Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Reactant: C1CCNC1
Product: CCc1cc(-c2cccc(CN3CCCC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with pyrrolidine as described in Method A, Example 123 to give the title compound. MS: m/e=298 (M+H). 1H NMR (CDCl3, δ ppm): 7.89 (t, 1H, J=7.8 Hz); 7.77 (s, 1H); 7.61 (d, 1H, J=7.8 Hz); 7.41 (d, 1H, J=7.8 Hz); 4.43 (s, 2H); 3.80 (m, 2H); 3.07 (m, 2H); 2.66 (q, 2H, J=7.4 Hz); 2.55 (s, 3H); 2.13 (m, 4H); 1.25 (t, 3H, J=7.4 Hz).
Reaction SMILES: C(OC([N:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])=O)C1C=CC=CC=1>[Pd].C(O)C>[Si:33]([O:32][CH2:31][CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])[CH:15]=2)[NH:11]1)([C:36]([CH3:39])([CH3:37])[CH3:38])([CH3:34])[CH3:35]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3C(=O)OCc2ccccc2)C(=O)O1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3)C(=O)O1
Reaction time: 2 h

Procedure:
A mixture of the product from Step 8 (2.2 g, 0.0040 mol), 10% palladium-on-carbon catalyst (0.4 g) and ethanol (150 ml) is hydrogenated at an initial pressure of 44 p.s.i. for 2 h. The catalyst is removed by filtration through celite and the filtrate is concentrated. The residue is dissolved in CH2Cl2, filtered and concentrated to give the titled product: MS (ES) m/z 420 (M+H+), 442 (M+Na+); 1H NMR (300 MHz, CDCl3) δ0.05 (s, 6H), 0.89 (s, 9H), 2.02 (s, 3H), 2.63 (q, 1H), 3.09 (q, 1H), 3.53 (m, 3H), 3.71 (m, 2H), 4.23 (broad s, 1H), 4.71 (m, 1H), 6.14 (t, 1H), 6.58 (d, 1H), 6.98 (d, d, 1H), 7.26 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]C(Br)(Br)Br>ClCCl>[Br:29][CH2:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ncccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccnc1CBr
Temperature: 25 °C
Reaction time: 22 h
Yield: 11 %

Procedure:
A solution of 285 mg (2.242 mmol) of (3-fluoropyridin-2-yl)methanol (CAS: 31181-79-0) in dry dichloromethane (9 ml) in an ice-water bath and under an argon atmosphere was admixed with 882 mg (3.36 mmol) of triphenylphosphine and 1.12 g (3.36 mmol) of tetrabromomethane. The reaction mixture was stirred at room temperature for 22 hours. The solvent was evaporated off and the residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: cyclohexane-ethyl acetate, gradient 15% to 30%), which gave 156 mg (11% yield, 98% pure) of the target compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:17])=[CH:20][CH:21]=1
Reactant: O=C(CCN1CCN(Cc2ccccc2)CC1)Nc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CCN1CCNCC1)Nc1ccc(F)cc1
Yield: 70.3 %

Procedure:
1-Benzyl-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine (2.9 g) was dissolved in acetic acid (100 ml), then 10% palladium carbon (7.2 g) was added thereto, and the mixture was stirred overnight in a hydrogen atmosphere. The 10% palladium carbon was filtered off, and the filtrate was evaporated, and water was added to the residue which was then basified by adding 1 N aqueous sodium hydroxide and subjected to extraction with chloroform, and the organic layer was washed with water, dried, and evaporated, whereby the title compound (1.5 g, 70%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=NC=[CH:17][CH:18]=2)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4].N[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(CC(=O)CCC=C)#N.C(Cl)Cl>CO>[CH2:1]([C:5]1[C:6](=[N:11][NH:12][C:13]2[CH:14]=[C:20]3[C:21](=[CH:17][CH:18]=2)[N:22]=[CH:23][CH:24]=[CH:25]3)[C:7]([NH2:10])=[N:8][N:9]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1=NN=C(N)C1=NNc1cccnc1
Reactant: Nc1cccnc1
Agent: C=CCCC(=O)CC#N
Solvent: ClCCl
Solvent: CO
Product: C=CCCC1=NN=C(N)C1=NNc1ccc2ncccc2c1
Yield: 54 %

Procedure:
In a similar manner, 5-but-3-enyl-4-(pyridin-3-ylhydrazono)-4H-pyrazol-3-ylamine was prepared from 3-aminopyridine (113 mg, 1.2 mmole) and 1-cyano-5-hexen-2-one (123 mg, 1 mmole). The crude material was pruified by preparative TLC (CH2Cl2:MeOH=21:1) to yield 131 mg (54%) of the title compound as an orange powder. MS (m/z, ES+): 243 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.68 (br s, 1H), 8.89 (s, 1H), 8.46 (m, 1H), 7.96 (d, 1H), 7.46 (dd, 1H), 7.19 (brs, 2H), 5.87 (m, 1H), 5.07 (dd, 1H), 4.96 (d, 1H), 2.84 (br m, 2H), 2.46 (t, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]([O:19][C:17]([CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C(C)(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of methyl 4-hydroxyphenyllactate (18.5 g), t-butyl bromoacetate (14 ml), anhydrous potassium carbonate (26.0 g) and anhydrous dimethylformamide (300 ml) was stirred at 60° C. for 10 hours and then allowed to stand at room temperature overnight The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=2:1-1:1 as the eluant to afford the title compound (17.5 g, Rf=0.62: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=1:1 as the eluant).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].C1(C)C=CC=CC=1.[CH3:14][C:15]([Si:20]([CH3:43])([CH3:42])[O:21][C@H:22]1[CH2:39][CH2:38][C@@:37]2([CH3:40])[C:24](=[CH:25][CH:26]=[C:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30][C:31]2=O)[CH2:23]1)([CH3:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O>[CH3:14][C:15]([Si:20]([O:21][C@H:22]1[CH2:39][CH2:38][C@@:37]2([CH3:40])[C:24](=[CH:25][CH:26]=[C:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30]/[C:31]/2=[CH:1]/[CH3:2])[CH2:23]1)([CH3:43])[CH3:42])([CH3:19])[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C/C=C1/CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 240.2 g (647 mmol) (ethyl)triphenylphosphonium bromide, 72.5 g (647 mmol) potassium t-butoxide, and toluene (1 L) was stirred at room temperature for 1 hr. Then, 185 g (430 mmol) (3β)-3-[[(1,1,2-trimethylpropyl)dimethylsilyl]-oxy]androsta-5,7-dien-17-one was added with the aid of 50 mL of toluene. The temperature was kept below 25° C. by water cooling. After stirring at room temperature overnight, the reaction was quenched with 24.5 mL (430 mmol) of acetic acid. After stirring for 1 hr, the solid was removed by filtration and washed with 600 mL of toluene. The combined filtrate and washes were concentrated. Then 200 mL of methanol was added and the mixture was concentrated again. The residue was dissolved in a mixture of 650 mL methanol. 65 mL water and 650 mL hexane. The methanol/water layer was back-extracted with 325 mL of hexane. The combined hexane layers were concentrated. Then, 200 mL of methanol was added and the mixture was concentrated again. The resulting solid was suspended in 800 mL of methanol containing 8 mL of triethylamine, and the suspension was refluxed for 30 minutes. After cooling in a refrigerator overnight, the precipitate was filtered, washed with 300 mL of cold methanol, and dried by suction for 4 hr. Further drying at 50° C. under high vacuum afforded, 178.1 g (93.7% yield) of (3β,17Z)-(1,1,2-trimethylpropyl)(pregna-5,7,17(20)-trien-3-yloxy)dimethylsilane as a yellow solid: mp 94°-97° C. [α]D -62.8° (c 0.94, ethanol); Anal. Calcd for C29H48OSi: C, 79.02; H, 10.98; Si, 6.37. Found C, 78.74; H, 11.23; Si, 6.50.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].S(Cl)(Cl)=O.[C:11]([O:15][C:16](=[O:20])CC#N)([CH3:14])([CH3:13])[CH3:12].[H-].[Na+]>C1COCC1.C(O)(=O)C>[C:11]([O:15][C:16](=[O:20])[CH:3]([C:4]#[N:5])[C:2](=[O:1])[CH3:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)CC#N
Reactant: CC(C)(C)OC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)C(C#N)C(=O)OC(C)(C)C

Procedure:
Scheme 2 below shows an alternative procedure for the preparation of 3-oxo-butyronitrile ii. This alternative procedure involves conversion of acetic acid vi to the corresponding acid chloride by reaction with a chlorinating agent such as thionyl chloride (SOCl2) followed by reaction of the anion of tert-butylcyanoacetate prepared by reaction of tert-butylcyanoacetate with a base such as sodium hydride (NaH) in a solvent such as THF to give 2-cyano-3-oxo-butanoic acid tert-butyl ester vii, which undergoes deprotection of the ester and decarboxylation to give 3-oxo-butyronitrile ii by reaction with an acid such as trifluoroacetic acid (TFA).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8])(=[O:3])[CH3:2]>C(Cl)(Cl)Cl.O=[Mn]=O>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
To a stirred solution of N-acetyl-2-amino-benzylalcohol (20 g) in dry CHCl3 (500 mL) was added MnO2 (160 g, 8 equivalents) and allowed to stir at room temperature for 12 h. The reaction mixture was filtered through celite and concentrated. The crude product was recrystallised from CHCl3/petrol ether to give N-acetyl-2-aminobenzaldehyde (14 g, 73%).
Reaction SMILES: COC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CC(=O)O)N.[NH2:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26].[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>>[C:34]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26])(=[O:35])[CH2:33][C:32]([CH3:31])=[O:36]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: C=C1CC(=O)O1
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
This invention encompasses a method and intermediates for preparing a commercial sweetening agent, α-L-aspartyl-L-phenylalanine methyl ester. The process involves reacting L-aspartic acid with diketene to form N-acetoacetyl-L-aspartic acid which is converted to N-acetoacetyl-L-aspartic anhydride by reaction with acetic anhydride. N-acetoacetyl-L-aspartic anhydride is reacted with L-phenylalanine methyl ester to provide N-acetoacetyl-α-L-aspartyl-L-phenylalanine methyl ester which is converted to α-L-aspartyl-L-phenylalanine methyl ester by reaction with hydroxylamine hydrochloride.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][CH2:14][NH2:15].[CH3:16][O:17][C:18]([C:20]1[N:21]=[C:22]([Cl:29])[N:23]([CH3:28])[C:24]=1[C:25](O)=[O:26])=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[N:21]=[C:22]([Cl:29])[N:23]([CH3:28])[C:24]=1[C:25](=[O:26])[NH:15][CH2:14][CH2:13][C:5]1[N:4]([CH3:3])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)=[O:19]
Reactant: COC(=O)c1nc(Cl)n(C)c1C(=O)O
Reactant: Cn1c(CCN)nc2ccccc21
Agent: Cl
Product: COC(=O)c1nc(Cl)n(C)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (125 mg, 504 μmol) and 2-chloro-1-methyl-1H-imidazole-4,5-dicarboxylic acid 4-methyl ester (172 mg, 787 μmol) according to the method described in example 8, step 3 as purple solid (77 mg, 205 μmol, 40.7%). MS: M=376.3 (M+H)+
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:6](=[O:31])[N:5]([CH3:32])[C:4]=2[N:3]=1.C([Li])CCC.[CH:38](=[O:42])[CH:39]([CH3:41])[CH3:40]>C1COCC1.O>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:7]1[C:8](=[O:19])[C:9]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:2]([CH:38]([OH:42])[CH:39]([CH3:41])[CH3:40])=[N:3][C:4]=2[N:5]([CH3:32])[C:6]1=[O:31])([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26]
Reactant: CC(C)C=O
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
Step 1 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.923 mmol, intermediate 77) was dissolved in THF (5 mL) and cooled to −78° C. To the clear solution was slowly added drop wise 2.5 M n-butyllithium in THF (0.35 mL, 0.877 mmol) followed by the immediate addition of isobutyraldehyde (0.42 mL, 4.61 mmol). The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with water (75 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield an oil. The oil was purified using a 25 g silica column eluted with a gradient of 10% to 30% ethyl acetate/hexanes yielding 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.20 g, 40% yield) as a light golden oil. LCMS retention time=4.923 min and 98% purity, LCMS MH+ 535.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][N:7]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)CCNCC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCN(Cc1ccccc1)CC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of the compound (27.8 g) obtained in step 2 and sodium carbonate (16.3 g) in acetonitrile (132 mL) was added benzyl bromide (14.4 g) at room temperature, and the mixture was stirred at 75° C. for 2 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give N-benzyl-N-[2-(3,4-dichlorophenyl)-3-ethoxy-3-oxopropyl]-β-alanine ethyl ester (34.6 g, 99%) as a colorless oil.
Reaction SMILES: O=C1C=C(C(O)=O)OC2C3C=CC=CC=3SCC1=2.COCC1C(=O)C2C[O+](=O)([O-])C3C=CC4CCCCC=4C=3C=2SC=1C(O)=O.O=[C:47]1[CH:52]=[C:51]([C:53]([OH:55])=[O:54])[NH:50][C:49]2C3C4CCCCC=4C=CC=3SC[C:48]1=2>>[N:50]1[CH:49]=[CH:48][CH:47]=[CH:52][C:51]=1[C:53]([OH:55])=[O:54]
Reactant: O=C(O)c1cc(=O)c2c([nH]1)-c1c(ccc3c1CCCC3)SC2
Agent: O=C(O)c1cc(=O)c2c(o1)-c1ccccc1SC2
Product: O=C(O)c1ccccn1

Procedure:
In the same manner, by using an appropriate amine of formula R16NH2 but replacing 4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid with an equivalent amount of one of the 4-oxo-tetrahydro-4H,5H-naphtho[2,1-b] or [2,3-b] or [1,2-b]thiopyrano[2,3-d]pyran-2-carboxylic acids (described in Example 79), 4-oxo-1,4,9,10,11,12-hexahydro-5H-naphtho[1',2' : 5,6]thiopyrano[4,3-b]pyridine-2-carboxylic acid (l; R3, R4, R5 and R15 = H, R1 and R2 together form a CH2CH2CH2CH2 chain, X = S and Y = NH), 4-oxo-1,4,8,9,10,11-hexahydro-5H-naphtho[2', 3' : 5,6]thiopyrano]4,3-b]pyridine-2-carboxylic acid (l; R1, R4, R5 and R15 = R2 and R3 together form a CH 2 CH2CH2CH2 chain, X = S and Y = NH), 4-oxo-1,4,7,8,9,10-hexahydro-5H-naphtho[2',1': 5,6]thiopyrano[4,3-b]pyridine-2-carboxylic acid (l; R1, R2, R5 and R15 = H, R3 and R4 together form a CH2CH2CH2CH2 chain, X = S and Y = NH), 1-ethyl-4-oxo-1,4,8,9,10,11-hexahydro-5H-naphtho[2', 3' : 5,6]thiopyrano[4,3-b]pyridine-2-carboxylic acid-6,6-dioxide (l; R1, R4, R5 and R15 = H, R2 and R3 together form a CH2CH2CH2CH2 chain, X = SO2 and Y = NC2H5) and 3-methoxymethyl-4-oxo-1,4,9,10,11,12-hexahydro-5H-naphtho[1', 2' : 5,6]thiopyrano[4,3-b]pyridine-2-carboxylic acid-6,6-dioxide (l; R3, R4 and R15 = H, R1 and R2 together form a CH2CH2CH2CH2 chain, R5 = CH2OCH3, X = SO2 and Y = NH) are obtained, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:23][C:24]1[C:25]([Cl:30])=[N:26][CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:30][C:25]1[C:24]([CH2:23][CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Clc1ncccc1CBr
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ncccc1CC(c1cccnc1)c1cccnc1
Reaction time: 0.17 h

Procedure:
A solution of bis-(3-pyridyl)methane in 150 mL of THF was cooled to −30 C. LDA (1.5 M solution in cyclohexane, 29.4 mL) was added dropwise to give a dark red solution containing some red solid matter. The mixture was then stirred at 0 C for 10 min. A solution of 3-(bromomethyl)-2-chloropyridine in 50 mL of THF was added dropwise over 25 min, and the reaction was stirred at 0 C for 2 h, after which the reaction was quenched by adding saturated aqueous NH4Cl. The mixture was partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3×), and the combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography gave 9.1 g of 2-chloro-3-(2,2-dipyridin-3-ylethyl)pyridine as a red, viscous liquid.
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1.C(O)(C(F)(F)F)=O>CC(O)C>[F:1][C:2]1[C:34]([F:35])=[CH:33][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[C:22]([C:23]5[CH:28]=[CH:27][N:26]=[C:25]([NH:49][C:46]6[CH:45]=[CH:44][C:43]([N:40]7[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]7)=[CH:48][CH:47]=6)[N:24]=5)=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3nccc(-c4cccnc4Oc4ccc(Nc5nc6cc(F)c(F)cc6[nH]5)cc4)n3)cc2)CC1
Temperature: 90 °C
Reaction time: 96 h

Procedure:
A resealable pressure bottle, under nitrogen, was charged with 5,6-difluoro-N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (0.13 g, 0.26 mmol), 4-(4-methylpiperazin-1-yl)benzenamine (0.25 g, 1.31 mmol), TFA (0.12 ml, 1.58 mmol), and 2-propanol (10.00 ml, 0.03 M). The reaction vessel was sealed and the mixture stirred at 90° C. for 4 days. The reaction mixture was cooled to RT and concentrated to brown residue. The residue was purified by Biotage silica gel chromatography (2%-8% MeOH/Dichloromethane) followed by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford 5,6-difluoro-N-(4-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a yellow solid. MS m/z=606.1 [M+H]+. Calc'd for C33H29F2N9O: 605.64.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:6]2[O:5][C:4]([NH:7][N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]2=[O:1])=[CH:20]1
Reactant: CCOC(=O)C1=C(NN2CCCCC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NN2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 4 %

Procedure:
To a solution of ethyl 4-oxo-2-(N-piperidinoamino)-4,5-dihydrofuran-3-carboxylate (0.25 g, 0.98 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.14 g, 0.98 mmol) in ethanol (10 mL), L-proline (0.011 mg, 0.096 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 4%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:13][OH:14])=[CH:3]1>CN(C=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH:13]=[O:14])=[CH:3]1
Reactant: Cn1cc(CO)c(=O)c2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
The 1-methyl-3-hydroxymethyl-4(1H)-quinolone from preparation 1 (18.9 g) was dissolved in DMF (300 ml) and activated manganese dioxide (280 g), added. The mixture was stirred at 80° C. for 16 hours, after which t.l.c. showed the reaction to be complete. The reaction mixture was filtered, the filtrates evaporated to dryness, and the solid residue washed with water to give the desired product 1-methyl-3-formyl-4(1H)-quinolone, m.p. 210°-212° C.