Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[C:16]1([NH:15][C:12]2[N:11]=[CH:10][C:9]([C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:8])=[CH:14][CH:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a stirred solution of 6-phenylamino-nicotinic acid (0.1 g, 0.00047 mol) in DMF (2 mL), was added DIPEA (0.181 g, 0.001401 mol), HOBt (0.0756 g, 0.00056 mol) and EDCI.HCl (0.107 g, 0.00056 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.0782 g, 0.00056 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.135 g (97%) of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 299.13 (M+1)+, 99%. To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid ethyl ester (0.135 g, 0.00045 mol) in a mixture of THF (5 mL), methanol (7 mL) and H2O (2 mL) was added LiOH.H2O (0.0568 g, 0.00135 mol) at ambient temperature and the resulting mixture was stirred for 2 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.078 g (64%) of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:22]1([Li])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:7]([N:6]([CH2:5][CH:4]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:1](=[CH:2][CH:10]=[CH:9][CH:8]=2)[O:3]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: [Li]c1ccccc1
Product: C1=C(c2ccccc2)c2ccccc2OC1CN(Cc1ccccc1)Cc1ccccc1

Procedure:
The process of Example 4 was repeated using N,N-dibenzylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), then following the precedure in part (b) and in part (c) using phenyl lithium in place of the 4-bromochlorobenzene/butyl lithium, to yield the title compound as an oil, after dehydration in dilute HCl as in part (d).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1.[Na].[N:11]1([C:22](=[O:23])[C:21]2[NH:20][CH:19]=[N:18][C:17]=2[N:15]([CH3:16])[C:13]1=[O:14])[CH3:12]>C(O)(C)C>[CH3:9][C:7]1[O:6][N:5]=[C:4]([CH2:3][CH2:2][N:20]2[C:21]3[C:22](=[O:23])[N:11]([CH3:12])[C:13](=[O:14])[N:15]([CH3:16])[C:17]=3[N:18]=[CH:19]2)[N:8]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: Cc1nc(CCCl)no1
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc(CCn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 91 %

Procedure:
2.92 g. of 3-(2-chloroethyl)-5-methyl-1,2,4-oxadiazole, 50 cm3 isopropylalcohol and 4.0 g. of theophylline sodium are heated for 8 hours. 5.3 g. (91% yield) 7-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl]-theophylline are obtained, m.p.: 113°-114° C. (water).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=S)[NH:7][CH:8]=1.ClCC(O)=[O:14].Cl>O>[CH3:1][O:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:14])[NH:7][CH:8]=1
Reactant: COc1c[nH]c(=S)[nH]c1=O
Reactant: O=C(O)CCl
Agent: Cl
Solvent: O
Product: COc1c[nH]c(=O)[nH]c1=O
Yield: 93.5 %

Procedure:
A mixture of 5-(methoxy)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (21.5 g; 0.137 moles), chloroacetic acid (21.5 g; 0.227 moles), and water (585 mL) was refluxed for 2 h. Concentrated HCl (85 mL) was added and the mixture was then refluxed for 16 h. Upon cooling, a solid formed and was collected by filtration, washed with water and dried to yield the desired product (18.2 g; 94% yield). MS: (M+H)+=143.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.O>CN(C=O)C.[Cu](I)I>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: Brc1ccc(Cc2ccncc2)cc1
Reactant: OCC(F)(F)F
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Cc2ccncc2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
In a stream of nitrogen, 2.0 ml of 2,2,2-trifluoroethanol was added to 52.8 mg of sodium hydride, and then a solution of 140 mg of copper iodide and 922 mg of 4-(4-bromobenzyl)pyridine in 4 ml of N,N'-dimethylformamide was added. The mixture was stirred at a bath temperature of 120° C. for 3 hours. After the reaction, water was added to the reaction mixture, and it was extracted with ethyl acetate. The extract was washed with water, and the solvent was evaporated. 0.78 g of the residue was distilled under reduced pressure by using a Kugel-Rohr. When 574 mg (yield 57%) of a fraction having a boiling point of 150° C. (0.2 mmHg) was separated, 4-[4-(2,2,2-trifluoroethoxy)benzyl]pyridine was obtained as colorless crystals having a melting point of 51° to 53° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[NH:29]N>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1cc(Cl)ccc1Cl
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cc(Cl)ccc1Cl
Yield: 23 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2,5-dichlorophenylhydrazine according to the method described for Example 1 in 23% yield. MS: M=383.0 (M+H)+
Reaction SMILES: C([C:3]1([C:17]([OH:19])=[O:18])[CH2:7][CH:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:5][CH:4]1[CH2:15][CH3:16])C.[OH-].[Na+]>O1CCOCC1>[CH2:15]([CH:4]1[CH2:5][CH:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:7][CH:3]1[C:17]([OH:19])=[O:18])[CH3:16]
Reactant: CCC1CC(OC2CCOCC2)CC1(CC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC1CC(OC2CCOCC2)CC1C(=O)O
Temperature: 70 °C

Procedure:
To a solution of ethyl 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acid (0.250 g, 0.925 mmol) in p-dioxane (15 mL) was added aqueous NaOH (1 M, 5.00 mL, 5.00 mmol) to give a colorless solution. The reaction was heated at about 70° C. for about 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure. The solution was diluted with Et2O (30 mL). The layers were separated and the aqueous layer was extracted with Et2O (30 mL). The organic layer was set aside. The aqueous layer was acidified with 5 N HCl (2 mL) to about pH 2. The solution was diluted with Et2O (30 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×30 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concd under reduced pressure to give 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylic acid containing 6 mol % of 1,4-dioxane as an excepient (0.194 g, 85%) as a colorless oil; LC/MS (Table 1, Method b) Rt=1.71 min; MS m/z: 243 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[Br:17][C:18]1[CH:22]=[C:21]([CH2:23]Cl)[O:20][N:19]=1>>[Br:17][C:18]1[CH:22]=[C:21]([CH2:23][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[O:20][N:19]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1cc(Br)no1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(Br)no1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-bromo-5-(chloromethyl)isoxazole (Example 325A): MS (ES) m/z 382 (M−1) and 384 (M−1, isotope).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH3:35])=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:26][CH:25]=5)[CH:23]=4)=[O:16])[CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.IC>O1CCCC1.CN(C)C=O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH2:35][O:3][CH:7]([CH3:8])[CH3:6])=[C:22]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:29]=5)[CH:23]=4)=[O:16])[CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)OCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Yield: 75.7 %

Procedure:
Sodium hydride (2.2 mg, 0.055 mmol, 60% by weight dispersion in oil) was slowly added to a stirred solution of 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N,2′-trimethylbiphenyl-4-carboxamide (21 mg, 0.048 mmol) in a mixture of 0.90 mL of anhydrous tetrahydrofuran (THF) and 0.10 mL of anhydrous N,N-dimethylformamide (DMF). The resulting suspension was allowed to stir for 3 minutes before iodomethane (0.0048 mL, 0.072 mmol) was added to the reaction mixture. An additional aliquot of sodium hydride and iodomethane were required to consume all of the starting material which was monitored by LCMS. The crude reaction product was evaporated to dryness, redissolved in a minimum of DMF and purified by preparative LCMS chromatography to yield 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(isopropoxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (9.1 mg, 42%) ESI-MS m/z calc. 456.2, found 457.5 (M+1)+. Retention time of 2.94 minutes. 1H NMR (400 MHz, CD3CN) δ 0.91-0.93 (m, 2H), 1.41-1.45 (m, 2H), 2.23 (s, 3H), 3.00 (s, 3H), 3.07 (s, 3H), 3.20 (s, 3H), 5.81 (s, 2H), 6.29-6.36 (m, 2H), 6.56 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 6.92 (dd, J=1.6, 7.9 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 7.46 (dd, J=1.8, 6.4 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]#[N:28])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].Cl.[NH2:32][OH:33].C(N(CC)CC)C>C(O)C>[OH:33][NH:32][C:27]([C:22]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[C:8]3[CH2:9][CH:10]4[N:5]([C:3](=[O:4])[C:2]([F:30])([F:29])[F:1])[CH:6]([CH2:12][CH2:11]4)[CH2:7]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)=[NH:28]
Reactant: N#Cc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F

Procedure:
A solution of 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-4-carbonitrile in ethanol (0.1 to 2 M solution) may be treated with hydroxylamine hydrochloride (1 to 2 equiv) and triethylamine (2 to 3 equiv) and may be heated to reflux for a period of 1 to 10 hr. After cooling, the mixture may be evaporated under reduced pressure, and the residue may be partitioned between equal amounts of water and an organic solvent such as ethyl acetate. The organic layer may be separated, dried over an appropriate drying agent such as magnesium sulfate, filtered, and evaporated. The residue may be purified via column chromatography to yield Compound 1f.
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]#[N:13])=[CH:4]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]#[N:13])=[CH:4]1
Reactant: N#Cc1cn(CO)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1cn(CCl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The obtained 1-hydroxymethyl-3-cyano-4-trifluoromethyl-1H-pyrole was dissolved to 3 ml of chloroform, and 3 ml of thionyl chloride was added, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled to 0° C., it was poured into ice-water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 800 mg of 1-chloromethyl-3-cyano-4-trifluoromethyl-1H-pyrole.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]4[S:24][C:25]([CH2:27]O)=[CH:26][C:22]=4[CH:21]=3)=[N:16][CH:17]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:3][CH2:27][C:25]1[S:24][C:23]2[CH:29]=[CH:30][C:20]([C:19]#[C:18][C:15]3[CH:14]=[CH:13][C:12]([C:9]4[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=4)=[CH:17][N:16]=3)=[CH:21][C:22]=2[CH:26]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Solvent: ClCCl
Product: ClCc1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Temperature: 0 °C
Reaction time: 70 h

Procedure:
1.07 mL (15 mmol) of thionyl chloride was added to a solution of 1.1 g (2.93 mmol) of {5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]benzo[b]thiophen-2-yl}methanol in 20 mL of DCM cooled to 0° C. and the reaction mixture was stirred for 70 hours at RT. It was evaporated down in vacuo, the residue was combined with semisaturated sodium bicarbonate solution, extracted exhaustively with DCM, and the combined organic phases were washed twice with water and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, PE/EtOAc 7:3). Yield: 0.65 g (56% of theoretical); C22H13Cl2NS (M=394.317); calc.: molpeak (M+H)+: 394/396/398 (2Cl); found: molpeak (M+H)+: 394/396/398 (2Cl); HPLC-MS: 7.6 minutes (method B).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:13](OCC)=[O:14])[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1([CH2:13][OH:14])[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2
Reactant: CCOC(=O)C1(C(=O)OCC)CC2C=CC1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(CO)CC2C=CC1C2
Temperature: 25 °C
Yield: 140.6 %

Procedure:
Into a solution containing 2,2-bisethoxycarbonyl-5-norbornene (10 g) in dry tetrahydrofuran (100 ml) was added a mixture of lithium aluminum hydride (4.3 g) and dry tetrahydrofuran (100 ml) with stirring at room temperature. The reaction mixture was refluxed for 2 hours. After consumption of excess LiAlH4 by addition of water, the reaction mixture was concentrated to give a residue, which was extracted with chloroform. The extract was washed with a saturated NaCl solution, dried and concentrated to give as a solid substance 2,2-bishydroxymethyl-5-norbornene (Compound No. 21-1) (9.1 g), M.P., 108°-110° C. (recrystallization from isopropanol). IRνmaxNujol (cm-1): 3300, 2950, 1020.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH3:23][S:20]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(S(C)(=O)=O)CCC1=O
Reaction time: 1 h
Yield: 23 %

Procedure:
To a mixture of 1 g (6.36 mmol) of methyl 4-oxopiperidine-3-carboxylate hydrochloride and 2.2 mL of Et3N in 12 mL of DCM is added dropwise at room temperature 0.5 mL of mesyl chloride. The reaction medium is stirred for 1 hour and then taken up in 50 mL of EtOAc, washed with 20 mL of water and 20 mL of brine and then dried over Na2SO4, filtered and concentrated under reduced pressure. 0.35 g of methyl 1-(methylsulfonyl)-4-oxopiperidine-3-carboxylate is obtained.
Reaction SMILES: CN(C)CC(N1C2C(=CC(OC)=C(NC3N4C(=NC5C(C4=O)=C(F)C=C(F)C=5)C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=3)C=2)CC1)=O.C(N)C.[CH3:52][N:53]([CH3:102])[CH2:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][C:62]([O:100][CH3:101])=[C:63]([NH:66][C:67]3[N:68]=[C:69]([NH:86][C:87]4[CH:97]=[C:96]([F:98])[CH:95]=[C:94]([F:99])[C:88]=4[C:89]([NH:91][CH2:92][CH3:93])=[O:90])[C:70]4[CH:75]=[CH:74][N:73](S(C5C=CC(C)=CC=5)(=O)=O)[C:71]=4[N:72]=3)[CH:64]=2)[CH2:59][CH2:58]1)=[O:56].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH3:102][N:53]([CH3:52])[CH2:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][C:62]([O:100][CH3:101])=[C:63]([NH:66][C:67]3[NH:72][C:71]4=[N:73][CH:74]=[CH:75][C:70]4=[C:69]([NH:86][C:87]4[CH:97]=[C:96]([F:98])[CH:95]=[C:94]([F:99])[C:88]=4[C:89]([NH:91][CH2:92][CH3:93])=[O:90])[N:68]=3)[CH:64]=2)[CH2:59][CH2:58]1)=[O:56]
Reactant: CCNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: CCN
Agent: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCNC(=O)c1c(F)cc(F)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added ethyl amine as a 2M solution in THF (1.11 mL, 2.22 mmol). The resulting mixture was let stir at rt for 3 h at which time it was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid, containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-N-ethyl-4,6-difluorobenzamide. This material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-ethyl-4,6-difluorobenzamide (60 mg, 0.101 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.14 Hz, 3 H) 2.18-2.31 (m, 6 H) 3.06-3.19 (m, 4H) 3.34 (dq, J=6.87, 6.65 Hz, 2 H) 3.78 (s, 3 H) 4.09-4.24 (m, 2 H) 6.25 (br. s., 1 H) 6.75-6.89 (m, 1 H) 6.93-7.03 (m, 2 H) 7.62-7.75 (m, 1 H) 8.39-8.49 (m, 1 H) 8.55 (br. s., 2 H) 10.55 (s, 1H) 11.26 (dd, J=2.56, 1.10 Hz, 1 H) (ESIMS (M+H)+=565)
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@@H:25]([CH2:59][OH:60])[C@@H:26]([OH:58])[C@@H:27]([OH:57])[C@H:28]([OH:56])[C:29]([NH:31][C@H:32]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:33][C:34]([O:36]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:35])=[O:30])=[O:23])[CH2:10][CH2:11][O:12]CC1C=CC(OC)=CC=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][C@H:9]([C:22]([NH:24][C@@H:25]([CH2:59][OH:60])[C@@H:26]([OH:58])[C@@H:27]([OH:57])[C@H:28]([OH:56])[C:29]([NH:31][C@H:32]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[O:23])[CH2:10][CH2:11][OH:12]
Reactant: COc1ccc(COCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CCO)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-(N-tert-butoxycarbonyl-O-(4-methoxybenzyl)-L-homoseryl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (200 mg) was added 4N hydrogen chloride in ethyl acetate (10 ml) at room temperature and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was dissolved in water and washed with diethylether. The aqueous layer was passed through a column of DIAION CHP-20P (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-diethylether to afford the title compound (53 mg).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[CH3:22][N:21]([CH2:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)[CH3:23]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(CN(C)C)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: CN(C)Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-dimethylaminomethyl-phenyl)-1H-pyridazin-4-one (A-25) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=390.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:43][C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=21
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Cl)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 564.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1COCC1>[Br:11][CH2:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH2:8]
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=C(CBr)c1ccc(Cl)cc1
Yield: 103.2 %

Procedure:
A mixture of 31.0 g (0.20 mol) of 4-chloro-α-methylstyrene, 38.0 g (0.21 mol) of N-bromosuccinimide, 3.9 g (0.02 mol) of p-toluenesulfonic acid monohydrate and 610 mL of THF was heated at reflux for 3 h and then concentrated at room temperature. The residue was partitioned between 400 mL of hexanes and 200 mL of H2O, the organic phase was washed twice with 100 mL H2O and dried (MgSO4). Removal of solvent gave 47.8 g of a yellow oil that was used without further purification. 1H NMR (CDCl3, 200 MHz) δ4.33 (s, 2H), 5.50 (d, 2H), 7.2-7.5 (m, 5H).