Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:29])[C@H:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16])[CH3:9].C(N(CC)CC)C.[CH2:37]([O:44][C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][C@@H:52]([C:61](O)=[O:62])[NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11](=[O:29])[C@H:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:16][C:61](=[O:62])[C@H:52]([CH2:51][CH2:50][CH2:49][CH2:48][NH:47][C:45]([O:44][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:46])[NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:58])[CH3:59])=[O:55])[CH3:9]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a mixture of 1.68 g (4 mmol) of L-phenylalanyl-L-leucine ethyl ester trifluoroacetate, 0.56 mL (4 mmol) of triethylamine and 32 mL of chloroform were added at 0° C., first 1.52 g (4 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine, and then 0.83 g (4 mmol) of dicyclohexylcarbodiimide, each being added in a single portion. The reaction mixture was warmed gradually to room temperature and then stirred overnight at that temperature. The precipitate which formed was removed by filtration. The filtrate was evaporated in vacuo and the residue was chromatographed on silica gel using 3:1 methylene chloride/ethyl acetate as eluent to give 2.48 g (92.7%) of the title compound as a white solid melting at 135°-136° C. after crystallization from a mixture of ethyl acetate and isopropyl ether. The product has the structural formula: ##STR93## as further confirmed by NMR, IR and elemental analyses.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:33]1[O:34][C:35]([CH3:38])=[N:36][N:37]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][N:26]([C:33]5[O:34][C:35]([CH3:38])=[N:36][N:37]=5)[CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1nnc(Br)o1
Reactant: FC1CNCCC1Nc1nc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccn2n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(N2CCC(Nc3nc4c(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cccn4n3)C(F)C2)o1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 269b, 68 mg, 152 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) and diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) dissolved in dry dioxane (2 mL) was stirred at 70° C. for 12 hours and then at 110° C. for 1 hour. Further diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) were added and heated to 110° C. for another hour. The solvent was evaporated and the residue directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as colorless oil (46 mg, 57%) as a mixture of cis- and trans-isomers.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16]>>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCCCBr
Product: N#Cc1ccc(OCCCCCCl)cc1
Yield: 90 %

Procedure:
In the fifth step, 4-hydroxy-benzonitrile (7) is reacted with 1-bromo-5-chloropentane, and thus, 4-(5-chloro-pentoxy)-benzonitrile (8) (yield: 90%) is obtained. As such, the reaction temperature is preferably maintained in the range from 20 to 82° C., and the reaction solvent is selected from polar solvents, including dichloromethane, acetonitrile, ethylacetate, lower alcohols such as methanol, ethanol or isopropanol, ethers such as tetrahydrofuran or 1,4-dioxane, dimethylformamide, or dimethylsulfoxide, and mixtures thereof. To ensure that the above reaction occurs under a basic condition, an inorganic base, including potassium carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide, or sodium ethoxide, and other base, may be used.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)[C:33](O)=[O:34])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=2)[C:33]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]3[C:16]4[N:12]([N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[CH:11]=[CH:10]3)[CH:4]=2)=[O:34])[CH2:28][CH2:29]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CN1CCN(c2cc(C(=O)O)cc(C(F)(F)F)c2)CC1
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(C(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
40 mg (0.14 mmol) of the compound of Example 6A and 44 mg (0.14 mmol) of 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/029038-A1, Example 14.2] were reacted and worked up analogously to the procedure of Example 33. This gave 43 mg (53% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][C:18]1([CH3:32])[CH2:23][C:22](=[O:24])[N:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:20](=[O:31])[CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:28]2[CH2:29][CH2:30][CH:25]([N:21]3[C:20](=[O:31])[CH2:19][C:18]([CH3:17])([CH3:32])[CH2:23][C:22]3=[O:24])[CH2:26][CH2:27]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC1(C)CC(=O)N(C2CCNCC2)C(=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCC(N4C(=O)CC(C)(C)CC4=O)CC3)nc(N)c2cc1OC
Product: Cl
Reaction time: 6 h

Procedure:
The mixture of 4.79 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 4.49 g of 4,4-dimethyl-1-(4-piperidinyl)-piperidin-2,6-dione, 4.24 g of anhydrous sodium carbonate and 75 ml of dimethylformamide is stirred at 150° under nitrogen for 6 hours. It is filtered, the filtrate evaporated, the residue dissolved in ethyl acetate and the solution washed with aqueous sodium carbonate and water. It is dried, evaporated, the residue triturated with isopropanol, filtered off and discarded. The filtrate is made strongly acidic with hydrogen chloride, the precipitate filtered off and triturated with 175 ml of boiling methanol, to yield the 1-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]-4,4-dimethyl-piperidin-2,6-dione monohydrochloride, melting at 279°-280° with decomposition.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.ClCCl>[CH2:24]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[N:3]=[CH:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(-c2ncc(-c3c[nH]cn3)cn2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc(Cn2cnc(-c3cnc(-c4ccccc4)nc3)c2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 36.5 %

Procedure:
To a solution consisting of 5-(1H-imidazol-4-yl)-2-phenylpyrimidine (Step B, 0.050 g, 0.193 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.133 g, 0.965 mmol) at room temperature under dry conditions. After heating the reaction mixture in an 80° C. oil bath for one hour, benzyl bromide (Aldrich, 0.039 g, 0.231 mmol) was added to the mixture. The solution was left stirring in an 80° C. oil bath for 24 hours. Upon cooling, the reaction was diluted with dichloromethane (100 mL) and washed with saturated aqueous ammonium chloride (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica. Elution through an 8-g Silicycle® flash silica cartridge with gradient of 100% dichloromethane to 5% methanol in dichloromethane afforded the title compound as a white solid (22 mg, 36%). Rf 0.56 with 95:5 v/v dichloromethane-methanol; melting point 195° C; 1H-NMR (400 MHz; DMSO-d6) δ 9.25 (s, 2H), 8.44-8.42 (m, 2H), 8.03 (s, 2H), 7.56-7.54 (m, 3H), 7.45-7.36 (m, 5H), 5.38 (s, 2H); MS (ESI+) m/z 313.1 (M+1); H-PGDS FPBA IC50: 4 μM.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCI
Reactant: CC(C)(C)c1cc(Br)ccc1O
Product: CCCCCCOc1ccc(Br)cc1C(C)(C)C
Yield: 95.8 %

Procedure:
Following the basic procedure of Example 46(a), by reacting 4.58 g (0.02 mol) of 3-tert-butyl-4-hydroxybromobenzene with 3.3 ml (0.022 mol) of 1-iodohexane, 6 g (97%) of 3-tert-butyl-4-hexyloxybromobenzene were obtained in the form of a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:12]1([S:18]([N:21]=[C:8]=[C:7]2[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH2:6]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1=CCC(=C=NS(=O)(=O)c2ccccc2)C=C1
Temperature: 25 °C

Procedure:
An equimolar mixture of 25.0 g (0.17 mol) 4-carboxybenzaldehyde and 26.7 g (0.17 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. After cooling to room temperature, the precipitated solid was filtered off and dried under vacuum. Yield: 45.7 g (94.8%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.59 (m, 2H); 7.78 (d, 1H); 8.02 (m, 2H); 8.12 (d, 2H); 8.18 (d, 2H); 9.30 (s, 1H); 13C-NMR (400 MHz, DMSO-d6): δ [ppm]=127.8; 129.7; 131.4; 134.1; 135.8; 136.0; 137.9; 166.5; 171.2; 192.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([OH:14])=O)=[C:5]2[OH:15].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:14])=[C:5]2[OH:15]
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ncc2ccc(Br)cc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1ncc2ccc(Br)cc2c1O
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-hydroxyisoquinoline-3-carboxylic acid (Preparation 8, 0.4 g), 4-chlorobenzylamine (0.219 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g) in DMF (20 mL) is stirred at room temperature until judged complete. The solution is then poured into ice water and the resulting solid collected and dried.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(C(C)=O)C.C(O)C.C1(C)C=CC=CC=1>[C:9]1([NH:15][C:16]([NH:1][C:2]2[N:3]=[CH:4][NH:5][C:6]=2[C:7]#[N:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C=Nc1ccccc1
Solvent: CCO
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1[nH]cnc1NC(=O)Nc1ccccc1
Yield: 40.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 4-amino-1H-imidazole-5-carbonitrile (1.1 g, 0.01 mole) and phenyl isocyanate (1.3 g, 0.011 mole) in 30 ml of dry methyl ethyl ketone was heated under reflux for 10 hours. The solvent was removed, and the residue was stirred with 50 ml of boiling tetrahydrofuran. The mixture was filtered hot, and the filtrate was concentrated under reduced pressure. The residual solid was slurried in 50 ml of diethyl ether and the solid was collected by filtration, washed three times with diethyl ether, and dried to give a solid (1.2 g; mp, 165° d). The solid was dissolved in hot ethanol/toluene and an insoluble material removed by filtration. The filtrate was concentrated under reduced pressure to give N-phenyl-N'-(5-cyano-1H-imidazol-4-yl)urea (0.93 g; mp, >300°).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:12][S:13][CH3:14]>O.CO>[OH:7][CH2:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:11][CH2:12][S:13]([CH3:14])=[O:2]
Reactant: CSCC[C@@H](CCO)NC(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)CC[C@@H](CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
A suspension of sodium periodate (7.0 g) in water (32 ml) was added to a solution of (R)-tert-butyl (1-hydroxy-5-(methylthio)pentan-3-yl)carbamate (8.16 g) obtained in Step 1 in methanol (98 ml) at a temperature 10° C. or lower, and the mixture was stirred at room temperature for 2 hours. The generated insoluble matter was filtered off, and the filtrate was distilled off under reduced pressure. The resulting residue was dissolved in a saturated sodium chloride solution, followed by extraction with chloroform for 3 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow solid (9.38 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:23])[NH:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C(Cl)(Cl)Cl>N1C=CC=CC=1.O>[CH3:23][C:16]1([CH2:15][CH2:14][CH2:13][O:12][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[NH:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CCCO)NC(=O)NC1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC2(C)NC(=O)NC2=O)cc1
Reaction time: 8 h
Yield: 58.6 %

Procedure:
P-toluenesulfonyl chloride (22.5 g., 0.118 mol) was added to a stirred solution of 5-(3-hydroxypropyl)-5-methyl-2,4-imidazolidine-dione (20.0 g, 0.116 mol) in pyridine (250 ml.) at 5° C. The mixture was stirred for one hour, refrigerated overnight and diluted with water (275 ml.) The resulting solution was extracted three times with chloroform (375, 190 and 190 ml.), the combined extracts were washed with 5 N aqueous sulfuric acid (4 × 125 ml.), water (2 × 150 ml.) and saturated aqueous sodium bicarbonate solution (2 × 125 ml). Concentration of the dried chloroform phase yielded 5-methyl-5- {3-[(4-methylphenyl)sulfonyloxy]-propyl}-2,4-imidazolinedione (22.2 g., 0.068 mol, 58%) upon addition of ether and petroleum ether, m.p. 126-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]O>>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][N:8]1[CH2:7][C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[S:9]1(=[O:19])=[O:18]
Reactant: OCCCCBr
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Product: O=S1(=O)N(CCCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 75 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.51 g, 1.7 mmol) was reacted with 4-bromobutanol (0.53 mL, 3.4 mmol) to afford 3-(4-bromobutyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.55 g, 74%) as a white solid:
Reaction SMILES: [CH:1]1([N:6]([CH3:28])[C:7]2[C:8]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([N:6]([CH3:28])[C:7]2[C:8]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
To a solution of methyl 3-(cyclopentyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120.0 mg, crude) in methanol (20 mL) was added sodium hydroxide (50.0 mg, 1.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 6 with hydrochloric acid (1N). The product was precipitated and filtered to afford 3-(cyclopentyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (20 mg).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[N:26][C:27]=3[NH2:29])[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:21]=2)=[CH:16][C:15]=1[O:37][CH3:38]>ClCCl.N1C=CC=CC=1>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:15]([O:37][CH3:38])[CH:16]=3)[C:28]=12
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
trans-2-Phenyl-1-cyclopropanecarbonyl chloride (31 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more trans-2-Phenyl-1-cyclopropanecarbonyl chloride (15 mg, 0.083 mmol) was added. After 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-Amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-trans-2-phenyl-1-cyclopropanecarboxamide (75 mg, 89%). 1H NMR (CDCl3) δ 1.42 (m, 1H), 1.77 (m, 1H), 1.85 (m, 1H), 2.03 (m, 1H), 2.24 (m, 2H), 2.37 (s, 3H), 2.46 (m, 2H), 2.62 (m, 1H), 3.05 (m, 2H), 3.96 (s, 3H), 4.77 (m, 1H), 5.69 (s, 2H), 7.24 (m, 7H), 8.11 (s, 1H), 8.35 (m, 1H), 8.45 (d, J=8.38 Hz, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=498.3, Rt=1.84 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)=[C:4]([CH3:24])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[N:19]([CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][O:36]4)[N:18]=3)[C:13]([Cl:23])=[CH:12][N:11]=2)=[C:4]([CH3:24])[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(Br)cc3C)ncc2Cl)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(Cl)c(Nc3cc(C)n(C4CCCCO4)n3)n2)c(C)cc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (280 mg, 0.69 mmol) in THF (3 mL) was added p-TSA (119 mg, 0.69 mmol) and 3,4-dihydro-2H-pyran (348 mg, 2.86 mmol). The mixture was stirred at room temperature for 14 h and then poured into saturated aqueous NaHCO3 solution (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were concentrated. The resulting residue was purified by flash column chromatography (silica gel, 0-50% EtOAc in hexanes gradient) to provide N2-(4-bromo-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 491.1 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:14])[C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[C:9](Cl)=[O:10])[C:4](Cl)=[O:5].[O:16]1CCOCC1.[CH2:22]([OH:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].N1C=CC=CC=1>O>[CH2:22]([O:34][C:9]([C:8]1[CH:7]=[C:3]2[C:4](=[O:16])[O:5][C:1](=[O:14])[C:2]2=[CH:13][CH:12]=1)=[O:10])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)c(C(=O)Cl)c1
Reactant: C1COCCO1
Reactant: CCCCCCCCCCCCO
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Yield: 81 %

Procedure:
In a 3-L flask equipped with a stirrer, a thermometer and a dropping funnel, 110 g (522.39 mmol) of anhydrous trimellitic chloride (4-chlorocarbonylphthalic anhydride) and 770 g of 1,4-dioxane were placed and were stirred at room temperature in an atmosphere of a nitrogen gas. To the resulting mixture, a mixture of 92.70 g (497.52 mmol) of 1-dodecanol, 41.32 g (522.39 mmol) of pyridine and 370 g of 1,4-dioxane was added dropwise over 1 hour. The mixture was stirred at room temperature for further 5 hours, followed by dropwise addition of 570 g of pure water over 30 minutes. Pyridine hydrochloride separated in a reaction system was then dissolved, and a crystal of target 4-dodecyloxycarbonylphthalic anhydride separated out. The resulting mixture was stirred for further 1 hour, the precipitate was separated by filtration and was rinsed with pure water, was then dried at 50° C. under reduced pressure and thereby yielded 145.26 g (402.99 mmol) of 4-dodecyloxycarbonylphthalic anhydride as a white powder. The yield was 80.1% on the basis of 1-dodecanol and 77.1% on the basis of anhydrous trimellitic chloride.