Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[N:38]([CH:39]6[CH2:44][CH2:43][O:42][CH2:41][CH2:40]6)[N:37]=[CH:36][C:19]=5[C:20](=[O:35])[N:21](CC5C=CC(OC)=CC=5OC)[C:22]=4[CH:23]=3)=[C:9]([CH3:45])[CH:8]=2)[CH2:3][CH2:2]1.C1COCC1.[H][H]>C(O)C.[C].[Pd]>[CH3:13][C:11]1[CH:12]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=[C:9]([CH3:45])[C:10]=1[C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:38]([CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:37]=[CH:36][C:19]=3[C:20](=[O:35])[NH:21][C:22]=2[CH:23]=1
Reactant: [H][H]
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)cc(C5=CCOCC5)cc4C)cc32)c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C2CCOCC2)cc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCOCC3)c12
Temperature: 60 °C
Reaction time: 14 h
Yield: 44.5 %

Procedure:
10% palladium carbon (50% wet, 15 mg) was added to a solution of 7-[4-(3,6-dihydro-2H-pyran-4-yl)-2,6-dimethylphenyl]-5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (44 mg) in ethanol (2 mL)-THF (2 mL). The reaction mixture was stirred at mom temperature for four hours and 35 minutes in a hydrogen atmosphere. The catalyst was removed from the reaction mixture by filtration, and the filtrate was then concentrated under reduced pressure. TFA (1.5 mL) was added to the resulting residue. The reaction mixture was stirred at 60° C. for 14 hours. The reaction mixture was returned to room temperature, and the reaction mixture was then concentrated under reduced pressure. Chloroform and a saturated aqueous sodium bicarbonate solution were added to the residue, and the organic layer was separated. The aqueous layer was re-extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform 100%, then ethyl acetate 100%). The target fraction was collected and concentrated. Ethyl acetate and MTBE were added to the resulting residue. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (14.8 mg).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][C:16]([C:31]([OH:33])=[O:32])=[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1-c1cccc2c(CCC=Cc3cccc4ccccc34)c(C(=O)O)[nH]c12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccccc1-c1cccc2c(CCCCc3cccc4ccccc34)c(C(=O)O)[nH]c12

Procedure:
A mixture of EXAMPLE 111D and Pd/C (catalytic) in ethyl acetate/ethanol was stirred at room temperature under hydrogen (balloon) overnight. The mixture was filtered, washed with ethyl acetate/ethanol and concentrated. The concentrate was purified on reverse phase HPLC (Zorbax SB-C18, 20100% acetonitrile/water/0.1% TFA). 1H NMR (300 MHz, DMSO-d6) δ 12.82 (brs, 1H), 10.36 (s, 1H), 8.03 (m, 1H), 7.90 (m, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.51 (m, 2H), 7.31 (m, 6H), 7.12 (t, 1H), 7.03 (m, 1H), 3.17 (m, 2H), 3.09 (m, 2H), 2.05 (s, 3H), 1.78 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:9]=2)[N:4]([CH3:30])[C:3]=1[C:31](O)=[O:32].Cl.[CH:35]([NH:38][C:39](=[O:48])[C@H:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:41])([CH3:37])[CH3:36].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:35]([NH:38][C:39](=[O:48])[CH:40]([NH:41][C:31]([C:3]1[N:4]([CH3:30])[C:5]2[C:10]([C:2]=1[Cl:1])=[CH:9][C:8]([NH:11][C:12]([C:14]1[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13])=[CH:7][CH:6]=2)=[O:32])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:37])[CH3:36]
Reactant: Cn1c(C(=O)O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reactant: CC(C)NC(=O)[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)C(NC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.3 %

Procedure:
The product from step (e) (292.5 mg, 0.619 mmol), (S)-N-isopropyl-2-phenylglycinamide hydrochloride salt (182.1 mg, 0.797 mmol), PyBroP (415.8 mg, 0.865 mmol) were suspended in anhydrous CH2Cl2 (6 ml), followed by the addition of DIEA (0.36 ml, 2.07 mmol). The reaction mixture was stirred at room temperature for 3.5 h. The product was purified by flash chromatography using 30:70 of hexane:EtOAc to afford 345.5 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:16]=[C:15]([O:17][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=[C:13]([O:18][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=1
Reactant: COC(=O)CN(CC(=O)OC)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OC)CC(=O)OC)c1
Reaction time: 48 h
Yield: 52.8 %

Procedure:
A mixture of 0.50 g (1.86 mmol) of N-[(3,5-Dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.81 ml (3.9 mmol) of 1-bromodecane and 0.77 g (5.57 mmol) of potassium carbonate in 15 ml of acetone was stirred at reflux for 24 hours. An additional 0.8 ml of 1-bromodecane was added and reflux was continued for 48 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated at reduced pressure to an oil which was purified by HPLC using 15% ethyl acetate-hexane to give 0.54 g (52% yield) of N-(2-methoxy-2-oxoethyl)-N-[3,5-bis-(decyloxy)phenyl]glycine methyl ester as an oil. The nmr and mass spectra of this product were identical to those obtained using the procedure of Example 5.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([C:18]1([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17].O>C1C=CC=CC=1>[C:16]([C:18]1([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:20][C:21]2([O:4][CH2:1][CH2:2][O:3]2)[CH2:22][CH2:23]1)#[N:17]
Reactant: N#CC1(c2cccs2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N#CC1(c2cccs2)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
Ethylene glycol (9.08 g) and p-toluenesulfonic acid (0.0139 g) were added to a solution of 4-cyano-4-(thiophen-2-yl)cyclohexanone (15 g) in benzene (120 ml) and the reaction mixture was boiled under reflux for 4 hours at 110° C. on a water separator (Dean-Stark apparatus). The reaction mixture was cooled to RT and the organic phase was washed with aqueous sodium bicarbonate solution (1×150 ml), water (1×150 ml) and saturated NaCl solution (1×150 ml). After drying over Na2SO4, the solvents were removed under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[N:3]=1.[NH2:21][C:22]1[CH:26]=[C:25]([C:27]#[N:28])[NH:24][N:23]=1.CO>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:26]=[C:25]([C:27]#[N:28])[NH:24][N:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: N#Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
A mixture of (4-chloroquinazoline-2-yl)(4-fluorophenyl)methanone from Example 3 (580 mg, 2.02 mmol), and 3-amino-1H-pyrazole-5-carbonitrile (218 mg, 2.02 mmol) in DMF (5 mL) was stirred at rt overnight. MeOH (10 mL) was then added to this mixture, and the precipitate was filtered washed with MeOH, and dried to afford 3-(2-(4-fluorobenzoyl)quinazolin-4-ylamino)-1H-pyrazole-5-carbonitrile (170 mg, 23.4%) 1H NMR (300 MHz, DMSO-d6) δ 6.89 (s, 1H), 7.40 (d, 2H), 7.83 (s, 1H), 7.98 (m, 2H), 8.11 (m, 2H), 8.56 (s, 1H), 11.18 (s, 1H), 13.84 (s, 1H); LC-MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:19][C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[N:25]4)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: Nc1cccc2ncccc12
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc3ncccc23)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 5-amino-quinoline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.68 (br, 1H), 8.93 (dd, 1H), 8.47 (d, 1H), 7.89 (2H), 7.79 (t, 1H), 7.70 (d, 1H), 7.57 (dd, 1H), 7.03-6.97 (2H), 6.49 (br, 1H), 3.97 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 371.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([OH:12])=O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2[CH:18]=1.CCN=C=NCCCN(C)C.NC1C=CC=CC=1>C1COCC1>[C:1]([NH:5][S:6]([CH2:9][C:10]([NH:19][C:17]1[CH:18]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:12])(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CC(C)(C)NS(=O)(=O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of compound 2-(N-tert-butylsulfamoyl)acetic acid (5 g, 25.6 mmol.) in dry THF (20 mL) was added HOBt (13.8 g, 102.4 mmol.) and EDCI (18.3 g, 102.4 mmol.). Then aniline (3.6 g, 38.4 mmol.) was added successively. The reaction mixture was stirred overnight at room temperature. TLC analysis showed the reaction complete. The mixture was quenched by adding water and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated. The residue was purified by column chromatography (PE:EtOAc=2:1) to afford 2-(N-tert-butylsulfamoyl)-N-phenylacetamide (3.5 g, 51%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.ClC1C=C(C(F)(F)F)C=CN=1>>[CH3:8][C:4]([O:3][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1)([CH3:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(O)C(=O)O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: FC(F)(F)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O

Procedure:
The title compound was prepared following the procedure described in Reference Example 36, Step A with 1.5 extra equivalent of sodium hydride substituting lithium lactate with hydroxyisobutyric acid and 2-chloro-4-trifluoromethylpyridine 2-chloro-5-trifluoromethylpyridine. 1H NMR (500 MHz, CD3OD): δ 8.38 (br, 1H), 7.94 (dd, 1H), 6.93 (d, 1H), 1.69 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3]1.[CH2:30]([C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38]Br)[CH2:31][CH3:32]>>[CH2:30]([C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[CH2:3][C:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14])[CH2:31][CH3:32]
Reactant: CCCc1ccccc1OCCCBr
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Product: CCCc1ccccc1OCCCOc1ccc2c(c1CCC)OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Yield: 80.9 %

Procedure:
The title compound (471 mg) was prepared by the method of Example 18 except that the title product of Example 1 (406 mg) was used instead of the title product of Example 2, and the title product of Example 11 (308 mg) was used instead of benzyl bromide.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]([NH2:26])=[O:25])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[O:29]1CCCC1>C(Cl)(Cl)Cl.CO.[Pd]>[OH:29][NH:26][C:24](=[O:25])[CH2:23][NH:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[CH:14][CH:15]=1)(=[O:20])=[O:21]
Reactant: C1CCOC1
Reactant: NC(=O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)NO
Reaction time: 10 h

Procedure:
A room temperature mixture of N-[phenyl-methyl)-oxy]-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonyl-amino]-acetamide (0.1115 g, 0.0002325 mol) in methanol-tetrahydrofuran (1:1, 25 mL) was hydrogenated at 50 p.s.i. over 5% palladium on barium sulfate (0.018 g) for approximately 10 hours. Additional catalyst (0.020 g) was added, and the mixture hydrogenated again for approximately 10 hours. The mixture was filtered through celite, and the filtrate was rotary evaporated to give a glaze. The glaze was dissolved in chloroform-methanol, silica gel (1.6 g, 230-400 mesh) was added, and the mixture was rotary evaporated to dryness. The powder was poured onto a column of silica gel (10 g, 230-400 mesh) and eluted with hexanes-ethyl acetate-acetic acid (10:20:1, 16×10 mL and 10:20:2, 16×10 mL). Fractions containing product were rotary evaporated, and the residue triturated with chloroform. The chloroform suspension was filtered, and the filtercake was dried in vacuo; yield 0.0054 g (6.0%), mp=164-166° C.
Reaction SMILES: [C:1](=[O:37])([O:6][C:7]([CH3:36])([CH3:35])[CH2:8][NH:9][C:10]([NH:12][C@H:13]([CH:32]([CH3:34])[CH3:33])[C:14]([N:16]1[CH2:21][CH2:20][C@@:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([OH:22])[C:18]([CH3:31])([CH3:30])[CH2:17]1)=[O:15])=[O:11])[O:2][CH2:3][CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[C:1](=[O:37])([O:2][CH2:3][CH2:4][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[O:6][C:7]([CH3:36])([CH3:35])[CH2:8][NH:9][C:10]([NH:12][C@H:13]([CH:32]([CH3:34])[CH3:33])[C:14]([N:16]1[CH2:21][CH2:20][C@@:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([OH:22])[C:18]([CH3:31])([CH3:30])[CH2:17]1)=[O:15])=[O:11]
Reactant: C1COCCN1
Reactant: CC(C)[C@@H](NC(=O)NCC(C)(C)OC(=O)OCCBr)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)NCC(C)(C)OC(=O)OCCN1CCOCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 2-bromoethyl 1-(3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)ureido)-2-methylpropan-2-yl carbonate (780 mg, 1.289 mmol) and K2CO3 (356 mg, 2.58 mmol) in DMF (3 mL) was added morpholine and the reaction was stirred at rt overnight. After drying the crude product overnight under high vacuum, the residual glass was purified via column chromatography (50% EA/hep to 100% EA to 5% MeOH/EA) to furnish 1-(3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)ureido)-2-methylpropan-2-yl 2-morpholinoethyl carbonate (620 mg, 1.014 mmol, 79% yield) as a foam. 1H NMR (CDCl3, 400 MHz, rotameric) δ 7.40-7.24 (m, 4H), 5.44 (dd, J=21.9, 8.8 Hz, 1H), 5.13 (dt, J=21.1, 5.7 Hz, 1H), 4.82 (m, 1H), 4.65 (br d, 0.5H), 4.20 (t, J=6.2 Hz, 2H), 3.95 (m, 0.5H), 3.71 (t, J=4.8 Hz, 4H), 3.58 (m, 1H), 3.43 (m, 3H), 3.15 (dt, J=13.1, 2.6 Hz, 0.5H), 3.05 (d, J=12.7 Hz, 0.5H), 2.64 (t, J=5.7 Hz, 2H), 2.51 (t, J=4.4 Hz, 4H), 1.96 (m, 1H), 1.54 (m, 1H), 1.47-1.43 (m, 6H), 1.06 (d, J=6.6 Hz, 1.5H), 0.97-0.76 (m, 10.5H). HPLC Purity: >99%, rt 3.23 min (Chromalith Speedrod, C18, 4.6×50 mm, 10% MeOH/water to 90% MeOH/water with 0.2% H3PO4, 4 min gradient, 4 mL/min) LCMS: 611.38 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C[C:11](C)=[CH:12][C:13](O)=[O:14].CS(O)(=O)=O>>[OH:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:11][CH2:12][C:13](=[O:14])[O:8]2)=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(C)=CC(=O)O
Reactant: Cc1cc(O)cc(O)c1
Agent: CS(=O)(=O)O
Product: Cc1cc(O)cc2c1CCC(=O)O2
Yield: 104.5 %

Procedure:
3 grams of 1,5-dihydroxy-3-methylbenzene are admixed with 3 grams of dimethylacrylic acid. There was then added 20 ml. of methanesulfonic acid and the mixture stirred for 1 hour at 70° C. The mixture was cooled and extracted with ether. The ether solution was washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated sodium chloride solution. The ether layer was dried over sodium sulfate and then evaporated to yield the corresponding 7-hydroxy-5-methylchromanone (4.5 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[CH3:29][O-:30].[Na+].C1(C)C=CC=CC=1>O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[C:2]2[O:30][CH3:29])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1nc(N(C)c2ccc(OC(C)C(=O)O)cc2)cc2ccc(Cl)cc12

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.25 g), sodium methoxide (0.63 g) and toluene was heated under reflux for 4 hrs. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic fraction was dried (MgSO4) and evaporated to give 2-{4-[N-(7-chloro-1-methoxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[N:18]=3)=[CH:8][CH:7]=2)[CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:24](C)=O.[Na+].C=O.C(O)(=O)C>CO>[Br:19][C:17]1[N:18]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH:4]3[CH2:5][N:2]([CH3:24])[CH2:3]3)=[CH:11][CH:10]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CNC3)cc2)c1=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 119.3 %

Procedure:
A mixture of 298c (100 mg, 0.24 mmol), NaBH(OAc)3 (100 mg, 0.48 mmol), HCHO (10 mL) and acetic acid (1 mL) in methanol (15 mL) was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the residue was neutralized with NaHCO3 solution until pH 8 was reached. The mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give 298d (100 mg), which was used for the next step without further purification. MS: [M+H]+ 349.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[C:31](OCC)(=[O:33])C>O1CCCC1.C(OCC)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:10](=[O:19])[CH2:11][CH2:12][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:31]1[OH:33]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CCCC(=O)Nc1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC=O
Product: CCOC(=O)C1CCC(=O)N(c2c(Cl)cccc2Cl)C1O
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen, to a solution of ethyl 5-[(2,6-dichlorophenyl)amino]-5-oxopentanoate (9.22 g, the compound described in Reference Example 1 of WO03/043988) in tetrahydrofuran (150 mL) were added a solution of lithium bis(trimethylsilyl)amide (1.6 mol/L) in tetrahydrofuran (56.8 mL) and ethyl formate (4.90 mL) at −78° C. and the mixture was stirred on ice bath for 2 hours and then at room temperature for 4 days. The reaction mixture was added by hydrochloric acid (1 mol/L) and ethyl acetate on ice bath, then the water layer was extracted with ethyl acetate. The obtained extract was dried with anhydrous sodium sulfate, filtrated and concentrated to give the title compound. The obtained compound was used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1.[H-].[Na+].[CH:25]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1
Reactant: BrC1CCCC1
Reactant: COc1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Reaction time: 1 h
Yield: 46.5 %

Procedure:
(2-Chloro-9H-purin-6-yl)-(3,4-dimethoxy-benzyl)-amine (799 mg, 2.5 mmol) was dissolved in dry DMF (10 mL). NaH (78 mg, 3.25 mmol) was added in portions and the resulting mixture was stirred for 1 h. Cyclopentyl bromide (633 mg, 4.25 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine (2×25 mL), dried over MgSO4, and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/Et2O) to afford the title compound as a white powder (451 mg, 46.5%). TLC (95:5 CH2Cl2/Et2O): RF=0.27.
Reaction SMILES: [CH:1]1([C:5]2[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11][CH:12]([CH:15]=O)[CH:13]=O>>[Br:11][C:12]1[CH:13]=[N:10][C:7]2[N:8]([N:9]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:6]=2)[CH:15]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1cc(C2CCC2)[nH]n1
Product: Brc1cnc2cc(C3CCC3)nn2c1

Procedure:
The title compound, yellow solid, MS: m/e=254.0/252.1 (M+H+), can be prepared in accordance with the general method of example 9, step 1 from 5-cyclobutyl-1H-pyrazol-3-ylamine and 2-bromomalonaldehyde.