Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:34]([O-:36])=[O:35])=[C:19]([CH:21]([O:29][Si](C)(C)C)[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=1>C(O)C.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:34]([O-:36])=[O:35])=[C:19]([CH:21]([OH:29])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=1
Reactant: CCOC(=O)CCC(O[Si](C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
Citric acid (0.51 g) was added to a solution of ethyl 4-(5-chloro-2-nitrophenyl)-4-(trimethylsilyloxy)butanoate (4.76 g) in ethanol (25 mL) and water (5 mL) and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) to obtain 3.8 g of ethyl 4-(5-chloro-2-nitrophenyl)-4-hydroxybutanoate.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>>[ClH:1].[ClH:1].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH3:2])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[S:21][CH:22]=[C:23]([CH3:25])[N:24]=3)[CH:14]=2)[CH:5]=1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3C)ccn2)n1
Reactant: CN(C)CCN
Agent: Cl
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN(C)C)ccc3C)ccn2)n1

Procedure:
The title compound was prepared according to the method of Example 107 from 4-methyl-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (Example 108) and N,N-dimethylethylenediamine. Yield: 0.065 g, 25%. 1H NMR (CDCl3), 8.84 (bs, 1H), 8.16 (d, 1H), 7.90 (d, 1H), 7.86 (bs, 1H), 7.37 (d, 1H), 6.80 (bs, 1H), 6.71 (dd, 1H), 6.38 (s, 1H), 3.89 (m, 2H), 3.35 (m, 2H), 2.91 (s, 6H), 2.37 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>O1CCCC1>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CNCCO
Solvent: C1CCOC1
Product: CN(CCO)c1nc2ccccc2o1
Temperature: 25 °C

Procedure:
A solution of 2-chlorobenzoxazole (15.4 g ) in dry tetrahydrofuran (50 ml) was added dropwise to an ice cooled solution of 2-methylaminoethanol (15.0 g) in dry tetrahydrofuran (100 ml) with stirring and protection from atmospheric moisture. The mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the product was dissolved in ethyl acetate (200 ml) and washed with brine (2×150 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated. Chromatography of the residue on silica-gel in dichloromethane gave the title compound (mp 62°-3° C.) which was used in Preparation 3 without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:8][N:7]4[C:2]([NH:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2nn3c(NCCN4CCOCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 140 °C
Yield: 73 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (150 mg, 0.36 mmol) and 4-(2-aminoethyl)morpholine (3 mL, 21.2 mmol) was heated at 140° C. for 4 hours. Concentration of the reaction mixture followed by flash chromatography (3:1 ethyl acetate-hexane to ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine (135 mg, 74%) as a pale yellow foam. 1H NMR (CDCl3): δ 8.01 (d, 1 H), 7.78 (d, 1 H), 7.61 (d, 2 H), 7.30 (t, 1 H), 6.99 (d, 2 H), 6.52 (t, 1 H), 6.36 (d, 1 H), 5.98 (d, 1 H), 5.08 (d, 1 H), 4.37 (m, 1 H), 3.88 (s, 3 H), 3.76 (m, 4 H), 3.46 (q, 2 H), 2.76 (t, 2 H), 2.54 (m, 4 H), 2.12–1.52 (m, 8 H); MS m/z 514 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[NH:5][CH2:6][CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][C:28](=[O:33])[CH:29](Cl)[CH2:30][CH3:31]>O>[Cl:27][C:28](=[O:33])[CH:29]([N:5]([CH2:6][CH:7]=[O:8])[C:4]1[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])[CH2:30][CH3:31]
Reactant: CCC(Cl)C(=O)Cl
Reactant: CCc1cccc(OC)c1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCc1cccc(OC)c1N(CC=O)C(CC)C(=O)Cl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-ethyl-6-methoxyanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chlorobutanoyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chlorobutanoyl-2-ethyl-6-methoxyanilino)acetaldehyde.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccncc1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCc2ccncc2)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-(aminomethyl)pyridine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): 303.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.61 (d, J=5.8 Hz, 2H); 8.57 (br s, 1H); 8.44 (d, J=5.5 Hz, 1H); 7.85 (d, J=8.0 Hz, 1H); 6.89 (d, J=5.5 Hz, 1H); 5.96 (br s, 1H); 4.78 (d, J=6.4 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[N:10]=1)=[O:5])C.[OH-].[Na+:20]>C1COCC1>[Na+:20].[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([C:4]([O-:5])=[O:3])=[N:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1nc2cc(C(F)(F)F)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-trifluoromethyl-benzothiazole-2-carboxylic acid ethyl ester (200 mg, 0.73 mmol) was added 3 mL of THF, and 0.73 mL (2 eq) of NaOH solution (2N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid was dried under vacuum to give 270 mg of 5-trifluoromethyl-benzothiazole-2-carboxylic acid sodium salt as an off-white solid.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]([NH:9]C#C)=[N:5][CH:6]=[CH:7][CH:8]=1.[F-].[CH2:15]([N+](CCCC)(CCCC)CCCC)[CH2:16]CC.O>O1CCCC1>[C:15]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:16]
Reactant: C#CNc1ncccc1[Si](C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-trimethylsilanyl ethinyl-pyridin-2-ylamine described in Preparation Example 1-1-4 (28.1 g, 148 mmoL) in tetrahydrofuran (300 mL) was added tetrabutyl ammonium fluoride (1M tetrahydrofuran solution, 20 mL, 20 mmol), which was stirred at room temperature for 15 minutes. To the reaction solution was added water and extracted four times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1 then 1:2) to obtain the title compound (16.4 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(Cc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (2 mL) and acetic acid (2 drops) was added to (S)-tert-butyl piperidin-3-ylcarbamate (100 mg, 0.5 mmol) and benzaldehyde (1 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (422 mg, 2 mmol) was added in one portion. The reaction was stirred overnight. Saturated sodium bicarbarbonate (5 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (3×10 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.CCN(CC)CC.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][O:9][S:30]([CH3:33])(=[O:32])=[O:31])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (22.0 g) and Et3N (24.5 ml) in DCM (250 ml) and cool to 0° C. Mesyl chloride (6.8 ml) was added dropwisely and the resulting mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was concentrated to give tert-butyl 4-(4-bromo-1-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (28.0 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:34])=[C:5]1[C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccc(OC(F)(F)F)cc3)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 103 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethoxy-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.077 mmol), β-alanine (682 mg, 7.7 mmol) and NaOMe solution (12 mL, 6.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as a yellow solid. MS: (+) m/z 528.27 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Cl:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:20].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:18].[ClH:1].[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([N:15]2[CH2:16][CH2:17][N:12]([CH2:3][C:4]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:5])[CH2:13][CH2:14]2)[CH3:20])=[CH:22][CH:23]=1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: CC(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(c1ccc(F)cc1)N1CCN(CC(=O)c2ccccc2)CC1
Yield: 62.6 %

Procedure:
A mixture of N-phenacyl piperazine dihydrochloride (1.39 g, 5 mmol), 1-(1-chloroethyl)-4-fluorobenzene (0.95 g, 6 mmol) and K2CO3 (2.42 g, 17.5 mmol) in 40 ml of acetone was treated according to general preparation 2 to give 1.25 g of compound (IV-24), yield 61%. M+ 326.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:22](=[O:23])[CH2:21][CH:20]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:19][C:18]1=[O:29].[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([O:23][C:22]1[CH2:21][CH:20]([CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH2:19][C:18](=[O:29])[C:17]=1[C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)CC(C3CCOC3)CC2=O)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)CC(C2CCOC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triethylamine (0.11 ml, 0.79 mmol) in dichloromethane (2 ml) is added dropwise to a chilled (ice-bath) solution of 2-(2,4,6-trimethylphenyl)-5-(tetrahydrofuran-3-yl)cyclohexane-1,3-dione (prepared by a method analogous to that described in Example 2) and acetyl chloride (0.056 ml, 0.79 mmol) in dichloromethane (4.5 ml). Once the addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane (35 ml) and washed with saturated aqueous sodium bicarbonate solution (20 ml). The organic phase is dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane to give 3-oxo-5-(tetrahydrofuran-3-yl)-2-(2,4,6-trimethylphenyl)cyclohex-1-enyl acetate.
Reaction SMILES: C(N1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[O:21][C:22]4[C:27]([C:28](=[O:30])[CH:29]=3)=[CH:26][C:25]([F:31])=[CH:24][C:23]=4[N:32]3[CH2:37][CH2:36][N:35](C)[CH2:34][CH2:33]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)CC.ClC(OC(Cl)C)=[O:41].[Na+].[I-].Cl>C(Cl)(Cl)Cl.ClCCCl>[N:8]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[O:21][C:22]4[C:27]([C:28](=[O:30])[CH:29]=3)=[CH:26][C:25]([F:31])=[CH:24][C:23]=4[N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6][O:41][CH2:10][CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cc(=O)c2cc(F)cc(N3CCNCC3)c2o1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Dry 6-flouro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide (Example 72)(1 g 1.9 mmol) was added to 100 mL of rigorously dried 1,2-dichloroethane in a flask under N2 atmosphere and magnetic stirring. The mixture was cooled to 0° C. and freshly distilled 1-chloroethyl chloroformate (650 ul, 858 mg, 6 mmol, 3 eq) was added drop wise. The reaction was then heated under reflux for 5 hours at which time LC/MS revealed complete consumption of starting material. NaI (1 g, 1 eq) was added and heating continued for 2 days more. The reaction was then allowed to cool and filtered and evaporated to dryness under reduced pressure. MeOH (100 mL) was added and heated to reflux for 4 h, filtered hot and evaporated to dryness. The product was isolated by chromatography using silica gel and CHCl3/5% MeOH as an eluent. This gave 700 mg of the product HCl salt as a yellow solid. LCMS−m/z=508.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:14]([C:15]2(O)[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1>[Pd].CO>[C:21]1([CH:18]2[CH2:17][CH2:16][CH:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ncccc1C1(O)CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C1CCC(c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 6 h
Yield: 16.7 %

Procedure:
TFA (3 mL) was added to 1-(2-aminopyridin-3-yl)-4-phenylcyclohexanol (246 mg) and the mixture was stirred at 40° C. under nitrogen for 6 hr. TFA was removed in vacuo and this product was subjected to the next reaction without further purification. MeOH (1 mL) and Pd/C (10 mg) were added and the mixture was stirred at room temperature under hydrogen for 2 days. The insoluble solid was removed by filtration through Celite-pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (38.6 mg) as colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:13][C:14]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>C(O)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]=2[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1c(N)cccc1Cl
Solvent: CCO
Product: COC(=O)c1ccc(C=Nc2cccc(Cl)c2C)cc1
Reaction time: 0.25 h

Procedure:
p-carbomethoxybenzaldehyde (0.20 moles) was treated with 2-methyl-3-chloroaniline (0.20 moles) with vigorous stirring in a 1 liter Erlenmeyer flask. After 15 mins., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 45 mins. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 95% ethanol gave N-(p-carbomethoxybenzylidene)-2-methyl-3-chloroaniline.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:32]>CN(C)C=O>[CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH3:32])[C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1N=C(C2CCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Yield: 77.7 %

Procedure:
To a solution of 5-cyclopentyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (1.47 g, 3.91 mmol) in anhydrous dimethylformamide (40 ml) under nitrogen, cooled in an ice bath, was added sodium hydride (55% dispersion in oil, 178 mg, 4.08 mmol) in portions and the resulting mixture stirred for lb. Iodomethane (0.26 ml, 4.1 mmol) was then added and the mixture stirred for 30 min. The solvent was evaporated and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The aqueous layer was re-extracted with dichloromethane (20 ml), the organic extracts were combined, dried (MgSO4), and evaporated. The residue was triturated with diethyl ether to afford the title compound (1.19 g, 78%) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.26 (1H, m), 1.46-2.00 (6H, m), 2.00-2.20 (1H, m), 3.30 (1H, m), 3.40 (3H, s), 5.08 (2H, d, J=1.4 Hz), 5.15 (1H, d, J=8 Hz.), 6.50 (1H, d, J=8 Hz), 7.24-7.62 (9H, m).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:15][C:16]1[N:21]=[C:20]([C:22]2[S:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26](=[O:28])[N:27]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:13][CH3:14]>C(OCC)(=O)C>[CH2:12]([S:15]([C:16]1[N:21]=[C:20]([C:22]2[S:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26](=[O:28])[N:27]=2)[CH:19]=[CH:18][CH:17]=1)=[O:9])[CH2:13][CH3:14]
Reactant: CCCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CCCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 75.7 %

Procedure:
A solution of 3-chloroperbenzoic acid (ca. 50%, 0.17 g, 0.49 mmol) in ethyl acetate (20 ml) was added dropwise to a solution of 2-(6-propylthio-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.15 g, 0.48 mmol), which was obtained in Example 59, in ethyl acetate (50 ml) with stirring. The reaction mixture was stirred at room temperature for 18 hrs, washed with saturated aqueous sodium hydrogen carbonate solution (50 ml×2) and saturated brine, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the titled compound (0.12 g, 76%) as crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl.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>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]4)[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: OCCN1CCN(c2cncc(Cl)n2)CC1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
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: [Cs+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: OCCN1CCN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CC1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.2 mmol, 1 eq) and 2-(4-(6-chloropyrazin-2-yl)piperazin-1-yl)ethanol (57) (49.5 mg, 0.2 mmol, 1 eq) in DME (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.4 mmol, 2 eq) followed by addition of Pd(PPh3)4 (1.0 mg, 0.04 mmol) and degassing and purging under argon for additional min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 3% MeOH/CHCl3 to obtain pale yellow solid compound 2-(4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazin-1-yl)ethanol 126 in 15 mg quantity. The compound 126 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 8.96 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.36 (m, J=289.99, 1H), 6.61 (m, J=301.8, 1H), 3.75 (m, J=5.0, 6H), 2.69 (m, J=4.84, 6H); MS m/z 324.9 (M+H)+.