Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.[Cl:16][C:17]1[CH:21]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:20][C:19](=[O:30])[CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[Si:23]([O:22][CH:21]1[CH2:20][C:19]([CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)([OH:30])[CH:18]=[C:17]1[Cl:16])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COc1ccc(CCCBr)cc1OC
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)C=C1Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CCCC2(O)C=C(Cl)C(O[Si](C)(C)C(C)(C)C)C2)cc1OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
128 mg (5.3 mmoles) of magnesium was taken, and 4 ml of dry tetrahydrofuran was added. Then, a small amount of a solution of 1.37 g of 1-bromo-3-(3,4-dimethoxyphenyl)propane in 10 ml of dry tetrahydrofuran was added. The mixture was heated. After the initiation of the reaction, a solution of 1-bromo-3-(3,4-dimethoxyphenyl)propane in tetrahydrofuran was added little by little, and the solution was refluxed for 1.5 hours. The resulting reagent was cooled to -78° C., and a cooled solution of 1.305 g of 3-chloro-4-t-butyldimethylsilyloxy-2-cyclopentenone in dry tetrahydrofuran was added. The mixture was stirred at -78° C. for 1.5 hours. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was chromatographed on a silica gel column to give 600 mg (yield 27%) of 4-t-butyldimethylsilyloxy-3-chloro-1-(3,4-dimethoxyphenylpropyl)-1-hydroxy-2-cyclopentene.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH:15]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16]1>C(#N)C>[CH:15]1([N:18]2[CH2:23][CH2:22][N:21]([C:8]3[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([O:3][CH:2]([F:14])[F:1])[CH:9]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Reactant: C1CN(C2CC2)CCN1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1OC(F)F
Temperature: 100 °C
Yield: 74.5 %

Procedure:
To 2.07 g (10.0 mmol) of the product prepared in step 14.1 in 30 mL of acetonitrile are added 5.99 mL (35.0 mmol) of diispropylethylamine and then 2.09 g (10.5 mmol) of finely ground N-cyclopropylpiperazine (supplier). The reaction mixture is heated at 100°C. for 1 hour 30 minutes, cooled and concentrated under vacuum. The residue is taken up in 75 mL of ethyl acetate and washed with saturated aqueous NaHCO3 solution and with saturated aqueous NaCl solution. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. After triturating in cyclohexane, the solid is drained by suction and dried in an oven under vacuum. 2.33 g of the expected product are obtained in the form of a yellow solid, which is used as obtained in the following step. Yield=74.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][CH2:26]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:26][CH2:25][O:24][CH3:23])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COCCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 100.5 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.5 g of 2-methoxyethanol were dissolved in 50 ml of benzene, followed by addition of 0.5 g of p-toluene sulfonic acid. Then, the mixture was heated under reflux for 3 hours. After completion of the reaction, to the reaction mixture was added 50 ml of ether. The resulting mixture was washed with water by the customary method and dried over anhydrous sodium sulfate, followed by evaporation-removal of the solvent under reduced pressure, thereby to obtain 3.9 g of 2-methoxyethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: [Na].N.[C:3]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22](Br)[CH3:23]>O.CCOCC>[C:3]1([C:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH3:23])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Reactant: CCBr
Agent: N
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CCC(c1ccccc1)(c1ccccc1)c1ccncc1
Reaction time: 0.33 h

Procedure:
Dissolve 2.5 g. of sodium in 500 ml. of liquid ammonia in the presence of a catalytic amount of ferric nitrate. Add dropwise to the resulting suspension over a 20 minute interval a solution containing 24.5 g. of 4-diphenylmethyl pyridine in 600 ml. of ether. Stir the resulting dark red mixture for an additional 20 minutes, then add 13 g. of ethyl bromide dropwise. Add an additional 500 ml. of ammonia, stir overnight, then add 300 ml. of ether followed by 150 ml. of water. Separate the solvent layers. Wash the ether layer with water until neutral, dry and remove the solvent under reduced pressure to a residue. Distill the residue at 192°-200° C./1.6 to 2 mm. and obtain thereby 14.7 g. of the title compound as an orange colored oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:29][C:30]1[CH:64]=[CH:63][C:33]([C:34](/[N:36]=[C:37]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:35])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:34](/[N:36]=[C:37]2/[N:16]([C@H:17]3[CH2:22][CH2:21][C@@H:20]([C:23](=[O:24])[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:18]3)[C:3]3[CH:4]=[C:5]([O:8][CH:9]4[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]4)[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:35])=[CH:63][CH:64]=1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OC3CCN(C)CC3)ncc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OC4CCN(C)CC4)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(5-amino-2-(1-methylpiperidin-4-yloxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used for (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2 (3H)-ylidene)benzamide. The product was isolated as an off-white solid (94 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (d, J=8H, 6H) 1.48-1.78 (m, 7H) 1.84-2.03 (m, 2H) 2.04-2.10 (m, 2H) 2.13-2.34 (m, 5H) 2.65 (m, 4H) 3.95-4.05 (m, 1H) 4.65-4.80 (m, 1H) 4.89-5.03 (m, 1H) 6.96 (s, 1H) 7.26 (dd, J=8.75 Hz, 2H) 7.68 (d, J=7.63 Hz, 1H) 8.23 (s, 1H) 8.31 (dd, J=8.56, 5.82 Hz, 2H) 12.60 (br. s., 1H). M/Z calc'd for C29H37FN6O3: 536.64. found 537 [M+H].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[C:12]([CH:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:13]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(C#N)c1ccc(Cl)c(Cl)c1
Yield: 42.1 %

Procedure:
5.9 g of sodium hydride as a 55% dispersion in oil are suspended in 50 ml of THF; the suspension is cooled in an ice bath and 25 g of 3,4-dichlorophenylacetonitrile in 25 ml of THF are added dropwise; the mixture is cooled again in an ice bath and a solution of 26.21 g of ethyl 4-bromobutanoate in 25 ml of THF is added dropwise. After one night at RT, the mixture is evaporated to dryness and the residue is then taken up with 2N hydrochloric acid solution and extracted with ether. The extract is washed with 2N hydrochloric acid solution and then with saturated sodium chloride solution. The organic phase is dried over MgSO4 and then concentrated under vacuum and the residue is chromatographed on silica using pure toluene up to a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 17 g of the expected product.
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:9]=1)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: COCCOc1cc(OC(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc(O)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a methylene dichloride (3 ml) solution of tert-butyl 4-tert-butyl-3-(2-methoxyethoxy)phenyl carbonate (792 mg, 2.4 mmol) was added trifluoroacetic acid (TFA) (3 ml) and the mixture was stirred for 1 hour at ambient temperature. The solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=⅓ to furnish 0.32 g (59% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])O.[Na+].[CH3:15][O:16][C:17](=[O:21])[CH:18](Br)[CH3:19]>>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])[CH3:19]
Reactant: COC(=O)C(C)Br
Reactant: Cc1cccc(Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C(C)Nc1c(C)cccc1Cl

Procedure:
35.4 g of 2-chloro-6-methylaniline, 21.3 g of sodium hydrogen carbonate and 84 ml of DL-α-bromopropionic acid methyl ester are stirred for 17 hours at 140° bath temperature. After cooling, the darkly coloured reaction mixture is filtered, and the excess α-bromopropionic acid methyl ester is distilled off in a water-jet vacuum. The residue remaining is fractionally distilled in high vacuum. There is obtained 25.9 g of α-(2-chloro-6-methylanilino)-propionic acid methyl ester, b.p. 72°-75°/0.001 Torr.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][CH:20]=[O:21])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[OH:21][CH:20](/[CH:19]=[CH:18]/[C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:23][CH:22]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(C=CC=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)/C=C/c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5 ml (60 mmol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 41.3 ml of n-butyllithium solution (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9.73 g (60 mmol) of 4-methoxycinnamaldehyde in 100 ml of tetrahydrofuran was added. The reaction mixture was stirred at -78° for 20 minutes, then warmed to -20° and treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed with water, dried over sodium sulphate and concentrated. Flash chromatography of the residue on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1) yielded methyl (E)-4-hydroxy-6-(4-methoxyphenyl)-5-hexen-2-ynoate as a yellow oil.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([N:33]=[C:34]=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:24]=[C:25]([NH:33][C:34]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a yellow solid (0.44 g, 51% yield), mp=68–71° C.; MS (−) ESI m/z=434 (M−H)−; [α]D25=+22.8° (c=1, EtOH).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C>[NH2:14][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1

Procedure:
1-Boc-piperazine and 4-nitrobenzenesulfonyl chloride were allowed to undergo the reaction in DMF in the presence of triethylamine, and then the nitro group was reduced in the sama manner as the catalytic hydrogenation shown in Reference Example 3 to obtain tert-butyl 4-[(4-aminophenyl)sulfonyl-]piperazine-1-carboxylate. FN: 340.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH:10][N:11]=[C:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[N:9]=[C:8]([N:10]([CH3:26])[N:11]=[C:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCC(=NNc2cccc(Br)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(N=C1CCCN(C(=O)OC(C)(C)C)CC1)c1cccc(Br)n1
Reaction time: 0.33 h
Yield: 103.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.83 g, 21 mmol) was added to a solution of tert-butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)azepane-1-carboxylate (6.4 g, 17 mmol) in DMF (54 mL) at room temperature under N2 and stirred for 20 min. Methyl iodide (1.1 mL, 18 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H2O (100 mL). The solution was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (4×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a dark orange oil. The oil was diluted with EtOAc (100 mL) and washed with brine (6×50 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to provide the title compound (7.00 g, quant.) as an amber oil: 1H NMR (300 MHz, DMSO-d6) δ 7.44-7.36 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.49-6.38 (m, 1H), 3.56-3.35 (m, 4H), 3.06-3.04 (m, 3H), 2.75-2.50 (m, 4H, overlaps with H2O), 1.72-1.51 (m, 2H), 1.43-1.15 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=O)[CH:8]=2)[N:3]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH3:27])([CH3:28])[C:24]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C(=O)O)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)C(C)(C)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylpropanoic acid [“A62”] with tert-butylamine);
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[NH:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[N:24]1[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[F:21]
Reactant: CC1CCCC(C)N1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2C(C)CCCC2C)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
A mixture of 66.69A (0.094 g, 0.30 mmol), 2,6-dimethylpiperidine (0.069 g, 0.61 mmol) (commercially available from Aldrich) and cesium carbonate (0.20 g, 0.61 mmol) in DMSO (4 mL) was stirred at 70° C. for 24 hours. The product was purified by reverse phase HPLC to give 66.69B in 30% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 77 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-4-oxobutanoate (Compound IV-17) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH2:6]([O:13][C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26]O>>[CH3:26][O:24][C:23](=[O:25])[C@H:17]([CH2:18][CH2:19][C:20](=[O:22])[NH2:21])[NH:16][C:14]([O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15]
Reactant: CO
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sulphuryl chloride (1 g) was added to a stirred mixture of N-benzyloxycarbonyl-L-glutamine (100 g) and methanol (1200 ml) and the mixture was stirred at ambient temperature for 24 hours. The mixture was evaporated to give N-benzyloxycarbonyl-L-glutamine methyl ester (105 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:20](=[O:26])[CH2:21][CH2:22][C:23](O)=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][C:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCC(=O)C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCC(=O)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirred solution of 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.49 mmol) in anhydrous CH2Cl2 under argon and cooled to 0° C., were added 4-Cyclopentyl-4-oxo-butyric acid (0.31 g, 1.79 mmol), EDC.HCl (0.35 g, 1.79 mmol), HOBt (0.24 g, 1.79 mmol), and TEA (0.25 mL, 1.79 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and the residue was partitioned between EtOAc and 1N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (80% EtOAc in hexanes) to provide the desired product (0.37 g, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.24-1.32 (m, 2H), 1.45 (s, 9H), 1.60-1.85 (m, 11H), 2.41 (t, J=6.4 Hz, 2H), 2.79-3.04 (m, 5H), 3.85-4.13 (m, 2H), 5.65 (s, 1H). MS(ESI):351 (MH−).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.C[O-].[Na+]>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[CH:4][C:3](=[O:2])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(=O)n(Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A mixture of 4-(1-benzylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (3 g, 10.4 mmol), triethylamine (1.5 mL, Et3N) and MeOH (200 mL) was refluxed for 23 h. NaOMe solution (0.12 mL, 0.52 mmol, 25 wt % in MeOH) was added, and the mixture was refluxed for 16 h. The mixture was cooled to r.t. and concentrated in vacuo. The residue was partitioned between saturated NH4Cl (100 mL) and CH2Cl2 (100 mL). 1M HCl was added until pH was about 1. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated to give 2.64 g of the title compound as a white solid. MS: (+) m/z 258.13 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7](C)[C:6](=[O:9])[NH:5][C:4](=[O:10])[CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:18][CH3:19])[CH3:17].CS(C)=O.[H-].[Na+]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:9])[N:5]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:18][CH3:19])[CH3:17])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: CO[C@H](C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CO[C@H](C)CCCCn1c(=O)cc(N)[nH]c1=O
Temperature: 90 °C
Yield: 63 %

Procedure:
A mixture of 6-amino-1-methyluracil (141 mg, 1.0 mmol), (R)-1-chloro-5-methoxyhexane (150 mg, 1.0 mmol), dimethylsulfoxide (2 ml) and sodium hydride (30 mg, 1.2 mmol) was heated to 90° C. for 18 hours. After cooling to room temperature, the mixture was treated with water (7 ml) and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate followed by 5% methanol-ethyl acetate to provide (R)-6-amino-3-(5-methoxyhexyl)uracil (152 mg, 60% yield) as an oil.