Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>CCN(CC)CC>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23]([NH:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a CHCl3 (350 mL) solution of tert-butyl 4-aminopiperidine-1-carboxylate (35.0 g), Et3N (122 mL) and 3-chloro-4-fluorobenzoyl chloride (37.1 g) were added under ice cooling and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to obtain tert-butyl 4-[(3-chloro-4-fluorobenzoyl)amino]piperidine-1-carboxylate (62.0 g). To an EtOAc (300 mL) suspension of the compound obtained, a 4 M HCl/EtOAc solution (300 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and 1 M aqueous NaOH solution (300 mL) was added to the residue and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was suspended in EtOAc/hexane (200 mL, 1/1; v/v) and the mixture was stirred for one hour. The precipitate was filtrated to obtain 3-chloro-4-fluoro-N-piperidin-4-ylbenzamide (37.7 g, a colorless solid).
Reaction SMILES: C(Cl)(=O)C.[CH:5]([O:8][CH2:9][C@@H:10]1[CH2:14][O:13]C(C)(C)[O:11]1)([CH3:7])[CH3:6]>CO>[CH:5]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:14][OH:13])([CH3:7])[CH3:6]
Reactant: CC(C)OC[C@@H]1COC(C)(C)O1
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(C)OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Acetyl chloride was added dropwise into a solution of MeOH (30 mL) at 0° C. with stirring for 5 min. A solution of (4R)-4-(isopropoxymethyl)-2,2-dimethyl-1,3-dioxolane (1.7 g) (the product from step (i), in MeOH (30 mL), was added dropwise to the reaction mixture. The solution was then warmed to room temperature and stirred for 2 h. The reaction mixture was evaporated to give the subtitle compound as clear oil. Yield: 0.8 g
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[CH:5]([OH:7])O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.CN(C=[O:24])C>>[CH3:3][C:4]([CH3:9])([CH2:5][O:7][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH2:8][OH:24]
Reactant: CC(C)(C)C(O)O
Reactant: CN(C)C=O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(COCC(C)(C)CO)cc1
Temperature: 0 °C

Procedure:
A mixture of 7.7 g (0.32 mole) of sodium hydride and 80 ml of DMF was stirred under an atmosphere of N2 and cooled with an ice-water bath. A solution of 33 g (0.32 mole) of 2,2-dimethylpropandiol in 100 ml of DMF was added dropwise. Stirring was continued until the gas evolution stopped, then a solution of 50 g (0.32 mole) 4-methoxybenzyl chloride was added. The reaction mixture was stirred at room temperature overnight. The resulting solution was poured into an ice-water mixture and the aqueous solution was extracted with ethyl ether three times. The ether solution was washed with H2O, saturated brine, and then dried over MgSO4.
Reaction SMILES: [F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8]OS(C)(=O)=O)[C:4]#[N:5].[I-:25].[Na+]>CC(C)=O.CCOCC>[F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8][I:25])[C:4]#[N:5]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-5-methanesulfonyloxypentanenitrile (42 g) and sodium iodide (35.7 g) in acetone (600 ml) is stirred and heated under reflux. After about 1/2 hour, the mixture solidifies. Acetone (500 ml) is added, and refluxing and stirring is continued overnight. The salts are removed by filtration and washed several times with acetone. The acetone is evaporated to give a residue which is dissolved in ether (1.5 l). The ether solution is washed subsequently with water (2×), sodium sulfite solution, and water again (3×). After drying (MgSO4) and evaporating the ether, 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile is obtained as an oil (34.1 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16]CC3C=CC=CC=3)=[CH:14][CH:13]=[C:12]([O:24][C:25](=[O:33])[NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]>CCOC(C)=O.CCO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([O:24][C:25](=[O:33])[NH:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cccc(-c2cc(OC(=O)NC3CCCCC3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)c1cccc(-c2cc(OC(=O)NC3CCCCC3)ccc2O)c1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a stirred suspension of cyclohexylcarbamic acid 3′-carbamoyl-6-benzyloxybiphenyl-3-yl ester (222 mg; 0.5 mmol) in EtOAc (2.5 mL) and EtOH (2.5 mL), 10% Pd/C (22 mg) was added. The mixture was hydrogenated at 4 atm at 50° C. for 4 h, cooled, filtered on Celite and concentrated. Purification of the residue by column chromatography (cyclohexane/EtOAc 1:9) and recrystallization gave URB937 as a white solid. Yield: 92% (0.163 g). Mp: 128-130° C. (CH2Cl2/n-hexane). MS (ESI) m/z: 355.2 (M+H). 1H NMR (200 MHz, CDCl3) δ: =1.13-2.02 (m, 10H), 3.55 (m, 1H), 5.13 (br d, 1H), 5.85 (br s, 1H), 6.59 (br s, 1H), 6.74-6.95 (m, 3H), 7.07 (s, 1H), 7.34-7.41 (m, 1H), 7.56 (m, 1H), 7.68-7.75 (m, 2H) ppm. IR (Nujol) nmax: 3333, 1701, 1655 cm−1.
Reaction SMILES: [Na].[C:2](OCC)(=[O:6])[C@H:3]([CH3:5])[OH:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH2:18][C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1.Cl>C(O)C.O>[CH3:5][CH:3]1[C:2](=[O:6])[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:21])([F:22])[F:10])[CH:13]=2)=[C:19]([NH2:20])[O:4]1
Reactant: CCOC(=O)[C@H](C)O
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1OC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Yield: 18.3 %

Procedure:
A dry, 500-ml, three-neck, round-bottom flask equipped with a mechanical stirrer, addition funnel and a reflux condenser was charged with 100 ml of ethanol. To the stirred solvent were added 3.5 g of sodium. After all the metal had dissolved, a solution of 13.0 g of ethyl L-(+)-lactate and 18.5 g of m-trifluoromethylphenylacetonitrile in 30 ml of ethanol was added dropwise to the reaction mixture. The mixture became a deep red and after the addition was complete, the mixture was heated at reflux overnight (about 18 hours). The mixture was then cooled to room temperature and added to 300 ml of water and the resulting mixture was acidified (pH about 1) with 10% hydrochloric acid. The mixture was then extracted with ether (three times) and the organic extracts were washed (two times) with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to yield a thick oil. This oil was taken up in a mixture of ether/petroleum ether and the desired compound crystallized as a yellow powder. Two crops of crystals were collected to afford a total of 4.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[C:25]1([C:31]2([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:34]2[CH2:33][CH2:32][C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]2)=[O:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(-c2cc(C(=O)O)sc2-c2ccc(Cl)cc2Cl)cc1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cc(C(=O)N3CCC(C(N)=O)(c4ccccc4)CC3)sc2-c2ccc(Cl)cc2Cl)cc1
Reaction time: 3 h

Procedure:
2 g of the compound obtained in stage 1E), 1.27 g of 4-phenylpiperidine-4-carboxamide (Preparation 2), 2.22 ml of Et3N and 1.86 g of TBTU are added to 40 ml of CH2Cl2. The mixture is stirred at AT for 3 hours. It is evaporated to dryness, water is added and extraction is carried out with ethyl acetate. The organic phase is dried and then evaporated. After purifying by chromatography on silica (eluent: heptane-AcOEt (gradient from 0% to 30%)), 2.8 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:20].[C:21]1([CH2:27][C:28](=[NH:32])OCC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[ClH:20].[F:18][C:16]([F:17])([F:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:28](=[NH:32])[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1C(F)(F)F
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1C(F)(F)F
Yield: 4.9 %

Procedure:
A mixture of 2-amino-3-(2-trifluoromethylbenzyloxy)pyridine (5.36 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.41 g), m.p. 105°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(Cl)Cl.Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:32]([C:13]2[N:12]3[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]3)=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH2:4][C:3]2[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=2[Cl:1])=[O:34])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(Cl)c1Cc1cn2ccccc2c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cc3c(F)cccc3Cl)c(-c3ccccc3)c3ccccn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
The compound of step 2 (0.576 g, 1.72 mmol) was dissolved in DCM (8 ml) under argon and cooled at 0° C. Pyridine (0.14 ml, 1.72 mmol) and triphosgene (0.509 g, 1.72 mmol) were added and the mixture was stirred at room temperature for 2 h. The mixture was then added dropwise to a solution of 1-tert-butoxycarbonyl-piperazine (1.28 g, 6.85 mmol) and triethylamine (0.86 ml, 6.85 mmol) in DCM (8 ml) cooled to 0° C. The mixture stirred at room temperature overnight, then diluted with 1 N hydrochloric acid and extracted with DCM. The combined organic phases were washed with a saturated sodium hydrogencarbonate solution and twice with a saturated sodium chloride solution, were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (cyclohexane/EA, 100:0, then 75:25) to give 0.895 g of the title compound as an off-white powder.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][C:23]=2[F:27])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:28]1[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]1>CCCCCCC.CCO.CO>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][C:23]=3[F:27])[C:2]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Reactant: O[C@@H]1CCNC1
Solvent: CCCCCCC
Solvent: CO
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2[nH]ncc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 5 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-fluoro-1H-pyrazol-5-yl)nicotinamide (Stage 25.1) and (R)-pyrrolidin-3-ol to afford a white powder. HPLC (Condition 4) tR=4.89 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV 210 nm) tR=9.34 min, UPLC-MS (Condition 3) tR=0.96 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.92 (m, 2H) 3.00 (d, J=11.73 Hz, 1H) 3.19-3.33 (m, 2H) 3.43 (m, J=7.00 Hz, 1H) 4.22 (br. s, 1H) 4.87 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 7.90-8.10 (m, 2H) 8.77 (br. s, 1H) 10.18 (s, 1H) 12.83-13.19 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:10]=1.N1(C2C=CC(N[C:40]([C:42]3[CH:43]=[C:44]([CH:52]=[CH:53][CH:54]=3)[CH2:45][S:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:41])=C(C3C=C(NCC4C=CC=C(C)C=4)N=CN=3)C=2)CCCCC1.NC1C=CC(N2CCCCC2)=CC=1C1N=CN=C(NCC2C=CC=C(C)C=2)C=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:42]2[CH:43]=[C:44]([CH:52]=[CH:53][CH:54]=2)[CH2:45][S:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:41])=[C:3]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[N:12]=[CH:13][N:14]=2)[CH:4]=1
Reactant: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)ncn2)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Agent: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3N)ncn2)c1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1

Procedure:
This compound was prepared from 6-(2-amino-5-chlorophenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine 65b using the procedure described for the preparation of 3-((3-((4-(piperidin-1-yl)-2-(6-((3-methylbenzyl)amino)pyrimidin-4-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 3.2 from 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-methylbenzyl)pyrimidin-4-amine 3.2b. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.79 (s, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 7.81 (d, J=5.7 Hz, 2H), 7.63 (s, 1H), 7.56 (m, 6H), 7.09 (s, 1H), 4.74 (s, 2H), 3.88 (s, 2H), 2.57 (d, J=4.8 Hz, 2H). MS (ES, m/z): 601 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4OCC)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4[N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Solvent: CCO
Product: O=c1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(N2CCOCC2)c1=O
Temperature: 25 °C

Procedure:
A mixture of 0.8 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione, 4 mL of morpholine, and 20 mL of ethanol was refluxed for 2 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.69 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-morpholin-4-yl-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 480.1, 482.1.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])[CH:9]=[CH:10][C:11]=1[Cl:12])([OH:3])=[O:2].[CH:24]1(O)[CH2:28][CH2:27][CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:24]1([O:2][C:1]([CH2:4][S:5][C:6]2[CH:7]=[C:8]([N:13]3[C:21](=[O:22])[C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:14]3=[O:23])[CH:9]=[CH:10][C:11]=2[Cl:12])=[O:3])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reactant: OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)OC1CCCC1
Yield: 44.3 %

Procedure:
2-(3-Carboxymethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (3.61 g), cyclopentanol (1.24 g) and p-toluenesulfonic acid monohydrate (0.18 g) were suspended in toluene (10 ml), molecular sieve 3A (0.2 g) was added thereto, and the resultant mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool, admixed with water and extracted with toluene. The extract was washed with water, dried, and concentrated. The precipitated crystals were washed with methanol to give 1.91 g of 2-(3-cyclopentyloxycarbonylmethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione. m.p., 57°-59° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:29]([NH:36][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: c1ccc(CNc2nccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To the solution of [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) (220 mg, 0.54 mmol) and benzyl-amine (70 mg, 0.65 mmol) in DMSO (15 mL) was added DIPEA (84 mg, 0.65 mmol). The mixture was heated at 130° C. with stirring under N2 for 4 hours. The solvent was removed under reduced pressure. The residue was first purified by column chromatography (silica gel, dichloromethane:MeOH, 50:1 to 30:1), then by prep-HPLC. Concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give [3-(2-benzylamino-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 40 mg, 17.1%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=[C:27]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:28]=[C:27]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (2.25 g), ethyl 4-hydroxy-2-phenylpyrimidine-5-carboxylate (1.50 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 0.2N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were recrystallized from tetrahydrofuran-ethyl acetate to give ethyl 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carboxylate as colorless prism crystals (2.50 g, yield 75%). melting point: 142-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][C:36](=C)[CH2:37]O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:36]([CH3:37])=[CH2:35])=[CH:18][CH:17]=1
Reactant: C=C(C)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C)COC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 57.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methyl-2-propen-1-ol (19 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (38 mg, yield 52%).
Reaction SMILES: NC[C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].[N:34]1C=CC=CC=1>>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([NH:34][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(NS(=O)(=O)CCCCl)no1

Procedure:
Method as for preparation 10 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 0.57 mmol) and 3-chloropropanesulphonyl chloride (83 μl, 0.68 mmol) as starting materials and pyridine as the base.