Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:32]([O:34]C)=[O:33])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:36]([F:39])([F:38])[F:37])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:32]([OH:34])=[O:33])[CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:36]([F:37])([F:39])[F:38])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CCN1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1C(=O)O

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 269 under basic conditions (aq. NaOH/EtOH). 1H NMR (DMSO-d6, 300 MHz) δ 2.60-3.30 (m, 3H), 3.40-3.50 (m, 1H), 3.62 (d, J=12.0 Hz, 1H), 3.80 (m, 1H), 4.25-4.35 (m, 4H), 4.55 (m, 1H), 7.00 (s, 2H), 7.00-7.06 (m, 1H), 7.25 (m, 2H), 7.5 (m, 1H), 7.80 (m, 1H), 8.10 (m, 1H). MS (APCI) m/z 553 (M+H)+. Calcd. Anal. C24H23F3N2O5.1.55H2O: C, 54.35; H, 4.20; N, 5.07. Found: C, 54.16; H, 4.19; N, 4.96.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 2.3 %

Procedure:
An ice-cooled (0° C.) stirred solution of (S)-proline tert-butyl ester (2) (24.5 g, 143 mmol) and anhydrous diisopropylethylamine (DIPEA) (32.4 mL, 186 mmol) in dry THF (400 mL) was treated with benzylchloroformate (24.6 mL, 172 mmol). After 5 min, the cooling bath and removed and the reaction mixture was stirred at room temperature for 6 h. The mixture was poured into ether (500 mL) and 1 N HCl (400 mL). The organic fraction was washed with H2O (200 mL) and brine (200 mL), and dried over MgSO4. The solvent was removed in vacuo and the resultant oil (43.0 g; 99% was used without further purification. A portion (1 g) was purified by flash chromatography (SiO2; 10% EtOAc in hexane, Rƒ0.25) yielding a clear colorless oil (990 mg): 1H NMR (200 MHz, CDCl3) δ 7.22-7.42 (m, 5H, Ar—H), 5.02-5.22 (m, 2H, OCH2), 4.18-4.20 (m, 1H, α-CH), 3.40-3.65 (m, 2H, δ-CH2), 2.10-2.24 (m, 1H), 1.80-2.10 (m, 3H), 1.35 & 1.43 (s, 9H, C(CH3)3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:53][CH2:52][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[CH:51]=[C:43]3[C:42]2=[O:54])=[N:28][CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].CC([O-])=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:53][CH2:52][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[CH:51]=[C:43]3[C:42]2=[O:54])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: CN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 89.8 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 113f (190 mg, 0.56 mmol), 113i (215 mg, 0.56 mmol), Pd (dppf)Cl2 (47 mg, 0.056 mmol), 1.0 M NaOAc (93 mg, 1.12 mmol, 2.0 equiv), 1.0 M K3PO4 (240 mg, 1.12 mmol, 2.0 equiv), and acetonitrile (3 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1, V/V) to afford 113j (300 mg, 94%) as a brown solid. LCMS: [M+H]+ 597
Reaction SMILES: [CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH3:5])([CH3:3])[CH3:2].[C@@H:15]1([NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH2:21]>>[CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:21][C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[N:22]=[CH:10][C:9]1[C:8](=[CH:7][C:6]([N:4]([CH3:5])[CH:1]([CH3:2])[CH3:3])=[CH:13][CH:12]=1)[OH:14])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)N(C)c1ccc(C=O)c(O)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Product: CC(C)N(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(N(C)C(C)C)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.59 mmol) of 4-(N-isopropyl-N-methylamino)salicylaldehyde and 141 mg (1.23 mmol) of trans-1,2-cyclohexanediamine. Yield: 504 mg (88%), yellow solid.
Reaction SMILES: Cl.Cl.Cl[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH2:18]([O:25][C:26]1[CH:34]=[C:30]([C:31]([NH2:33])=[O:32])[C:29]([NH2:35])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CC>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:35][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[C:30]([CH:34]=1)[C:31]([NH2:33])=[O:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCCN1CCN(c2ccccc2)CC1
Reactant: NC(=O)c1cc(OCc2ccccc2)ccc1N
Agent: Cl
Solvent: CCCO
Product: NC(=O)c1cc(OCc2ccccc2)ccc1NCCN1CCN(c2ccccc2)CC1
Yield: 29.5 %

Procedure:
1-(2-Chloroethyl)-4-phenylpiperazine dihydrochloride (3.3 g) was converted to the base and added to 1.2 g 5-Benzyloxyanthranilamide in 125 ml propanol. The solution was refluxed 3 hours, cooled, filtered, and the filtrate concentrated to dryness. The residue was chromatographed on alumina to give 0.63 g product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8]C(C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K+].[Br-].[C:13]([OH:16])(=[O:15])[CH3:14]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:14]([C:13]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1

Procedure:
600 g of p-nitrotoluene were oxidized in 2700 ml of glacial acetic acid by the method described above, in the presence of 8 g of KBr and amounts of 5 g, 10 g, 15 g, 20 g, 30 g, 40 g and 50 g of cobalt(II) acetate tetrahydrate in Examples 1 to 7, respectively. The reaction temperature was increased to 180° to 200° C after the start-up temperature was reached, and then held constant until the absorption of oxygen had ceased. The start-up temperatures and yields of the p-nitrobenzoic acid identified by the infrared spectrum are to be found in Table I.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[N:2]=1.[Cl:12]N1C(=O)CCC1=O>CO>[Cl:12][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=[N:2][C:3]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc2ccccc2cn1
Solvent: CO
Product: Nc1ncc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To isoquinolin-3-amine (2.02 g, 14.0 mmol) in methanol (60 mL) was added N-chlorosuccinimide (2.19 g, 16.4 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours, then concentrated in vacuo. The crude material was chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield 4-chloroisoquinolin-3-amine (2.1 g, 11.8 mmol, 84% yield) as a solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.86 (s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.68 (td, J=6.7, 1.8 Hz, 1H), 7.24-7.35 (m, 1H), 6.32 (br. s., 2H). MS (LC/MS) R.T.=1.50; [M+H]+=178.96.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:11]([OH:13])=[O:12].[CH3:15][O:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(N(CC)CC)C.CCOCC>CC(C)=O>[CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:11]([O:13][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH2:17][O:16][CH3:15])=[CH:19][CH:20]=1)=[O:12]
Reactant: COCc1ccc(CBr)cc1
Reactant: COC(=O)C=CC1C(C(=O)O)C1(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COCc1ccc(COC(=O)C2C(C=CC(=O)OC)C2(C)C)cc1
Yield: 94.8 %

Procedure:
4.1 g of 2,2-dimethyl-3-(3-methoxy-3-oxo-1-propenyl) cyclopropanecarboxylic acid was dissolved in 50 ml of acetone, and 4.3 g of 4-methoxymethylbezylbromide was added to the solution. Next 2.4 g of triethylamine was added to the solution and underwent reaction at 60-80° C. for 3 hours while agitated, after which ether was added. After the ether solution was fully washed with diluted hydrochloric acid, sodium hydrogencarbonate aqueous solution and brine, it was dried with mirabilite. Ether was distilled under reduced pressure, and 6.3 g of 4-methoxymethylbezyl 2,2-dimethyl-3-(3-methoxy-3-oxo-1-propenyl)cyclopropanecarboxylate was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([C:6]1[CH:7]=[C:8]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].CCN(CC)CC.[CH2:28]([N:31]([CH2:35][C:36]1[S:40][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:37]=1)[CH2:32][CH:33]=[CH2:34])[CH:29]=[CH2:30]>C(Cl)Cl>[CH2:32]([N:31]([CH2:28][CH:29]=[CH2:30])[CH2:35][C:36]1[S:40][C:39]([S:41]([N:16]2[CH2:17][CH2:18][CH:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([C:2]([F:1])([F:19])[F:20])(=[O:5])=[O:4])[CH:7]=3)[CH2:14][CH2:15]2)(=[O:43])=[O:42])=[CH:38][CH:37]=1)[CH:33]=[CH2:34]
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)Cl)s1
Reactant: O=S(=O)(c1cccc(NC2CCNCC2)c1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(Nc3cccc(S(=O)(=O)C(F)(F)F)c3)CC2)s1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 4-(3-trifluoromethanesulfonyl-phenylamino)-piperidine (731 mg, 237 mmol) and Et3N (0.5 mL, 3.58 mmol) in CH2Cl2 (20 mL) was treated with the diallylamino sulfonyl chloride 269b 23° C. A thick precipitate appeared within 5 min, and the mixture was stirred overnight (even if complete within minutes). Dilution with CH2Cl2 (50 mL), washing (1120; brine), drying (MgSO4), and evaporation afforded the crude product, which was filtered over silica gel (AcOEt:cyclohexane 1:1) to afford 1.15 g (86%) of the title bisallylamine, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH2:17][NH2:18].[BH4-].[Na+]>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 1-(4-carbomethoxyphenyl)propan-2-one (2.25 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.4 g) in benzene (100 ml) was refluxed under Dean & Stark conditions for 2 hours. The resulting adduct was reduced with sodium borohydride and the product was isolated as in part 1). Crystallisation from ether gave the title compound m.p. 73°-88° as a 50:50 mixture of diastereoisomers. Recrystallisation of this mixture from ethyl acetate gave a sample m.p. 82°-85°, predominantly the RS,SR diastereoisomer (12:88).
Reaction SMILES: [OH-].[K+].C([CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:9](=[O:11])[CH3:10])(OCC)=O.S(=O)(=O)(O)O.O>CO>[CH:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:8][C:9](=[O:11])[CH3:10])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(CCCCCCOC(C)C)C(C)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)CCCCCCCOC(C)C
Temperature: 25 °C

Procedure:
1.4 g (0.025 mol) of solid potassium hydroxide are dissolved in 30 cc of 50% aqueous methanol. 4.1 g (0.015 mol) of 3-carbethoxy-9-isopropoxy-2-nonanone are added to this solution and the mixture is heated to boiling temperature. After 1 hour at reflux the reaction mixture is cooled to 50°, neutralized with 50% sulphuric acid, cooled to room temperature after 10 minutes, and 50 cc of water added. The product is extracted from the heterogeneous mixture with ether, the ether extract is washed with saturated salt solution, dried with sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9:1. Pure 9-isopropoxy-2-nonanone is obtained as a colourless oil.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(NCC)C>[CH2:7]([N:8]([CH2:9][CH3:10])[C:19](=[O:21])[CH2:18][CH2:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=1)[CH3:1]
Reactant: CCOC(=O)CCc1nc(-c2ccccc2)nc2ccccc12
Solvent: CCNCC
Product: CCN(CC)C(=O)CCc1nc(-c2ccccc2)nc2ccccc12
Temperature: 250 °C
Yield: 94 %

Procedure:
A mixture of ethyl 2-phenyl-4-quinazolinepropionate (4.3 g) and diethylamine (30 cc) is heated to 250° C. for 40 hours. After the mixture is cooled, the excess diethylamine is evaporated off. The residue is chromatographed on silica gel with a cyclohexane/ethyl acetate (1:1 by volume) mixture as eluant. The product (3.2 g) is recovered and recrystallized in isopropyl ether. N,N-Diethyl-2-phenyl-4-quinazolinepropanamide (2.2 g), m.p. 103° C., is obtained.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20]CC1C=CC=CC=1)[CH:16]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=1)[NH:15][CH2:14][CH2:13]2)C1C=CC=CC=1.CO>Cl>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[OH:20])[CH:16]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=1)[NH:15][CH2:14][CH2:13]2
Reactant: c1ccc(COc2cc3c(cc2OCc2ccccc2)C(Cc2ccc(-c4ccccc4)cc2)NCC3)cc1
Agent: Cl
Solvent: CO
Product: Oc1cc2c(cc1O)C(Cc1ccc(-c3ccccc3)cc1)NCC2

Procedure:
6,7-bis-hydroxy-1-biphenyl-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride (3) was prepared as follows: A stirred mixture of 2.5 g (4.56 mmol) of 6,7-bis-benzyloxy-1-biphenyl-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride in 10 ml of concentrated aqueous HCl solution/10 ml of methanol was refluxed for 10 hours. The solvents were evaporated under reduced pressure, the solid residue was mixed with 10 ml of ether and separated on a glass filter funnel, and then washed with ether (2×10 ml). This solid was recrystallized using ether/methanol mixture to give 1.3 g (78%) of off-white crystals, mp 208-210° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(O)(C)C.Cl>[ClH:1].[OH:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc(O)c3)ncnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (49 mg, 0.16 mmol) and 3-hydroxyaniline (21 mg, 0.19 mmol) in isopropanol (3 ml) and isopropanolic hydrogen chloride (0.2 ml of a 5M solution) was stirred at 80° C. for 1 hour. The precipitated solid was collected by filtration, washed with isopropanol and ether and dried under vacuum to give 4-(3-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (56 mg, 93%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 4.01(s, 3H); 4.64(t, 2H); 4.78(t, 2H); 6.71(d, 1H); 7.1(m, 2H); 7.28(t, 1H); 7.41(s, 1H); 7.74(s, 1H); 7.83(s, 1H); 8.21(s, 1H); 8.87(s, 1H); 9.22(s, 1H) MS-ESI: 378 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25](I)[C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH3:12])[C@H:7]1[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])=[O:5].C([Sn](CCCC)(CCCC)[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC.[F-].[Cs+]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH3:12])[C@H:7]1[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])=[O:5]
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 2-(((2S,3R)-1-(2-fluoro-6-iodobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.6 g, 1.185 mmol), 2-(tributylstannyl)pyrimidine (0.437 g, 1.185 mmol), CsF (0.36 g, 2.37 mmol), CuI (0.023 g, 0.119 mmol) and Pd(PPh3)4 (0.14 g, 0.119 mmol) in DMF (5 mL) was degassed and heated at 100° C. for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% EtOAc/hexanes) to yield the title compound as a white solid. MS (ESI) 459 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[C:8]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]1=[O:27])[CH:7]=[CH:6]2)#[N:2].C(O)(C(F)(F)F)=O>>[CH3:13][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:27])=[N:9]2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Cc1cc2nc(N3CCN(C(=O)OC(C)(C)C)CC3=O)ccc2cc1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2nc(N3CCNCC3=O)ccc2cc1C#N
Reaction time: 0.33 h

Procedure:
tert-Butyl 4-(6-cyano-7-methylquinolin-2-yl)-3-oxopiperazine-1-carboxylate was treated with TFA (2 mL) and stirred for 20 minutes. Analysis of the reaction mixture by LC indicated that reaction had gone to completion. The solution was concentrated in vacuo and crude was azetroped (3×) with dichloroethane to furnish the title compound. LC/MS (IE, m/z): [M+1]+=267.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH:9]3[CH2:11][C:5]([OH:12])([CH2:6][CH:7]1[CH2:8]3)[CH2:4]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>CS(C)=O.CCOC(C)=O>[OH:12][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:6]1)[C:3]([NH:2][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22])([CH2:10]3)[CH2:4]2
Reactant: NC12CC3CC1CC(O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a stirred mixture of the compound obtained in step I (280 mg, 1.5 mmol) and K2CO3 (820 mg, 6 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (205 mg, 1.2 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-hydroxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile as a viscous liquid (150 mg) in 35% yield. m/z (M+1) 291; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.0 Hz, 1H), 3.75-3.38 (m, 2H), 3.43 (s, 2H), 2.45-37 (m 1H), 2.35-1.95 (m, 8H), 1.90-1.60 (m, 6H), 1.53-1.40 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].C12BC(CCC1)CCC2.[OH-:30].[Na+].OO>O1CCCC1.O>[OH:30][CH2:4][CH2:3][C@H:2]([OH:1])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCO
Temperature: 50 °C
Yield: 100.4 %

Procedure:
The resultant compound from Example 121 (327.6 mg, 1.16 mmol) in tetrahydrofuran (THF, 2 ml) at 0° C. was treated with 9-borabicyclo(3.3.1)nonane (4.6 ml, 2.2 mmol in THF). After 3 h at room temperature water (0.1 ml) then NaOH (280 mg, 7.0 mmol) in water (1 ml) then 30% H2O2 (0.70 ml, 6.9 mmol) were added and the mixture was heated at 50° C. for 90 min. The mixture was concentrated, dissolved in ethyl acetate, washed with brine, dried over Na2SO4, evaporated and chromatographed on silica gel with 2% methanol in chloroform to give 351.1 mg (100%) of the desired compound as an oil. DCI-MS: (M+H)=302.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[C:4]([O:22][CH3:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O>CN(C=O)C>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([O:1][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:7]=[CH:6][C:5]=1[C:8](=[O:21])[CH2:9][S:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1
Reactant: COc1cc(O)ccc1C(=O)CSc1ccnc2ccccc12
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(C(=O)CSc2ccnc3ccccc23)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
4-[2-(4-Hydroxy-2-methoxyphenyl)-2-oxoethylthio]-quinoline (Compound 12; 83 mg, 0.25 mmol) and potassium carbonate(42 mg, 0.25 mmol) were suspended in dry DMF (2.0 ml). Hexylbromide (0.041 ml, 0.28 mmol) was addded at -15° C. to the suspension and stirred at room temperature overnight. The reaction mixture was added with water under ice cooling, extracted with ethyl acetate, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed by silica gel chromatography (n-hexane:ethyl acetate=1:4) to obtain 82.1 mg of the titled compound (80.3%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]#N)[CH2:10][CH2:9]1)C1C=CC=CC=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CO>[CH3:14][C:11]1([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Reactant: C1COCCN1
Solvent: CO
Product: CC1(N2CCOCC2)CCNCC1

Procedure:
A solution of 5.25 g (23.8 mmol) 1-benzyl-4-hydroxy-piperidine-4-carbonitrile and 2.2 mL (25.2 mmol) morpholine in 30 mL MeOH was refluxed for 6 h. The mixture was evaporated to dryness i. vac., while the product was obtained in the form of crystals.