Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([F:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:9][C:4]1[C:3]([C:1]#[C:2][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1I
Reactant: C#Cc1cccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(F)ccc1C#Cc1cccnc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
Into a round bottom flask was added 3-ethynyl-2-fluoropyridine (0.3 g, 0.002 mol), 4-fluoro-1-iodo-2-nitrobenzene (0.675 g, 0.00253 mol), bis(triphenylphosphine)palladium(II) chloride (0.09 g, 0.1 mmol), copper(I) iodide (0.04 g, 0.2 mmol), and triethylamine (0.52 mL, 3.7 mmol) in N,N-dimethylformamide (4 mL). The reaction was stirred at room temperature for 2 hours. The reaction was extracted with ethyl acetate, and the combined organic extracts were washed with brine (3×), dried over MgSO4, and purified by column chromatography on silica gel (10% ethyl acetate 90% hexanes), to give 0.443 g of product. 1H NMR (400 MHz, CDCl3): δ 8.44-8.50 (m, 1H), 7.99-8.02 (m, 1H), 7.79-7.90 (m, 1H), 7.78-7.82 (m, 1H), 7.37-7.42 (m, 1H), 7.23-7.29 (m, 1H). MS [M+H]=261.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:15][C:16](O)=[O:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.C([O:39][C:40](=[O:43])[CH2:41][NH2:42])(C)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:15][C:16]([NH:42][CH2:41][C:40]([OH:43])=[O:39])=[O:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)N1CCN(C(=O)C(CC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)C(CC(=O)NCC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-carboxyethyl]aminocarbonyl-4-methoxyquinoline (50 mg, 0.11 mmol) in tetrahydrofuran (THF) (2 mL) was added glycine t-butyl ester hydrochloride (20 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (23 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBT) (16 mg, 0.12 mmol) and diisopropylethylamine (DIEA) (0.16 g, 0.12 mmol). The reaction was stirred at ambient temperature overnight. The resultant solution was partitioned between water and ethyl acetate. The organic layer was concentrated in vacuo to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(((carboxy)methyl)aminocarbonyl)ethyl]aminocarbonyl-4-methoxyquinoline as an oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[F:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 4-fluoro-N-methoxy-N-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: O=[C:2]([CH2:13][CH2:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:20][CH2:19][CH2:18][O:17]1)[CH2:3][C:4]([NH:6]C1C=CC=CC=1)=[O:5].[NH2:27]N>C1COCC1>[C:21]1([C:16]2([CH2:15][CH2:14][CH2:13][C:2]3[CH2:3][C:4](=[O:5])[NH:6][N:27]=3)[O:20][CH2:19][CH2:18][O:17]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: O=C(CCCC1(c2ccccc2)OCCO1)CC(=O)Nc1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(CCCC2(c3ccccc3)OCCO2)=NN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
Step AAH (5): To a soln of 3-oxo-N-phenyl-6-(2-phenyl-1,3-dioxolan-2-yl)hexanamide (444 mg, 1.256 mmol) in THF (1 mL) was added hydrazine (0.059 mL, 1.88 mmol). The mixture was stirred at rt for 2 h, then at 65° C. for 2 h. The reaction mixture was concentrated in vacuo. Dichloromethane (10 mL) was added to the crude residue. After cooling to 0° C., the product crystallized out. The solid was collected by vacuum filtration and dried under high vacuum to afford 3-(3-(2-phenyl-1,3-dioxolan-2-yl)propyl)-1H-pyrazol-5(4H)-one (250 mg, 73% yield). LC-MS (M+H)+ 275.1.
Reaction SMILES: [OH:1][C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH:10]2[CH:6]([CH2:7][N:8]([C:11](=[O:21])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[CH2:9]2)[C:5](=[O:22])[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>CO>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:2]1([OH:1])[CH2:3][CH2:4][CH:5]([OH:22])[CH:6]2[CH:10]1[CH2:9][N:8]([C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:7]2
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)CCC(O)(c3ccccc3OC)C2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1CC(=O)N1CC2C(O)CCC(O)(c3ccccc3OC)C2C1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a suspension, cooled to +5° C., of 0.5 g of (3aRS,7RS,7aSR)-7-hydroxy-7-(2-methoxyphenyl)-2-[(2 -methoxyphenyl)acetyl]-4-perhydroisoindolone in 50 cm3 of methanol is added 0.027 g of sodium borohydride. After stirring for 2 hours at 5° C., 0.2 cm3 of 1N hydrochloric acid is added to the reaction solution which is then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of water and 70 cm3 of dichloromethane. After stirring, the suspension obtained is filtered and the organic phase of the filtrate is washed with water and then dried over. magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of (3aRS,4RS,7SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-4,7-perhydroisoindolediol is obtained in the form of a white foam.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17]O)=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCO)nc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-4, 46.4 mg, 0.15 mmol, 1.0 equiv) was added to anhydrous DCM (1.5 mL) and cooled to −10° C. Triethylamine (90 μL, 0.64 mmol, 4.2 equiv) and methanesulfonyl chloride (26 μL, 0.33 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 32-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give 32-5 as a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][Cl:10])[N:3]=1.[CH2:11]([NH:14][CH2:15][CH:16]=[CH2:17])[CH:12]=[CH2:13]>>[NH2:1][C:2]1[N:3]=[C:4]([CH2:9][Cl:10])[CH:5]=[C:6]([N:14]([CH2:15][CH:16]=[CH2:17])[CH2:11][CH:12]=[CH2:13])[N:7]=1
Reactant: Nc1nc(Cl)cc(CCl)n1
Reactant: C=CCNCC=C
Product: C=CCN(CC=C)c1cc(CCl)nc(N)n1

Procedure:
3.56 Parts of 2-amino-4-chloro-6-chloromethylpyrimidine and 3.9 parts of diallylamine were reacted together according to the method of Example 15 to give 2-amino-4-chloromethyl-6-diallylaminopyrimidine m.p. 53°-55° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[S:14][C:8]3[C:7]([OH:25])=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(C(C)(C)C)cc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(-c2nc3cnc(C(=O)NCC(=O)O)c(O)c3s2)cc1
Yield: 58.4 %

Procedure:
2-(4-tert-Butyl-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (100 mg, 0.28 mmol) and glycine (442 mg, 5.89 mmol) were suspended in 11.2 mL of 0.5 N sodium methoxide in methanol. The reaction was heated at reflux temperature overnight, cooled, and concentrated. The residue was dissolved in water (30 mL), and the solution was acidified to pH 1˜2 with 2 N HCl, extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated to produce 63 mg of a yellow solid. MS: (+) m/z 386.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[CH3:15])=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Cc1ccccc1N
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1C

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22](O)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:38]([CH3:39])[CH2:37][CH2:36][N:35]([CH3:40])[C:34]2=[O:41])=[CH:29][CH:28]=1>>[CH3:40][N:35]1[CH2:36][CH2:37][N:38]([CH3:39])[CH:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:22]3[N:21]=[CH:20][C:19]4=[CH:18][CH:17]=[C:16]([C:12]5[CH:13]=[CH:14][CH:15]=[C:10]([S:7]([N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)(=[O:9])=[O:8])[CH:11]=5)[N:24]4[N:23]=3)=[CH:28][CH:29]=2)[C:34]1=[O:41]
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCOCC1
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Product: CN1CCN(C)C(c2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)N6CCOCC6)c5)n4n3)cc2)C1=O

Procedure:
1,4-Dimethyl-3-(4-{7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperazin-2-one was prepared from 7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as an orange foam (91 mg, 55%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.57 (d, 1H, J=7.5 Hz), 8.30 (s, 1H), 7.78-7.65 (m, 2H), 7.58 (d, 2H, J=8.3 Hz), 7.38 (d, 2H, J=8.3 Hz), 7.05 (d, 1H, J=4.7 Hz), 6.90 (bs, 1H), 6.86 (d, 1H, J=4.7 Hz), 3.80-3.68 (m, 6H), 3.27-3.19 (m, 1H), 3.12-3.00 (m, 5H), 3.00 (s, 3H), 2.74-2.63 (m, 1H), 2.21 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[O:17])([O-:3])=[O:2]
Reactant: CCOCCOC(=O)CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O

Procedure:
A mixture of 3-nitrobenzaldehyde (4.54 g), 2-ethoxyethyl acetoacetate (5.23 g) and piperidine (85.2 mg) in benzene (15 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant mixture was washed with water, an aqueous solution saturated with sodium chloride and water in turn, dried and concentrated to give an oil of 2-ethoxyethyl 2-(3-nitrobenzylidene)acetoacetate. To this oily product was added ethyl 3-amino-4,4-diethoxycrotonate (6.5 g). The mixture was heated at 110° C. for about 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with water twice and dried. The solvent was removed from the mixture to give an oil (15.58 g). This oil was subjected to column chromatography on silica gel with an eluent (a mixture of 10 parts of benzene and one part of ethyl acetate by volume) to give an oily substance (8.09 g). This oily substance (0.93 g) was treated with a mixture of n-hexane and diethyl ether to give crystals, which were further recrystallized from a mixture of n-hexane and diethyl ether to give yellow granules (565.2 mg) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 99° to 100° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C([O-])(=O)C.[Na+].[Br:19]Br.O>C(O)(=O)C>[Br:19][C:8]1[CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1n[nH]c2ncccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 120 °C
Yield: 31 %

Procedure:
A mixture of methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VI) (0.177 g, 1 mmol), sodium acetate (0.492 g, 6 mmol) and bromine (0.308 mL, 6 mmol) in glacial acetic acid (5 mL) was heated overnight at 120° C. in a sealed tube. The solution was cooled and poured into water. The solids formed were filtered, washed with water and dried at room temperature under vacuum. The crude product was purified on a flash silica gel column (100% DCM→100:2 DCM:MeOH) to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VII) as a white solid (78 mg, 0.31 mmol, 30% yield). 1H NMR (CDCl3) δ ppm 3.95 (s, 3 H), 8.62 (d, J=3.01 Hz, 1 H), 8.73 (d, J=3.01 Hz, 1 H); ESIMS found for C8H6BrN3O2 m/z 256.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH3:17][NH2:18]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:18][CH3:17])[N:3]=1
Reactant: CN
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: CNc1nc(N)nc(-c2ccco2)c1C#N
Yield: 69.4 %

Procedure:
A stirred solution of 200 mg (0.87 mmol) 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and 5.0 ml (129 mmol) methylamine in 15 ml ethanol in a pressure tube was heated at 100° C. for 16 h. The reaction mixture was then concentrated in vacuo and the resulting crystals washed with ether and ether/ethanol to afford 130 mg (75%) 2-amino-4-furan-2-yl-6-methylamino-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 215 (M+, 100), 214 ([M—H]+, 76), 186 (40).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:26]=[O:27])C>C1COCC1.CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:9]([CH:10]=1)[CH:26]=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2)=N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1
Temperature: -20 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a solution of 101c (50 g, 0.22 mol) in anhydrous THF (750 mL) was added 2.4 M solution of n-butyllithium in hexane (225 mL) at −78° C. under nitrogen atmosphere. The clear amber solution was warmed to −20° C. and stirred for 4 hr. The reaction mixture became red-amber and cloudy. The mixture was re-cooled to −78° C. and stirred rapidly before 72 mL of DMF was added drop wise at such a rate that the temperature was controlled below −60° C. After the addition, the reaction mixture was stirred at −78° C. for 15 min then stirred at −20° C. for 1 hr and room temperature for 1 hr. The reaction mixture was quenched with 200 mL of 0.5 M aqueous KHSO4. More KHSO4 solution was added in until the pH was adjusted to 4-5. The aqueous phase was extracted with EtOAc (3×500 mL) and the combined organic phases was washed with 400 mL of brine and dried over Na2SO4, filtered and concentrated in vacuo to give 101d (35 g, 62%) as a yellow solid which was used in the next step without further purification. LCMS, ESI, m/z 260 (M+1)+.
Reaction SMILES: C([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[ClH:18]>O1CCOCC1>[ClH:18].[NH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(N-Me,N-Et Carbamyloxy) N-Boc aminoindan (7.8 g, 23.3 mmol) was dissolved in dioxane (80 ml), and a 20% solution of gas. HCl in dioxane (80 ml) was added. After 2 hr stirring at RT the solvent was evaporated in-vacuo and the residue was treated with dry ether (200 ml) and the mixture stirred at RT for 4 hrs and filtered, to give 6.15 g (0.7 mmol, 97%) of 6-(N-Me, N-Et carbamyloxy) aminoindan hydrochloride.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([CH2:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH2:33]([C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:34]
Reactant: CCc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Reactant: C1COCCN1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCN4CCOCC4)c23)ccc1OCc1ccccn1
Yield: 45 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-ethyl-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 19) and morpholine to give the title compound in 45% yield; NMR Spectrum: 1.20 (t, 3H), 2.50-2.52 (m, 4H), 2.66 (q, 2H), 2.78 (t, 2H), 3.54-3.56 (m, 4H), 4.42 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.34-7.38 (m, 1H), 7.41 (d, 1H), 7.49-7.55 (m, 2H), 7.85 (td, 1H), 8.23 (s, 1H), 8.28 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[C:12](=[O:13])[CH:11]2[C:14]([CH3:16])([CH3:15])[CH:7]([C:8](=[O:18])[NH:9][C:10]2=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=1[CH2:29]Cl>CN(C)C=O>[CH2:1]([N:5]1[C:6](=[O:19])[CH:7]2[C:14]([CH3:15])([CH3:16])[CH:11]([C:10](=[O:17])[N:9]([CH2:29][C:28]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:27]=3[CH3:26])[C:8]2=[O:18])[C:12]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C2C(=O)NC(=O)C(C1=O)C2(C)C
Reactant: Cc1ccc(C)c(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C2C(=O)N(Cc3cc(C)ccc3C)C(=O)C(C1=O)C2(C)C
Temperature: 120 °C
Yield: 32 %

Procedure:
2.6 g of 3-butyl-9,9-dimethyl-2,4,6, 8-tetraoxo-3,7-diazabicyclo[3,3,1]nonane were heated to 120° C. in 50 ml of dimethyl formamide with 1.7 g potassium carbonate for one hour. After cooling, a solution of 1.8 g of 2,5-dimethylbenzyl chloride in 20 ml of dimethyl formamide was added dropwise to the reaction mixture, and the reaction mixture was heated to 120° C. for another 3 hours. The reaction mixture was worked up by distilling off the dimethyl formamide, taking up the residue in dichloromethane, and washing with water adjusted to an alkaline pH value. The dichloromethane phase was separated, dried over magnesium sulfate, and concentrated. After recrystallizing the remaining crude product residue from ether/acetone, 1.2 g of 3-butyl-7-(2,5-dimethylbenzyl)-9, 9-dimethyl-2,4,6,8-tetraoxo-3,7diazabicyclo[3,3, 1]nonane was obtained having a melting point of 159-161° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:30][C:22]([F:31])([C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCI
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.6 g of 1-iodo-3,3,4,4,5,5,5-heptafluoropentane were dissolved in 5 ml of ethylene glycol dimethyl ether, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 8 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.75 g of 2-(3,3,4,4,5,5,5-heptafluoropentyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (71)).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9](B3OCCCO3)[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.Br[C:24]1[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=1[CH3:29]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:24]3[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=3[CH3:29])[CH:8]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: Cc1nn(C)c(C)c1Br
Reactant: Nc1nc2ccccc2n1-c1cccc(B2OCCCO2)c1
Product: Cc1nn(C)c(C)c1-c1cccc(-n2c(N)nc3ccccc32)c1

Procedure:
2-Amino-1-[3-(1,3,5-trimethyl-4-pyrazolyl)phenyl]benzimidazole was prepared from 3-(2-amino-1-benzimidazolyl)-phenyl-1,3,2-dioxaborinane and 4-bromo- 1,3,5-trimethylpyrazole by method A. mp 198°-200° C.
Reaction SMILES: CC([N:5]([C:9]([CH3:32])([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1([CH3:30])[C:25]2[C:20]([O:19][C:16]3[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:32])([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 1,1-dimethylethyl[2-({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 74, 11 mg) in dry dichloromethane (2 ml), TFA (0.077 ml, 0.997 mmol) was slowly added at 0° C. and the reaction mixture was stirred for 2 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge. The cartridge was washed with 3 CV of methanol and then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). This afforded the title compound (8.5 mg).