Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:36](O)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C.C(Cl)Cl>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A mixture of the compound obtained in Example 3 (361 mg), methylene chloride (10 ml), triethylamine (85 mg), benzoic acid (103 mg), N-hydroxybenzotriazole (114 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (162 mg) is stirred at room temperature overnight. The reaction solution is washed, dried and evaporated to remove the solvent. The resulting oily residue is purified by silica gel column chromatography (solvent; chloroform/methanol=20:1) to give methyl 2-butyl-5-benzoyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (297 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:28](=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCC=O
Reactant: COC(=O)c1cc(NCc2ccc(C#Cc3ccccc3)cc2)ccc1F
Product: CCCCCCN(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(F)c(C(=O)OC)c1

Procedure:
The title compound was prepared following the procedure described in Example 23 step b) using methyl 2-fluoro-5-{[4-(phenylethynyl)benzyl]amino}benzoate (213 mg, 0.59 mmol) and hexanal (Aldrich, 0.11 mL, 0.95 mmol). The title compound was obtained as a pale yellow oil (215 mg, 82%). HPLC, Rt: 6.1 min (purity: 94.5%). LC/MS, M+(ESI): 444.2. 1H NMR (CDCl3) δ: 7.51-7.44 (m, 4H), 7.32 (m, 3H), 7.17 (m, 3H), 6.92 (dd, J=9.8, 9.7 Hz, 1H), 6.74 (m, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 3.35 (t, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.29 (m, 6H), 0.88 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:5][C:4]=1[N+:20]([O-])=O.C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:9][C:8]1[CH:7]=[C:6]([C:12]([CH3:19])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([NH2:20])[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)COC(C)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(N)cc(C(C)(C)COC(C)=O)cc1N
Temperature: 40 °C
Yield: 99.1 %

Procedure:
Acetic acid 2-(4-methoxy-3,5-dinitro-phenyl)-2-methyl-propyl ester (625 mg, 2.00 mmol) was dissolved in 10 mL MeOH. Ethyl acetate (10 mL), ammonium formate (1.26 g, 20.0 mmol), and Pd/C (56 mg) were added and the mixture was heated to 40° C. overnight. The mixture was then filtered through celite and partitioned between sat'd NaHCO3 and EtOAc. The EtOAc extract was washed with brine. The washes were extracted once more with EtOAc. The extracts were combined, dried with Na2SO4, filtered, and concentrated to provide 500 mg of acetic acid 2-(3,5-diamino-4-methoxy-phenyl)-2-methyl-propyl ester.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26]>CC(=O)CC.CN(C)C=O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][C:25]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=[O:26])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C(CCCl)N1CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 50 °C

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine, hydrochloride (8.0 g) and potassium carbonate (15 g) in a mixture of butanone (50 mL) and dimethyl formamide (5 mL) was heated to 50° C. followed by the addition of 3-chloro-1-(2,3-dihydro-1H-indol-1-yl)propan-1-one (6.0 g). The resulting mixture was boiled under reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystalline material was collected by filtration and washed with acetone (8.5 g). Mp 157–158° C. 1H NMR (DMSO-d6): 2.60 (s, 4H); 2.60–2.80 (m, 4H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.10–7–15 (m, 2H); 7.20 (d, 1H); 7.25–7.35 (m, 2H); 8.10 (d, 1H). MS m/z: 404 (MH+), 243.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]1=[O:26])[CH2:7][CH2:6]2)#[N:2].C(O)C>CCCCCCC>[O:26]=[C:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C@H:8]1[CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(C#N)ccc3C2)C(=O)C1
Solvent: CCCCCCC
Solvent: CCO
Product: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1=O)C2

Procedure:
tert-Butyl 4-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-oxopiperazine-1-carboxylate was resolved on the OD column with 20% Ethanol and Heptane. The faster eluting isomer was tentatively assigned as the (S)-isomer, and the slower isomer as the (R)-isomer. Treating the (S)-isomer with 4N HCl gave rise to (6S)-6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, and the (R)-isomer gave rise to (6R)-6-(2-oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].[N:30]([O-])=O.[Na+]>O.O1CCOCC1.Cl>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:30]1
Reactant: CNc1cc(-c2ccc(OCc3cccnc3)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4cccnc4)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
To a suspension of 3-amino-4-(methylamino)-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (1.33 g) in water (15 ml) and 1,4-dioxane (15 ml), 2N hydrochloric acid (2.5 ml) was added at 0° C. and sodium nitrite (0.332 g) in water (3 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 70 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 1.14 g brown solid. Purified by Biotage SNAP cartridge KP-Sil column (100 g, heptane:ethyl acetate=1:0, 2:1, 1:1, 1:2 to 0:1 then ethyl acetate:methanol=25:1, 20:1 to 15:1 then dichloromethane:methanol=15:1, 10:1), fractions were passed through Strata SCX column (5 g) to give 560.7 mg light brown solid as 1-methyl-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (41%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.C(O)C(O)C.Cl[S:17]([C:20]1[N:28]=[C:27]2[N:22]([C:23]([O:30][CH3:31])=[N:24][CH:25]=[C:26]2[F:29])[N:21]=1)(=[O:19])=[O:18]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][S:17]([C:20]2[N:28]=[C:27]3[N:22]([C:23]([O:30][CH3:31])=[N:24][CH:25]=[C:26]3[F:29])[N:21]=2)(=[O:18])=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: COc1ncc(F)c2nc(S(=O)(=O)Cl)nn12
Reactant: Nc1c(F)cc(Cl)cc1F
Solvent: CC(O)CO
Solvent: ClCCl
Product: COc1ncc(F)c2nc(S(=O)(=O)Nc3c(F)cc(Cl)cc3F)nn12
Temperature: 35 °C

Procedure:
A mixture of 24.0 g (147 mmol) of 4-chloro-2,6-difluoroaniline and 22.9 g of 1,2-propanediol was placed in a round bottom flask and heated to 35° C. with stirring. A mixture of 14.5 g (49 mmol) of 88 percent purity 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine with 29.1 g of dichloromethane was prepared and was added in 1 mL shots over a 4 hour period. The resulting mixture was heated another 4 hours and was then stirred overnight at ambient temperature. It was then cooled to about 20° C. and filtered, collecting the solids present. The solids were slurried in 30 mL of a 1:1 mix of 2-propanol and water, collected by filtration, washed with 2×30 mL of 2-propanol, and air dried to obtain 14.8 g (75 percent of theory) of the title compound as a white powder of 98 percent purity melting at 203-204° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[C:6]([OH:18])=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23]>C(O)(C)C.O>[Cl:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[C:6]([O:18][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:5][CH:4]=1
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Reactant: ClCCCBr
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: O=c1c2ccccc2sc2c(OCCCCl)ccc(Cl)c12
Yield: 71.9 %

Procedure:
A 500 mL flask was charged with the sodium salt of 1-chloro-4-hydroxy-9H-thioxanthen-9-one (28.5 g; 0.100 mol), 1-bromo-3-chloropropane (17.4 g; 0.111 mol) and isopropyl alcohol (280 mL). The turbid reaction mixture was refluxed for 24 h. The hot solution was diluted with isopropyl alcohol (130 mL), drowned out in water (1400 mL) and the resulting suspension was extracted with dichloromethane (3×250 mL). The organic phase was separated, dried (MgSO4), filtered and solvent removed in vacuo to give 1-chloro-4-(3-chloropropoxy)-9H-thioxanthen-9-one (24.4 g; 72% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]1
Reactant: OC1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of 1.55 g (10 mmol) of 2-fluoro-5-nitrotoluene in 35 mL of N,N-dimethylformamide were added 1.01 g (10 mmol) of 4-hydroxypiperidine and 1.8 g (13 mmol) of potassium carbonate, and the mixture was stirred for 2 hours at 120° C. The reaction mixture was poured into ice and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 1.5 g (63%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2.N1C=CC=CC=1.[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34]>ClCCl>[CH3:1][N:2]([C@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C:3]1[C:4]([O:17][S:33]([C:36]([F:39])([F:38])[F:37])(=[O:34])=[O:32])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (320 mg, 0.95 mmol) in dichloromethane (30 mL) was added pyridine (313 mg, 3.96 mmol), and Tf2O (559 mg, 1.98 mmol). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum to get a residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to give (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a yellow solid (432 mg, crude).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[N:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([F:16])[CH:3]=1.C([N-]C(C)C)(C)C.CN([CH:27]=[O:28])C.O>C1COCC1>[Br:1][C:2]1[C:3]([CH:27]=[O:28])=[C:4]([F:16])[C:5]([N:9]=[N:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Br)cc(F)c1N=NN1CCCC1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In a 200 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, (4-bromo-2,6-difluoro-phenyl)-pyrrolidin-1-yl-diazene a8 (6.06 g, 0.021 mol.) in THF (50 ml) is added to a solution of diisopropylamide (2 M in THF, 12.5 ml) cooled at −78° C. After 2 h at this temperature, dry DMF (3.2 ml) is added to the green solution. After 1 h, it is poured into water (200 ml), extracted with ether (3×200 ml) and the organic phase is dried over MgSO4, filtered and concentrated in vacuo to give the crude aldehyde a9 (6.62 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][S:22]([C:15]1[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])(=[O:24])=[O:23]
Reactant: NCCCO
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCCO)c1c(Cl)cc(Cl)cc1Cl

Procedure:
To 40 parts of tetrahydrofuran are added 1.4 parts of 3-amino-1-propanol and 1.8 parts of triethylamine. Into this solution, 10 parts of tetrahydrofuran containing 5 parts of 2,4,6-trichlorobenzenesulfonyl chloride is dropped with stirring. After the dropping, the resultant mixture is stirred for 1 hour. After completion of the reaction, the salt is removed by filtration, and the filtrate is freed from the solvent. The resulting oily substance is charged with water and then allowed to stand to form a solid. This solid is recrystallized from toluene to obtain 3.8 parts of N-3-hydroxypropyl-2,4,6-trichlorobenzenesulfonamide, m.p. 104.5°-106.5° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].O>C(O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][C:13]2[CH2:2][C:3](=[O:4])[NH:5][CH2:6][CH2:7][C:8]=2[CH:9]=1
Reactant: COc1cccc(CCNC(=O)CCl)c1
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCNC(=O)C2

Procedure:
A quantity of 3.1 gm (0.0136 mol) of N-chloroacetyl-N-(2-(3-methoxy-phenyl)-ethyl)-amine is dissolved in 270 ml of ethanol and 1530 ml of water and illuminated for ten hours under a nitrogen atmosphere with a mercury high pressure lamp at 20° to 25° C. The solution is concentrated down to about 400 ml, mixed with sodium bicarbonate, and extracted several times with ethyl acetate. The extracts are dried over magnesium sulfate and concentrated by evaporation, and the residue is purified over a silica gel column with ethyl acetate as eluant.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:31])[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[C:8]([O:10]CC)=[O:9])C>O.C(O)C>[OH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:7]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])([C:8]([OH:10])=[O:9])[C:6]([OH:31])=[O:5]
Reactant: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)(C(=O)O)C(=O)O
Yield: 60.1 %

Procedure:
To a stirred solution of KOH (4.83 g, 75 mmol) in water (4.2 mL) and ethanol (15 mL) was added 2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester (15 g). The reaction mixture was heated to reflux for 14 h, then concentrated in vacuo, and extracted with chloroform. The aqueous layer was acidified with HCl until pH 1 and extracted with diethyl ether (3×50 mL). The ethereal solution was dried over anhydrous MgSO4 and concentrated in vacuo to afford get 2,2-bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid (7.8 g, 82.3%) as a yellow solid. 1H NMR (300 MHz, CD3OD/TMS): (ppm) 4.86 (s, 4 H), 3.22 (s, 4 H), 1.9-1.8 (m, 4 H), 1.36-1.10 (m, 12 H), 0.84 (s, 12 H). 13C NMR (75 MHz, CD3OD/TMS): (ppm) 176.0, 72.0, 58.7, 39.8, 36.0, 34.1, 26.5, 25.5, 24.5. Mp.: 178-180 C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(OC([N:37]([CH2:44][CH3:45])[C:38]1([C:41](O)=[O:42])[CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:41]([C:38]4([NH:37][CH2:44][CH3:45])[CH2:40][CH2:39]4)=[O:42])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CCN(C(=O)OC(C)(C)C)C1(C(=O)O)CC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (67.3 mg, 0.17 mmol), 1-(tert-butoxycarbonyl(ethyl)amino)cyclopropanecarboxylic acid (38.0 mg, 0.17 mmol), HATU (63.0 mg, 0.17 mmol) and diisopropylethylamine (57 μL, 0.34 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water, the combined organic extracts were dried (Na2SO4) and then concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA and was then stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(ethylamino)cyclopropyl)methanone; ESMS m/z 527.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH3:30])[CH2:19][CH2:18]1.Cl>>[CH2:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:18][CH2:19]1)[CH3:30]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CCc1ccccc1N1CCN(CCCCl)CC1
Agent: Cl
Product: CCc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 70 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-ethylphenyl)-piperazine; yield 70% of theory; m.p. of the hydrochloride (recrystallized from water) 209°-210°C;
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:6]([F:18])[CH:5]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35](O)=[O:36])[N:27]=[C:28]([C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)[C:21]=12.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([CH2:34][C:35]([N:15]3[CH2:14][CH2:13][N:12]([C:7]4[CH:8]=[C:9]([O:10][CH3:11])[C:4]([Cl:3])=[CH:5][C:6]=4[F:18])[CH2:17][CH2:16]3)=[O:36])[N:27]=[C:28]([C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)[C:21]=12
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Reactant: COc1cc(N2CCNCC2)c(F)cc1Cl
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: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4c(N)ncnc43)CC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-piperazine dihydrochloride salt (65.2 mg, 0.206 mmol, 1 equiv), [4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid (50 mg, 1 equiv), BOP reagent (109 mg, 1.7 equiv) and N,N-diisopropylethylamine (0.165 mL, 5 equiv) in DMF (0.5 mL) was stirred at room temperature overnight. Reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) purification gave 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-piperazin-1-yl]ethanone. MS (ES) m/z 486.5 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:36]=[CH:35][C:15]([O:16][CH2:17][C:18]2[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:21][CH:22]=2)=[CH:14][CH:13]=1.[NH:37]1[CH:41]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:39]=[N:38]1.O>CN(C)C=O>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[CH:23]/[C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:16][C:15]3[CH:35]=[CH:36][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:37]4[CH:41]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:39]=[N:38]4)=[CH:13][CH:14]=3)[N:19]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c[nH]nn1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCCCc2ccc(OCc3coc(/C=C/c4ccc(C(F)(F)F)cc4)n3)cc2)nn1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
Potassium carbonate (2.4 g) was added to a solution of 4-[[4-(4-iodobutyl)phenoxy]methyl]-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole (7.5 g) and ethyl 1H-1,2,3-triazole-4-carboxylate (2.1 g) in dimethylformamide (100 ml), and the mixture was stirred at 70° C. for 5 hr. After the reaction was completed, the reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=3:1), and recrystallized from ethyl acetate-hexane to give the titled compound (1.85 g) as a colorless crystal powder.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[O:12]([C:13]1[CH:14]=[CH:15][C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chlorosulfonic acid (4.3 mL, 64.6 mmol) in dichloromethane (20 mL) is added dropwise to a solution of diphenyl ether (10 g, 58.8 mmol) in dichloromethane (20 mL) at 0° C. under nitrogen atmosphere. The reaction mixture is slowly warmed up to RT and stirred for 2 h. To the mixture are added oxalyl chloride (6.5 ml, 76.4 mmol) and then DMF (1.5 mL) at RT. After being heated at 40° C. for 1 h, the reaction mixture is stirred at RT for 15 h. The mixture is poured to ice-water and extracted with ether. The organic layer is dried over MgSO4 and evaporated in vacuo to give the title compound quantitatively: NMR (CDCl3) 7.10 (t, 4H, J=8.6 Hz), 7.22-7.30 (m, 1H), 7.46 (t, 2H, J=8.6 Hz), 7.98 (d, 2H, J=9.1 Hz).