Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([CH:12]([F:14])[CH3:13])[N:5]=1.[OH-].[Na+]>C(O)(=O)C>[NH2:3][C:4]1[N:9]=[C:8]([Cl:1])[N:7]=[C:6]([CH:12]([F:14])[CH3:13])[N:5]=1
Reactant: ClCl
Reactant: CSc1nc(N)nc(C(C)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(F)c1nc(N)nc(Cl)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Chlorine gas was passed into a suspension of 38 g of 2-amino-4-methylthio-6-(1-fluoroethyl)-1,3,5-triazine in 0.25 l of glacial acetic acid (15 min) at 20 to 25° C. The reaction mixture was stirred for 30 min at approx. 20° C., sprayed for 1 hour with nitrogen gas at room temperature, poured into 1.25 l of ice-cold aqueous solution of 87 g of sodium hydroxide and stirred for 5 min. After extraction with ethyl acetate, the organic phase was washed with water and dried over magnesium sulfate, and the solvent was removed in vacuo. The crude product was purified by stirring in heptane. After filtration with suction and drying, 25 g (70%) of 2-amino-4-chloro-6-(1-fluoroethyl)-1,3,5-triazine were obtained as a white powder (m.p. 131° C.); 1H NMR (CDCl3): δ=1.7 (dd, 3 H), 5.4 (dq, 1 H), 6.1 (s br., 1 H), 6.7 (s br., 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g, 0.0194 mol) in toluene (25 mL) was added to a suspension of activated manganese dioxide (27 g) in toluene (325 mL) which was previously concentrated with a Dean Stark water separator at reflux for one hour. The suspension was heated at 100° C. for 17 hours. The solids were filtered and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde, as an oil. NMR and IR were consistent with the structure.
Reaction SMILES: C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:53])=[CH:42][C:41]=1[CH2:54][OH:55])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O[C:57]1[CH:64]=[CH:63][C:60]([CH:61]=[O:62])=[CH:59][CH:58]=1>C1COCC1>[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:53])=[CH:42][C:41]=1[CH2:54][O:55][C:59]1[CH:58]=[CH:57][CH:64]=[CH:63][C:60]=1[CH:61]=[O:62])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(COc2ccccc2C=O)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine were added to a THF solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methanol and 4-hydroxybenzaldehyde, followed by stirring at room temperature for 14 hours to obtain 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxybenzaldehyde.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1(S[CH2:22][C:23]#[N:24])C=CC=CC=1.Cl>CS(C)=O>[CH3:11][O:10][C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]([CH3:3])=[C:9]([CH2:22][C:23]#[N:24])[CH:8]=1
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Reactant: N#CCSc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(CC#N)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a suspension of powdered sodium hydroxide (5.76 g, 144.0 mmol) in anhydrous dimethylsulfoxide (0.14 mL) was added a mixture of 4-methyl-2-nitro-anisole (2.0 mL, 14.4 mmole) and phenylthioacetonitrile (1.88 mL, 14.4 mmole) in anhydrous dimethylsulfoxide (14 mL). The reaction mixture was kept under 30° C. After stirring for one hour at room temperature, the reaction mixture was poured into ice water (400 mL) and 6N hydrochloric acid (40 mL). The mixture was extracted with dichloromethane. The organic layer was washed with water, dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure. The resulting solid was washed with a small amount of hexanes and a small amount of ethyl acetate to give (5-methoxy-2-methyl-4-nitro-phenyl)-acetonitrile as a solid (2.40 g, 81%). 1H NMR (CDCl3) δ: 2.32 (s, 3H), 3.73 (s, 2H), 3.99 (s, 3H), 7.15 (s, 1H), 7.73 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]1([N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[C:18]1([N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:25][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: NN(c1ccccc1)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NN(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 6.8 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (500 mg, 2.2 mmol) and N,N-diphenyl-hydrazine (422 mg, 2.2 mmol) in DMF (3 mL) is stirred at 50° C. for 15 min. The mixture is treated with DMTMM (633 mg, 2.2 mmol) and stirred at 50° C. for 3 h. The mixture is diluted with EtOAc (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 75% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid N′,N′-diphenyl-hydrazide (60 mg, 7%). MS: 399 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.30 (d, 1H), 8.15 (m, 1H), 7.61 (m, 1H), 7.44 (m, 1H), 7.35 (m, 4H), 7.22 (m, 4H), 7.04 (m, 2H), 2.64 (s, 3H). IC50=16 nM.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[CH3:10][N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH:25]2[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH:25]2[CH2:30][CH2:29][N:28]([C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH2:27][CH2:26]2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CCC(C2c3ccccc3N(C)c3ccccc32)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1c2ccccc2C(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Trichloroethyl chloroformate (1.06 mL, 7.7 mmol) is added over a 10 minute period to a solution of 9,10-dihydro-10-methyl-9-(1-methyl-4-piperidinyl)acridine (453 mg, 1.55 mmol) [(Tetrahedron Letters, 29, 5701 (1988)] and triethylamine (649 μl, 4.65 mmol) in 20 mL of dry toluene at 85° C. The reaction is worked up after 30 minutes by extracting with EtOAc and washing with a 10% NaOH solution. The crude product is obtained after the solvent is removed.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[NH:18][C@@H:17]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:18][C@@H:17]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1[C@H](Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
TFA (68.5 g, 601 mmol) was added dropwise at 0° C. to a solution of tert-butyl 1,3-(S)-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (13.5 g, 31.0 mmol) in CH2Cl2 (93 ml) and the mixture was stirred at this temperature for 15 min. After warming to RT, the reaction mixture was stirred for a further 2.5 h. Subsequently, the reaction solution was adjusted with aqueous saturated NaHCO3 solution to pH 7-8, the organic phase was separated off and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was distilled off. The workup was carried out by means of column chromatography and afforded 1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one in a yield of 7.8 g (75%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.[CH3:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[C:18]([NH:20][CH:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:5][CH:6]([CH3:11])[CH3:7])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(C=O)nc1
Reactant: Cc1cc(N)cc(C)c1-c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Nc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of methyl 6-formylnicotinate (200 mg, 1.21 mmol) in toluene (8 mL) containing activated molecular sieves was added 2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-amine (316 mg, 1.33 mmol). The reaction mixture was heated to 90° C. and stirred overnight. The reaction mixture was concentrated and the residue dissolved in tetrahydrofuran (8 mL). The solution was cooled to 0° C. Zinc chloride (3.64 mL of a 1.0M solution in diethyl ether, 3.64 mmol) was added, followed by isobutylmagnesium bromide (1.82 mL of a 2.0M solution in THF, 3.64 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL). The mixture was diluted with dichloromethane (30 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (30 mL) two more times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinate (290 mg, 51%). 1H NMR (400 MHz, CDCl3, δ): 9.20 (s, 1H), 8.25 (d, 1H), 7.62 (d, 4H), 7.50 (d, 2H), 7.45 (d, 1H), 7.20 (d, 2H), 6.30 (s, 2H), 4.62 (m, 1H), 3.95 (s, 3H), 3.5 (s, 3H), 1.87 (s, 6H), 1.73 (d, 3H), 1.26 (m, 3H), 1.10 (m, 6H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:11]([CH:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1)=[O:13])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)C1COc2ccccc2O1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])C1COc2ccccc2O1
Yield: 33.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.91 g of 1,4-benzodioxane-2-carboxylic acid and 0.85 g of nitroxyethylamine nitrate, 0.45 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][N:26]=[CH:16][C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NOCc1ccccc1
Reactant: CCc1cc(-c2ccc(C=O)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C=NOCc3ccccc3)o2)c(C)[nH]c1=O

Procedure:
Example 198 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]furan-2-carbaldehyde and benzyloxyamine to afford the title compound. MS: m/e=337 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([N:27]4[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]4)[CH:14]=[CH:15][CH:16]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(Br)cc23)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)CC1
Yield: 80 %

Procedure:
Following the procedures of Example 144, 5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl piperazine-1-carboxylate were reacted, triturated with ethyl ether, and collected by filtration to afford 910 mg (80%) of tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate. ESI MS m/z 543.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1OC
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice and with saturated sodium bicarbonate solution 50 ml. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 294.6 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][O:40][CH2:41][CH:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][C:45]([NH:44][CH:42]([CH3:43])[CH2:41][O:40][CH3:39])=[O:53])[CH2:48][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCC(C)NC(=O)CN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)COC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-methoxy-1-methyl-ethyl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide (example 15) in an analogous manner as described in example 25. LR-MS: 719.4 [(M+H)+]
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH3:25])[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 1.5 g, 5 mmol) in 50 mL of DMF was added to a suspension of sodium hydride (0.24 g, 5.9 mmol) in 20 mL of DMF and stirred for 30 minutes. Methyl iodide (3.1 mL, 49 mmol) was added, and the mixture was stirred at 25° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 1.6 g of the title compound as a solid, mp 167-169° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: NCc1ccccc1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(NCc2ccccc2)CN1Cc1ccccc1
Reaction time: 3 h

Procedure:
1-Benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester and a corresponding benzylamine are dissolved in DCM, acetic acid and NaBH(OAc)3 is then added. After stirred for about 3 hours the reaction mixture is diluted with DCM, washed, dried and concentrated. The residue is purified to afford 1-benzyl-4-(benzylamino)-pyrrolidine-2-carboxylic acid methyl ester (26).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:5]=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[I:18]I>CCCCCC.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:5]=[C:4]([F:12])[C:3]=1[I:18]
Reactant: II
Reactant: C=CCCc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCc1cc(F)c(I)c(F)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
0.41 mol 1,3 difluoro-5-(3-butenyl)-benzene was added to a dry round bottom flask with 300 ml anhydrous tetrahydrofuran. After cooling under a nitrogen atmosphere to −70° C. a solution of 0.46 mol of n-butyllithium in 280 ml hexane was added. After stirring at −70° C. for 30 minutes a mixture of 0.46 mol of Iodine in 200 ml tetrahydrofuran was added slowly over 2 hours. The reaction was left to warm to room temperature overnight. The reaction was quenched by pouring onto ice/hydrochloric acid mixture. The layers were separated and the aqueous layer extracted twice with diethyl ether (2×100 ml). The combined organic layers were washed with 50 g sodium thiosulphate in 200 ml water to remove excess iodine, then with water (2×50 ml) and dried over anhydrous sodium sulphate. Removal of the solvent yielded 126 g of the title compound as a beige solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>ClCCl>[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:14][CH2:15][N:16]([C:38]([CH:35]4[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)=[O:39])[CH2:17][CH2:18]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(C(=O)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (500 mg, 1.45 mmol, 1.00 equiv) in dichloromethane (50 mL) at room temperature. To the resulting mixture was then added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (332 mg, 1.45 mmol, 1.00 equiv), in portions at room temperature, followed by BOP (767 mg, 1.74 mmol, 1.20 equiv), in portions at room temperature. To the resulting mixture was added DIPEA (280 mg, 2.17 mmol, 1.50 equiv), in portions at room temperature. The resulting solution was stirred for 4 h at room temperature. The resulting mixture was washed with water (1×50 mL). The resulting solution was extracted with DCM (3×50 mL), the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1) to yield tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidine-1-carbonyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [CH2:1]1O[C:4]([N:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][C:12]3=[O:16])[CH2:9]2)([O:5]CC)[O:3][CH2:2]1>S(=O)(=O)(O)O>[O:16]=[C:12]1[CH2:11][CH:10]2[CH2:15][CH:13]1[CH2:14][N:8]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:9]2
Reactant: CCOC1(N2CC3CC(=O)C(C3)C2)OCCO1
Agent: O=S(=O)(O)O
Product: CCOC(=O)N1CC2CC(=O)C(C2)C1
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A 2% solution of aqueous sulfuric acid (100 ml) was added to ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate ethylene ketal (6.72 g, 27.9 mmol) and the mixture was allowed to stir for 1 h. The mixture was then extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over potassium carbonate, filtered, concentrated by rotary evaporation, and then distilled on a Kugelrohr apparatus (0.2 mm Hg, 132-162° C.) to yield a clear colorless oil (3.49 g, 64%).