Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>>[C:26]1([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:1][C:2]3[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=3)[C:5]([CH:7]3[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]3)=[O:6])=[O:24])=[CH:21][CH:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(-c4ccccc4)cc3)c2)CC1
Yield: 33.8 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-biphenylcarbonyl chloride (150 mg, 0.687 mmol), 30.8 mg (34%) of the title compound were recovered.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9](=[O:18])[C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[O:17][N:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:18])[C:3]=2[CH:4]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1cc(I)ccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1noc2ccc(I)cc2c1=O
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A solution of ethyl 3-(2-fluoro-5-iodophenyl)-2-(hydroxyimino)-3-oxopropanoate (Preparation 16, 1.3 g) in toluene (20 mL) is heated to reflux under nitrogen for 48 h. The reaction mixture is cooled to room temperature and concentrated in vacuo to give 1.33 g of a crude yellow solid which is recrystallized from ether to afford 0.65 g of the title compound as a yellow crystalline solid. Physical characteristics: mp 130-131: 1H NMR (300 MHz, CDCl3) δ 1.45, 4.51, 7.35, 8.09, 8.50; IR (drift) 2475, 2425, 2382, 2350, 2260, 1742, 1663, 1456, 1332, 1240, 1195, 1150, 1010, 987, 831 cm−1; HRMS (FAB) m/z 345.9581 (C11H8INO4+H). Anal. Found: C, 38.03; H, 2.52; N, 4.06.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]([F:41])([F:40])[C:12]1[CH:13]=[C:14]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:16].O>ClCCl>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:14]([CH:13]=[C:12]([C:11]([F:10])([F:40])[F:41])[CH:35]=1)[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:19][C@H:18]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:16]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CCCCC1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 4 h

Procedure:
Cyclohexyl isocyanate (0.06 ml) was added to a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.2 g) in dichloromethane (10 ml) at room temperature. After stirring for 4 hours, dichloromethane (10 ml) and water (5 ml) were added. The organic layer was separated, washed with brine and dried over magnesium sulfate. After evaporation of the solvent in vacuo,.the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-cyclohexylcarbamoyl-2-(1H-indol-3-yl-methyl)piperazine (0.18 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([O:30][CH3:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[C-:32]#[N:33].[Na+]>CS(C)=O>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[O:14][CH:13]([CH2:12][C:32]#[N:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: [C-]#N
Reactant: COc1cc2c(c(-c3ccccc3OC)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(c(-c3ccccc3OC)c1)OC(CC#N)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.25 g, 0.57 mmol) in dimethylsulfoxide (20 mL) was added sodium cyanide (0.07 g, 1.43 mmol) and the reaction mixture was allowed to stir at 50° C. for 1 h. The reaction was quenched by the addition of water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were washed with water (3×20 mL), saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) gave (±)-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]acetonitrile as a colorless oil. The oil was dissolved in ethanol (30 mL), 28% aqueous ammonium hydroxide (20 mL), and treated with rhodium on alumina (0.1 g, 5 wt. %) generally according to procedure described for Example 1 to afford 0.025 g (13%) of (±)-{2-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a yellow solid, hydrochloride salt. mp 240-242° C.
Reaction SMILES: CNC([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[C:14](=[O:23])[N:15]([CH3:22])[C:16]3([N:21]=[C:6]12)[CH2:20][CH2:19][CH2:18][CH2:17]3)=O.[OH-].[Na+]>C1COCC1>[CH3:22][N:15]1[C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:21][C:6]2=[N:5][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]2[C:14]1=[O:23]
Reactant: CNC(=O)N1C2=NC3(CCCC3)N(C)C(=O)N2c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1C(=O)n2c(nc3ccccc32)NC12CCCC2

Procedure:
The reaction product of Example 26 was hydrolyzed by 10% aqueous sodium hydroxide and THF to give the title compound, employing the procedure of Example 1, paragraph 2. The product was recrystallized from acetone to give a solid, mp 180°-182° C. The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: ClC1C=CC([NH:8][NH2:9])=CC=1.Cl[C:11]1[C:16]([C:17]([O:19]CC)=O)=[CH:15][N:14]=[C:13]2CCC[C:12]=12>C(O)CCC>[N:8]1[C:11]2=[CH:12][CH:13]=[N:14][CH:15]=[C:16]2[C:17](=[O:19])[N:9]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCC2
Solvent: CCCCO
Product: O=C1N=Nc2ccncc21

Procedure:
A mixture of 1.1 g of p-chlorophenylhydrazine and 1.9 of ethyl 4-chloro-6,7-dihydro-5H-cyclopenta[b]-pyridine-3-carboxylate (Example 2a) in 100 mL of n-butanol is refluxed for 24 hours under nitrogen atmosphere. The precipitate is collected and recrystallized from ethanol to yield 2-p-chlorophenyl-2,3,5,6,7,8-hexahydrocyclopentab]pyrazolo[3,4-d]pyridin-3-one, m.p. above 350°, showing IR peaks at 900, 835, 805, 798, 765, and 740 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16]O)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)[Cl:26].CS(Cl)(=O)=O>O.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16][Cl:26])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)nc1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(CCl)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Add 3-(tert-butoxycarbonylamino-methyl)-6-hydroxymethyl-pyridine (2.3 g, 9.65 mmol) and triethylamine (2.05 mL, 14.5 mmol) to DCM (30 mL). Cool the mixture to 0° C. and add methanesulfonyl chloride (0.83 mL, 10.6 mmol) to the mixture. Allow the mixture to warm to room temperature and stir overnight. Dilute the mixture with water (10 mL) and saturated aqueous NaHCO3 (10 mL). Separate the layers, and extract the aqueous layer with DCM (3×20 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (1.14 g, 46%). MS (APCI+) m/z: 257 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)O[CH2:17][CH2:16][O:15]1>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:17][CH2:16][OH:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: O=C1OCCO1
Solvent: CN(C)C=O
Product: OCCOc1cccc(-c2ccccc2)c1
Yield: 86 %

Procedure:
The title compound was prepared according to the procedure of Example 114, Step 1 starting from 3-phenylphenol (1.72 g, 10.1 mmol) and ethylene carbonate (0.80 g, 9.1 mmol) and DMF (3 mL). Semi-solid; yield 86%. MS m/z 214 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>CC(N(C)C)=O>[F:16][C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([N:1]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:7][CH2:6]2)=[N:11][C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]([F:27])([F:28])[F:29])=[N:13][CH:14]=1
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2F)CC1
Solvent: CC(=O)N(C)C
Product: Fc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 100 °C

Procedure:
N4-[(trans-4-aminocyclohexyl)methyl]-5-fluoro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (71 mg, 0.17 mmol) was dissolved in DMA (2 mL). To this solution was added 1,4-dibromobutane (81 μL, 0.68 mmol) and NaCO3 (72 mg, 0.68 mmol). The reaction was heated in the microwave at 100° C. for 20 min. The volatiles were removed and the reaction was diluted with EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude product was purified by twice running on a 1000 micron SiO2 Prep TLC plate, eluting with 10:1 CH2Cl2:MeOH (1% NH4OH) to afford 36 mg (45%) of the title compound, m/z 468.6 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=O)=[CH:4][N:3]=1.[NH2:20][NH2:21]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:20][N:21]=[C:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:5]2=[CH:4][N:3]=1
Reactant: NN
Reactant: COc1ccc(F)cc1C(=O)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1n[nH]c2nc(Cl)ncc12
Reaction time: 0.33 h

Procedure:
To a stirred solution of (2,4-dichloro-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (602 mg, 2 mmol) in THF (8 m), hydrazine (Aldrich, 98%, 64 mg, 2 mmol) was added and the mixture was stirred for 20 minutes followed by a second portion of hydrazine (0.1 mL). The reaction finished in 5 minutes. The solvent was removed and the solid was washed with water/acetonitrile (3:1) to give a yellow solid. 456 mg, 82%. MS (M+H)+, 278.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-chloro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.3 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.81 g, 4.3 mmol). The product was isolated as a white foam. Yield 1.15 g (64%). mp 90°-95° C. FDMS m/e=423 (M+ of free base). α[D]589 =+8.81 (c=0.98, methanol/dimethylsulfoxide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9]C)=[CH:4][C:3]=1[C:11](=O)[CH3:12].[C:14](O)(=O)C>[Zn]>[CH2:11]([C:3]1[CH:4]=[C:5]([OH:9])[C:6]([O:8][CH3:14])=[CH:7][C:2]=1[F:1])[CH3:12]
Reactant: COc1cc(C(C)=O)c(F)cc1O
Reactant: CC(=O)O
Agent: [Zn]
Product: CCc1cc(O)c(OC)cc1F
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 1-(2-fluoro-4-hydroxy-5-methoxyphenyl)ethanone (18.0 g; 97.7 mmol; 1 eq; which may be prepared as hereinbefore described for D1) in glacial acetic acid (800 mL) is stirred at 70° C. before adding added zinc dust (63.9 g; 977 mmol; 10 eq). The resulting grey heterogeneous mixture is then heated at reflux and stirred overnight using a mechanical stirrer. After this period, zinc has aggregated and conversion rate reaches 90% according to the 1H NMR analysis of a crude aliquot. Therefore, the zinc metal is removed by filtration on a fritted glass and fresh zinc dust (6.4 g; 98 mmol) is added to the resulting limpid yellow filtrate. The solution is heated at reflux overnight until completion of the reaction. The solution is filtered on a fritted glass and basified until pH 11-12 is reached with a saturated aqueous solution of potassium carbonate (1.5 L) and with additional solid potassium carbonate if needed. The resulting aqueous layer is then extracted with ethyl acetate (1.0 L), dried over sodium sulphate or by azeotropic toluene distillation, filtered and concentrated under vacuum to afford the pure title compound (16.1 g; 94.7 mmol; 97%) as a pale yellow oil. It should be noted that the title compound is a volatile product and should be kept in the fridge under Argon away from light (darkens with oxygen and/or UV exposure).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:26]1([C:32]2[N:33]=[CH:34][NH:35][C:36]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:35]=[CH:34]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCCCc1oc(-n2cnc(-c3ccccc3)c2-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 39.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 4,5-diphenylimidazole (270 mg), anhydrous potassium carbonate (220 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 12 hours. The reaction mixture was poured into water, the resulting solid precipitate was filtered and air-dried. Recrystallization of this solid from acetone-isopropyl ether gave 4-(4-chlorophenyl)-2-(4,5-diphenyl-1-imidazolyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (220 mg, 46%). Melting point 118-119° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH2:62][CH2:63]O)[C:56]([C:58]([CH3:61])([CH3:60])[CH3:59])=[O:57]>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:63][CH2:62][N:55]([CH3:54])[C:56]([C:58]([CH3:61])([CH3:60])[CH3:59])=[O:57])[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: CN(CCO)C(=O)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Diethyl azodicarboxylate (679 mg, 3.9 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin4-one (918 mg, 3 mmol), triphenylphosphine (1 g, 3.9 mmol) and 2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (682 mg, 3.9 mmol), prepared as described below, in methylene chloride (20 ml) and the mixture stirred for 1 hour at ambient temperature. Further 2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (105 mg, 0.6 mmol), triphenylphosphine (786 mg, 3 mmol) and diethyl azodicarboxylate (522 mg, 3 mmol) were added and the mixture stirred for 30 minutes at ambient temperature. The mixture was concentrated to half volume by evaporation and purified by column chromatography eluting with methylene chloride/ether (7/3 increasing to 1/1) to give 6-methoxy-7-(2-(N-methyl-N-(t-butylcarbonyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.3 g, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[O:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[O:23]1[CH:27]=[CH:26][C:25]([CH2:28][N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)=[CH:24]1
Reactant: O=Cc1ccoc1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccccc2N2CCN(Cc3ccoc3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (50 mg, 0.166 mmol) produced in Example (8b), furan-3-carbaldehyde (0.02 mL, 0.231 mmol) and tetrahydrofuran (3 mL) was added sodium triacetoxyborohydride (43 mg, 0.203 mmol), followed by stirring for 20 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled off by nitrogen stream. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-furan-3-ylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Diethyl ether was added to the obtained residue to produce a solid, and after further adding hexane, the solid was triturated by sonication. The supernatant solution was removed and the obtained solid was dried to give 33 mg of the title compound as colorless crystals.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.[O-:34][CH2:35][CH3:36].[Na+]>C(O)C>[CH2:35]([O:34][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1)[CH3:36]
Reactant: CC[O-]
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(NC(=O)[C@H]2CCCN2c2nc3c(c(Nc4cc(C(C)C)[nH]n4)n2)CCC3)cn1
Temperature: 100 °C
Yield: 1.9 %

Procedure:
A suspension of (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (200 mg, 0.44 mmol) and sodium ethoxide (100 mg, 1.42 mmol) in ethanol (2 mL) was heated at 100° C. in a microwave for 1 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc (50 mL). The solution was washed with saturated sodium bicarbonate solution (20 mL) followed by brine (20 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC followed by chiral HPLC to afford 4 mg of (R)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1HNMR (400 MHz, CDCl3) δ (ppm): 1.18-1.32 (m, 6H), 1.38 (t, 3H), 1.90-2.20 (m, 5H), 2.60-2.77 (m, 3H), 2.84-2.98 (m, 3H), 3.60-3.79 (m, 2H), 4.28 (q, 2H), 4.78 (d, 1H), 6.40 (s, 1H), 6.62 (d, 1H), 6.70 (s, 1H), 7.85 (brs, 1H), 7.79 (s, 1H). The other enantiomer is prepared using the (S) starting material.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:24]([O:26][CH3:27])=[O:25])=[CH:5][C:4]=2[N:3]=1.[O:28]=[C:29]1[CH:33]=[CH:32][C:31](=[O:34])[N:30]1[CH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([C:42](ON2C(=O)CCC2=O)=[O:43])[CH2:38][CH2:37]1.CCN(CC)CC>CN(C=O)C>[CH2:20]([C:13]1[N:14]([CH2:15][C:16]([OH:19])([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:24]([O:26][CH3:27])=[O:25])=[CH:5][C:4]=3[N:3]=[C:2]([NH:1][C:42]([CH:39]3[CH2:38][CH2:37][CH:36]([CH2:35][N:30]4[C:29](=[O:28])[CH:33]=[CH:32][C:31]4=[O:34])[CH2:41][CH2:40]3)=[O:43])[C:11]=2[N:12]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Reactant: O=C(ON1C(=O)CCC1=O)C1CCC(CN2C(=O)C=CC2=O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(NC(=O)C3CCC(CN4C(=O)C=CC4=O)CC3)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Yield: 68 %

Procedure:
To a solution of 4-amino-2-butyl-1-(2-hydroxy-2-methylpropyl)-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline S7 (37 mg, 0.1 mmol, 1.0 equiv) and 2,5-dioxopyrrolidin-1-yl 4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]cyclohexanecarboxylate (66 mg, 0.20 mmol, 2.0 equiv) in DMF (2.0 mL) at 25° C. was added NEt3 (40 μL, 0.30 mmol, 3.0 equiv) in one injection. The reaction was heated at 50° C. for 24 h. The solvent was then removed in vacuo and the solid was redissolved in 1:9 MeOH/EtOAc (50 mL), washed successively with saturated NaHCO3 solution (15 mL), H2O (15 mL) and saturated aqueous NaCl (15 mL) and the organic layer concentrated. TLC and MS analysis indicated existence of both the imidazoquinoline starting material and the desired product. Purification by flash column chromatography on silica gel (CH2Cl2-1/9 MeOH/CH2Cl2, gradient) afforded the title compound 550 (40 mg, 68%) as a white solid: 1H NMR (CD3OD, 600 Hz) δ1.04 (t, J=7.2 Hz, 3H), 1.11-1.18 (m, 2H), 1.26 (br s, 6H), 1.51-1.66 (m, 4H), 1.68-1.85 (m, 3H), 1.91 (pent, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 3.40 (d, J=7.2 Hz, 2H), 6.83 (s, 2H), 7.98 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.66 (s, 1H); 13C NMR (CD3OD, 150 Hz) δ 12.9, 22.3, 27.2, 28.5, 28.7, 29.5, 29.6, 36.6, 43.1, 45.4, 51.4, 54.9, 71.1, 119.9, 121.4, 123.7, 126.5, 126.6, 126.6, 128.0, 128.8, 130.5, 133.9, 135.2, 142.5, 144.3, 158.2, 159.9, 160.0, 166.8, 171.4; MS (APCI+): calcd C32H40N5O6 [M+H]+ 590.3. found 590.3.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][O:7][C:5](=[O:6])[CH2:4]1)=[CH2:2].C([O-])(=O)C.[Na+].[CH3:14][OH:15]>>[OH:15][CH2:14][CH:3]([CH:1]=[CH2:2])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CO
Reactant: C=CC1COC(=O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CC(CO)CC(=O)OC

Procedure:
A solution of RS 3-vinylbutyrolactone (3.5 g) and sodium acetate (2.56 g) in methanol (30 ml) was kept for 20 hours. Solvent was evaporated and the residue was partitioned between water and ether. The aqueous layer was extracted twice more with ether and the extracts combined, filtered through phase separating paper and evaporated. The residue was purified by filtration chromatography on silica gel (Merck 7736) starting with 1/9 ethyl acetate/hexane and progressing to 4/6 ethyl acetate/hexane as eluent to give methyl 4-hydroxy-3-vinylbutyrate as an oil; NMR(CDCl3) δ 5.73(1H,m), 5.15(2H,m), 3.68(3H,s), 3.60(2H,t), 2.76(1H,m), 2.48(2H,m), 1.69(1H,t); m/e 145(M+H)+.