, and thorough shaking is effected. The ethereal phase is collected, dried over sodium sulfate and concentrated. The crystalline residue is recrystallized from chloroform/cyclohexane to yield 41.8 g of the title compound (as yellowish crystals), m.p. 92° to 93°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1ccc(O)cc1OC
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (90 mg) and commercially available 3,4-dimethoxyphenol (187 mg) were mixed and stirred at 180° C. for 30 minutes, and the mixture was then purified by column chromatography on silica gel eluting with hexane/acetone to obtain 26 mg of the title compound (yield: 19%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][NH:33]2)=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:34]4[C:30](=[CH:29][CH:28]=[C:27]([CH3:26])[CH:35]=4)[CH:31]=[N:32]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1ccc2cn[nH]c2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2cnn(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2c1
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 328 μmol), 6-methyl-1H-indazole (41.7 mg, 316 μmol) in dioxane (2 mL) was added sodium tert-butoxide (66.8 mg, 695 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.1 mg, 31.6 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(6-methyl-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) d: 9.08 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.23 (d, J=1.0 Hz, 1H), 8.03 (br. s., 1H), 7.85 (s, 1H), 7.29 (s, 1H), 5.72 (s, 2H), 3.55-3.61 (m, 2H), 2.50 (s, 3H), 1.59 (s, 9H), 0.77-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[NH:7][C:6]=2[CH:13]=1.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:13]=1
Reactant: CC(C)c1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
A mixture of 6-bromo-2-isopropyl-4-nitro-1H-benzo[d]imidazole (4.7 g), 1-(bromomethyl)naphthalene (4.01 g) and K2CO3 (4.55 g) in DMF (150 mL) was stirred at 80° C. for 2 h. It was cooled to room temperature and filtered. The filtrate was then poured into water (1 L). It was then filtered to afford a solid that was washed with water and then dried in-vacuo to afford the crude product (7.2 g). LC-MS: m/e=425 [M+1]+
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Cl:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][C:19]([OH:26])=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1.[CH3:27][O-:28].[Na+]>C1(C)C=CC=CC=1>[ClH:11].[ClH:11].[N:1]1([CH2:7][CH2:8][CH2:9][CH2:27][O:28][C:13]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([O:26][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:20][CH:21]=4)[CH2:16][C:15]=3[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: C[O-]
Reactant: ClCCCCN1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl
Product: c1cc2c(cc1OCCCCN1CCCCC1)Cc1cc(OCCCCN3CCCCC3)ccc1-2
Reaction time: 12 h

Procedure:
A solution of 13.1 g (0.075 mole) of 4-piperidinobutyl chloride in 100 ml of toluene is added to a mixture of 4.9 g (0.025 mole) of 2,7-dihydroxyfluorene and 2.7 g (0.05 mole) of sodium methoxide in 200 ml of toluene. The mixture is refluxed with stirring for 12 hours. Upon cooling, the mixture is filtered to remove the precipitated sodium chloride. The toluene solution is washed with water, then with sodium chloride solution and dried over anhydrous magnesium sulfate. This mixture is filtered and the filtrate acidified to Congo Red with ethereal HCl. The precipitate is collected and recrystallized from butanone-methanol to give 2,7-bis(4-piperidinobutoxy)fluorene dihydrochloride.
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.[C:4]([NH:7][C@H](C(O)=O)C[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[CH3:5]>>[CH2:3]1[O:1][CH:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:4]([NH2:7])(=[O:6])[CH3:5]
Reactant: C1CO1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(N)=O
Product: c1ccc(C2CO2)cc1

Procedure:
According to the process of this invention described hereinabove, the N-acyl-α-amino acid of formula (I) can be produced in good yields in one step from the oxirane (II) and the amide compound (III) with great industrial advantage. For example, according to the process of this invention, N-acetylphenylalanine can be obtained in a yield of as high as 72 to 98% from styrene oxide and acetamide as will be seen from Examples given hereinafter.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH2:8][CH2:9]Cl)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:27][C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[NH:30][N:29]=1>CN(C)C=O.O>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([CH:8]([C:6]3[C:5]([O:11][CH2:12][CH3:13])=[C:4]([CH:14]4[CH2:18][O:17][C:16](=[O:19])[NH:15]4)[C:3]([F:20])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:29]=[C:28]([CH3:27])[C:36]=12
Reactant: CCOc1c(CCCl)cc(Cl)c(F)c1C1COC(=O)N1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1COC(=O)N1
Temperature: 80 °C

Procedure:
4-[3-chloro-5-(chloroethyl)-6-ethoxy-2-fluorophenyl]-1,3-oxazolidin-2-one (160 mg, 0.50 mmol) (from Step 11) was stirred in N,N-dimethylformamide (21 mL) with cesium carbonate (324 mg, 0.99 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.60 mmol) was added. The mixture was heated to 80° C. for 1.5 hours and cooled to rt. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by preparative LCMS (pH 10) using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) separated the two diastereomers (peak 1 [compound 353] Rt=4.9 min. and peak 2 [compound 354] Rt=5.6 min.); providing compound 354 as the desired single enantiomer, 28 mg, 13%. peak 2: LCMS calculated for C19H21ClFN6O3 (M+H)+: m/z=435.1; found: 435.1. 1H NMR (300 MHz, CD3OD): δ 8.15 (s, 1 H), 7.62 (m, 1 H), 6.31 (m, 1 H), 5.39 (m, 1 H), 4.79 (m, 1 H), 4.40 (m, 1 H), 3.95 (m, 1 H), 3.80 (m, 1 H), 2.60 (s, 3 H), 1.80 (m, 3 H), 1.40 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15](=[O:21])[CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.[CH2:29]([CH:31]([CH2:35][CH3:36])[C:32](Cl)=[O:33])[CH3:30]>C(Cl)Cl>[CH2:17]([CH:16]([CH2:19][CH3:20])[C:15]([N:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[CH:3][C:4]=2[F:28])[CH2:9][CH2:10]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])[CH3:18]
Reactant: CCC(CC)C(=O)Cl
Reactant: CCC(CC)C(=O)N(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1ccc(N2CCC(N(C(=O)C(CC)CC)c3ccccc3)CC2)c(F)c1
Reaction time: 16 h
Yield: 31.1 %

Procedure:
To a mixture of N-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-2-ethyl-N-phenyl-butyramide (0.30 mmol) and TEA (2.0 mmol) in DCM (10 mL) was added 2-ethyl-butyryl chloride (1.0 mmol). After 16 h, the mixture was washed with H2O (10 mL). The organic layer was concentrated and the residue was purified by PTLC to provide the title compound (45 mg, 31%). MS (ESI): mass calcd. for C29H40FN3O2, 481.31. m/z found, 482.4 [M+H]+. 1H NMR (CDCl3): 7.50-7.35 (m, 5H), 7.15-7.03 (m, 2H), 6.86 (t, J=8.8, 1H), 4.90-4.72 (m, 1H), 3.44-3.30 (m, 2H), 2.80-2.67 (m, 2H), 2.30-1.30 (m, 14H), 0.95 (t, J=7.3, 6H), 0.80 (t, J=7.2, 6H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]2[O:10][C:11]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:12][C:8]=2[CH:7]=1)(=O)C.[OH-].[K+]>>[OH:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]2[O:10][C:11]([S:13](=[O:15])(=[O:16])[NH2:14])=[CH:12][C:8]=2[CH:7]=1
Reactant: CC(=O)OCc1ccc2oc(S(N)(=O)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc2cc(CO)ccc2o1

Procedure:
5-Acetoxymethyl-sulfamoylbenzo[b]furan is saponified with KOH to give the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:24])[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[N:14][C:13]=2[CH3:15])[CH2:8][CH2:9][C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C)c2c(c1O)CCC(=O)N2Cc1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c1N(Cc1ccccc1)C(=O)CC2
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-methyl-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (96 mg, 0.29 mmol), glycine (2.94 g, 39 mmol) and NaOMe solution (59 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3 with 4M HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 100 mg of the title compound as an off-white solid. MS: (+) m/z 370.05 (M+1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:16]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[N:12]3[N:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[C:13]3[N:14]=[CH:15][C:16]=2[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:31][CH2:30]2)=[O:28])=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(=O)(=O)NC(C)(C)C)cnn12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(N)(=O)=O)cnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
N-tert-Butyl-7-(4-fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.874 g, 1.548 mmol) obtained in step 4 was dissolved in trifluoroacetic acid (13 mL), anisole (0.4 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (0.442 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH3:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]4[NH:13][C:4](=[O:6])[C:3]5[C:2](=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][CH:7]=5)[N:1]=4)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: N
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: COc1cccc2c(=O)[nH]c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-methoxybenzoic acid, ammonia and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][P:5]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:20])[C:16]=1OCC)(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3]>>[CH2:2]([O:4][P:5]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:20])[C:16]=1[NH2:1])(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3]
Reactant: N
Reactant: CCOc1c(NC/C=C/CP(=O)(OCC)OCC)c(=O)c1=O
Product: CCOP(=O)(C/C=C/CNc1c(N)c(=O)c1=O)OCC
Reaction time: 72 h
Yield: 68 %

Procedure:
Ethanolic ammonia (235 mL) was combined with [(E)-4[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid diethyl ester (7.15 g, 21.6 mmol) and the solution was left stirring for 3 days and then evaporated. Recrystallization from methanol in ethyl acetate removed a yellow impurity, but flash chromatography (7.5 cm diameter, elution with 5% methanol in dichloromethane) was required to eliminate a more polar contaminant. Recrystallization of this material with methanol in ethyl acetate (final volume=200 mL) afforded [(E)-4-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-butenyl]phosphonic acid diethyl ester as a flocculant white solid (4.43 g, 68%, mp 145°-147° C.); IR (KBr, cm-1): 3280, 3100, 1800, 1640; MS (+FAB): 303 (MH+, 100), 135 (62); 1H NMR (DMSO, 400 MHz): δ 7.5 (br s, 3NH), 5.74-5.68 (m, 1H), 5.57-5.48 (m, 1H), 4.09 (br s, 2H), 4.02-3.91 (m, 4H), 2.64 (d of d, J=21.5 and 7 Hz, 2H), 1.19 (t, J=7 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[C:23]([F:32])=[C:24]6[C:28](=[CH:29][CH:30]=5)[NH:27][C:26]([CH3:31])=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:33][CH3:34])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH3:39])[C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[C:23]([F:32])=[C:24]6[C:28](=[CH:29][CH:30]=5)[NH:27][C:26]([CH3:31])=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:33][CH3:34])[CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(NCC2CC2)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(N(C)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 27 (50 mg) was mixed with HCHO (2 eq, 37% in H2O), NaBH(OAc)3 (2 eq) in DCM (5 ml) and stirred at RT for 3 hours. The reaction was evaporated and purified with silica gel column to give the titled product (20 mg). Mass: (M+1), 476
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]5)[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCC(N5CCN(S(C)(=O)=O)CC5)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 175 °C
Yield: 39.4 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.20 mmol), 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 58, Step B) (0.073 g, 0.20 mmol) and para-toluenesulfonic acid (0.090 g, 0.47 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-2-(ethyloxy)-5-(3-{2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}-imidazo[1,2-a]pyridin-2-yl)benzamide (0.066 g, 40%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.37 (br. s., 1H), 8.45 (s, 1H), 8.21 (d, J=5.2 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.65-7.81 (m, 2H), 7.35-7.50 (m, 3H), 7.28 (d, J=8.6 Hz, 1H), 7.16-7.25 (m, 2H), 6.88-7.02 (m, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.46-6.61 (m, 2H), 4.22-4.33 (m, 2H), 3.81 (s, 3H), 3.71-3.79 (m, 2H), 3.03-3.15 (m, 4H), 2.87 (s, 3H), 2.64-2.73 (m, 2H), 2.58-2.64 (m, 4H), 2.38-2.46 (m, 1H), 1.80-1.89 (m, 2H), 1.50-1.62 (m, 2H), 1.44 (t, J=6.9 Hz, 3H). MS (M+H, ES+) 838.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)N1CCC(N)CC1
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)NC1CCN(C(C)C)CC1

Procedure:
The titled compound was prepared analogously as describe in EXAMPLE 82, using 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid and 1-isopropyl-4-aminopiperidine. MS 443.2 and 445.2 (M+H, Cl pattern).