Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][CH2:14][C@H:15]([NH:17][CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:10]=2[CH:9]=1)=[O:5])C.[OH-].[Na+:32]>C(O)C>[OH:28][C@H:19]([CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][NH:17][C@H:15]1[CH2:14][CH2:13][CH2:12][C:11]2[CH:29]=[CH:30][C:8]([O:7][CH2:6][C:4]([O-:5])=[O:3])=[CH:9][C:10]=2[CH2:16]1.[Na+:32]
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)COc1ccccc1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])COc1ccc2c(c1)C[C@@H](NC[C@H](O)COc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-1-[((6S)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (249 mg) in ethanol (1 ml) was added 1N sodium hydroxide at 5° C. After stirred at room temperature for 2 hours, the mixture was evaporated in vacuo to afford sodium [(6S)-6-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-3-yloxy]acetate (210 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[Cl:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[C:17]1[N:28]=[N:29][C:2]2[CH:1]3[CH2:7][CH:4]([C:3]=2[CH:16]=1)[CH2:5][CH2:6]3
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cc(Cl)ccc1Cl)OC
Solvent: O
Product: Clc1ccc(Cl)c(-c2cc3c(nn2)C2CCC3C2)c1

Procedure:
yellow crystalline solid. MS (ESI): 291.0 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(2,5-Dichloro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([I:11])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:20](=[O:27])[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:15])([CH3:14])[CH3:13]>ClCCCl>[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:20]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:3]3[S:10][C:9]([I:11])=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:22]1)=[O:27])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Reactant: Clc1ncnc2cc(I)sc12
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Yield: 10.3 %

Procedure:
To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine (0.22 g, 0.742 mmol) in DCE (5 mL)/TEA (2 mL) was added [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (25 mg, 0.68 mmol). The mixture was refluxed for 2 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford the product {1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (44 mg, 95%). 1H NMR (CDCl3, 400 Hz) δ 8.47 (s, 1H), 7.64 (s, 1H), 7.27-7.25 (d, J=8.4 Hz, 2H), 7.17-7.15 (d, J=8.0 Hz, 2H), 5.44 (d, J=8.8 Hz, 1H), 4.85-4.81 (m, 1H), 3.86-3.50 (m, 7H), 3.24-3.19 (m, 1H), 2.99-2.97 (d, J=7.2 Hz, 2H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 628.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:20])=[O:13])[C:4]=2[CH:3]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Product: CN(C(=O)C1c2ccccc2COc2ccc(Br)cc21)c1ccccc1
Yield: 49.2 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.41 g of N-methylaniline in place of aniline to obtain 0.63 g of Compound 43.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]([C:19]2[C:27]3[CH:26]=[N:25][CH:24]=[N:23][C:22]=3[N:21]([CH:28]([CH3:30])[CH3:29])[CH:20]=2)=[O:18])[CH:14]=[N:15][CH:16]=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1>>[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([C:17]([C:19]3[C:27]4[CH:26]=[N:25][CH:24]=[N:23][C:22]=4[N:21]([CH:28]([CH3:30])[CH3:29])[CH:20]=3)=[O:18])[CH:12]=2)=[O:40])=[N:36][CH:37]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Br)cn3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 1 with DIPEA using (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and (5-bromopyridin-2-yl)acetic acid to afford the title compound as a yellow solid in 45% yield, 75 mg. LCMS (System 9): Rt=2.97 min; m/z 479 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:26]1[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(S(C)(=O)=O)cc1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromophenyl methyl sulfone, the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C.C(O)(=O)C>C(#N)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])=[O:9]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Nc1ccc(Cl)cc1C(=O)NC1CCC(=O)NC1=O
Temperature: 150 °C
Yield: 44 %

Procedure:
A stirred mixture of 5-chloroisatoic anhydride (0.51 g, 2.5 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (0.42 g, 2.5 mmol), triethylamine (1.8 mL, 12.7 mmol), and acetic acid (1.5 mL, 25.3 mmol) in acetonitrile (5 mL) was heated at 150° C. in a microwave oven for 5 miutes. The suspension was filtered and washed with water (50 mL) and ethyl acetate (20 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide as a white solid (0.31 g, 42% yield): 1H NMR (DMSO-d6) δ 1.91-2.12 (m, 2H, 2CHH), 2.50-2.56 (m, 1H, CHH), 2.72-2.80 (m, 1H, CHH), 4.71-4.76 (m, 1H, NCH), 6.58 (brs, 2H, NH2), 6.74 (d, J=8 Hz, 1H, Ar), 7.19 (dd, J=2, 9 Hz, 1H, Ar), 7.58 (t; J=2 Hz, 1H, Ar), 8.62 (d, J=8 Hz, 1H, NH), 10.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ 23.99, 30.89, 49.00, 114.62, 117.60, 118.04, 127.25, 131.63, 148.61, 167.37, 172.20, 172.93; LCMS: MH=282, 284.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)nc1n2C[C@H](NC(=O)OC(C)(C)C)[C@@H](c2cc(F)c(F)cc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(C(=O)O)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 380 mg (0.80 mmol) of the product from Step B in 7.5 mL of 2:1 THF/methanol was added 2.5 mL (2.5 mmol) of 1N aqueous lithium hydroxide solution. The reaction mixture was stirred at ambient temperature for 3 h, then the organic solvent removed in vacuo. The mixture was quenched with 50 mL of 1N aqueous hydrochloric acid, and extracted with 50 mL of ethyl acetate. The organic solution was next washed with 1N aqueous hydrochloric acid, once with saturated aqueous brine (50 mL each), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 0% to 80% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 462.4 (M+1).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2([CH2:10][OH:11])[CH2:8][OH:9].[H][H]>C(O)C.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2([CH2:8][OH:9])[CH2:10][OH:11]
Reactant: OCC1(CO)CC2C=CC1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCC1(CO)CC2CCC1C2
Reaction time: 6 h
Yield: 92.7 %

Procedure:
138.18 g of 5-norbornene-2,2-dimethanol (commercially available from Tokyo Kasei Industry Co., Ltd.) was dissolved in 481.63 g of ethanol, and 6.92 g of 5% Pd—C was added, then a hydrogen balloon was attached and the mixture was stirred for 6 hours. The Pd—C was filtered off, then the reaction solution was concentrated and dried to thereby obtain 129.83 g of 2,2-norbornanedimethanol (purity by gas chromatography: 99.1%, yield: 92.9%).
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:7]=1.[CH2:13]([OH:15])[CH3:14]>>[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11](=[NH:12])[O:15][CH2:13][CH3:14])[CH2:9][CH2:10]2)[CH:7]=1
Reactant: N#CC1(n2cc(F)cn2)CC1
Reactant: CCO
Agent: [Na]
Product: CCOC(=N)C1(n2cc(F)cn2)CC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Sodium metal (47 mg, 1.98 mmol) was added to anhydrous ethanol (4 mL) at room temperature. The mixture was stirred for 15 min. A solution of 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (0.1 g, 0.66 mmol) in ethanol (2 mL) was added and the reaction mixture was heated to 70° C. for 90 min. The resulting solution was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc2nc(-c3c(-c4ccccc4)noc3C)cn2c1
Yield: 38 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using methyl 6-aminonicotinate instead of 2-aminopyridine, to the title compound (64 mg, 38%) which was obtained as a light yellow solid. MS: m/e=334.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21].C(N(CC)CC)C>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21]
Reactant: Cn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 38 %

Procedure:
Pyrrolidine (0.07 mL, 0.8 mmol) was added to a solution of 6,7-difluoro-3-hydroxy-1-methyl-1H-quinazoline-2,4-dione (Example L, 0.15 g, 0.66 mmol) and triethylamine (1.2 mL, 8.6 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give a solid. The solid was triturated with chloroform, filtered, and dried to give 0.07 g of the title compound as a solid, mp >250° C.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[O:13][C:12]1[CH:28]=[CH:29][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: COc1cc2ncnc(Oc3ccc(OCc4ccccc4)cc3)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Oc3ccc(O)cc3)c2cc1OC

Procedure:
4-(4-Benzyloxy-phenoxy)-6,7-dimethoxyquinazoline (1.2 g) was heated at reflux with TFA (10 mL) for 20 h, and the mixture was concentrated in vacuo. The residue was diluted with water and basicified with NH4OH (conc.) and a solid precipitated. The solid as filtered, washed with water and Et2O and used directly in the next step. MS(MH+)=NA; Calc'd 298.30 for C16H14N2O4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:3]=12.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[CH2:15]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[C:3]2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:16]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3ccccc3nc21
Reaction time: 48 h
Yield: 90.5 %

Procedure:
To a mixture of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoline (10 g, 0.043 mol) and DMSO (75 ml) is added cyclohexanemethylamine (10.75 g, 0.095 mol). The reaction mixture is refluxed for about four hours, then is allowed to stand for about 2 days. About 40-50 ml of the DMSO is removed in vacuo and the residue is pured into ice waterl. A precipitate forms which is collected by filtration, washed with water and dried. The PG,13 solid precipitate is dissolved in CH2Cl2, washed with water, then brine and is then dried over MgSO4. The solvent is filtered and concentrated in vacuo and the residue is purified by column chromatography on silica gel eluting with ethyl acetate/cyclohexane (3/7) followed by recrystallization from hexane to afford 12 g (90.2%) of 1-ethyl-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as light yellow crystals, m.p. 161°-163° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:19][CH2:20][O:21][CH3:22])[N:15]([CH2:16][CH2:17][CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:6][C:5]=2[N:4]=1.[OH-].[Na+]>C(O)C.O>[NH2:27][CH2:26][CH2:25][CH2:24][O:23][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:15]([CH2:16][CH2:17][CH3:18])[C:14]([CH2:19][CH2:20][O:21][CH3:22])=[N:13][C:12]=3[C:3]([NH2:2])=[N:4][C:5]=2[CH:6]=1
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCNC(=O)OC(C)(C)C)ccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OCCCN)ccc3c21
Temperature: 25 °C
Yield: 69.9 %

Procedure:
Concentrated hydrochloric acid (8.5 mL) was added to a solution of tert-butyl 3-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propylcarbamate (prepared as described in Example 393, 12 g, 26 mmol) in ethanol (300 mL). The solution was heated at reflux for 4 hours. Upon cooling to ambient temperature a precipitate formed. The solid was isolated by filtration and the filtrate was evaporated to afford a white solid. The solids were combined and dissolved in water (40 mL). The solution was adjusted to approximately pH 12 with 50% aqueous sodium hydroxide and then was extracted with dichloromethane (4×250 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated to yield a solid that was purified by trituration in hot acetonitrile to provide 6.5 g of 7-(3-aminopropoxy)-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as yellow crystals, mp 165-166.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Br-].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][Zn+]>C1COCC1.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:13][C:12]2[C:11]([F:10])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[N:3][CH:4]=1
Reactant: Fc1cccc(F)c1C[Zn+]
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Cc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromopyridine (10 g) in THF was added Tetrakis (2.2 g) and 2,6-difluorobenzylzinc bromide (126 mL, 63 mmol). The reaction was heated to reflux until reaction was complete by TLC. The reaction was cooled to room temperature, filtered through celite, and concentrated in vacuo. The title compound was purified by silica gel (Hexanes/methylene chloride).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C([O-])(=O)C.[Na+]>[Pd].CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])#[N:5]
Reactant: N#Cc1ccccc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccccc1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
0.67 ml of the stock solution from Example 52, 3.05 g (16.8 mmols) of 2-bromobenzonitrile, 1.99 ml (18.4 mmols) of ethyl acrylate and 1.50 g (18.4 mmols) of anhydrous sodium acetate are added, under argon, to 16.3 ml of DMF, and the reaction mixture is stirred at 130° C. for 3 hours. After working up as described in Example 1, the crude product is recrystallised from a mixture of pentane and carbon tetrachloride. 1.5 g (7.5 mmols) of ethyl o-cyanocinnamate are obtained in the form of white crystals of melting point 56° C., corresponding to a yield of 44% of theory (conversion figure 4400; Pd content 0.01 mol %). Analysis for C12H11NO2 (molecular weight 201.23): calculated C 71.63; H 5.51; N 6.96; O 15.90, found C 71.17; H 5.64; N 6.88; O 16.56.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]([C@@H:14]1[C@@H:18]([CH2:19]O)[O:17][C@@H:16]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:15]1)=[N+:12]=[N-:13].[C:30]([CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl.CS(C)=O.C(Cl)Cl.C(N(CC)CC)C>[C:30]([CH:35]=[CH:19][C@H:18]1[O:17][C@@H:16]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:15][C@@H:14]1[N:11]=[N+:12]=[N-:13])([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
A solution of DMSO(426 μl, 6 mM) in methylene chloride (1.5 ml) was added to a stirred solution of oxalyl chloride (288 μl, 3.3 mM) in methylene chloride (7.6 ml) at -78° C. under nitrogen. After 5 minutes, a solution of 3'-azido-3'-deoxythymidine (801 mg; 3 mM) in DMSO/CH2Cl2 (1.12 ml/3.47 ml) was added over a ten minute period. Stirring was continued for 20 minutes, and then triethylamine (2.09 ml, 15 mM) was added and the reaction mixture was stirred for an additional 5 minutes. (Carbethoxymethylene)triphenylphosphorane (1.57 g; 4.5 mM) was added in a solution of methylene chloride (9 ml), and the reaction mixture was stirred at -78° C. for 30 minutes and then allowed to stand at room temperature for 1 hour. The crude reaction mixture was then quenched with cold water (20 ml) and extracted into ethyl acetate (2×50 ml), washed with brine and dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography (SiO2 : 60 g; 60% ethyl acetate/hexane) to afford 765 mg (76%) of the title compound. Rf -0.47(7/3 EtOAc/Hexane).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2=[N:19][O:20][N:21]=[C:17]2[CH:16]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[N:19]1[O:20][N:21]=[C:17]2[CH:16]=[C:15]([CH2:14][N:37]3[CH2:38][CH2:39][N:35]([C:27]4[S:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]([CH3:24])[N:26]=4)[C:36]3=[O:40])[CH:23]=[CH:22][C:18]=12
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccc2nonc2c1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc4nonc4c3)C2=O)nc1C
Yield: 92 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 5-(bromomethyl)benzo[c]-[1,2,5]oxadiazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 92% yield: MS (ES+) m/z 388.1 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1.[N-:24]=[N+:25]=[N-:26].[Li+]>CS(C)=O>[N:24]([CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1)=[N+:25]=[N-:26]
Reactant: CCCc1cc(CBr)ccc1OC(C(=O)OC)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Product: CCCc1cc(CN=[N+]=[N-])ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
To a solution of 45 mg (0.12 mmol) of the product from Step H in 0.37 ml of dry DMSO was added 7.3 mg (0.15 mmol) of lithium azide. The solution was stirred at room temperature under N2 for 4.5 hours. After flash chromatography on silica gel (elution with 10:1 hexane-EtOAc), 33 mg (83%) of the title compound was obtained as a gum; satisfactory purity by TLC in 4:1 hexane-EtOAc.
Reaction SMILES: [C:1]([C@H:4]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:7][N:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:5]1)(O)=[O:2].C(N1C=CN=C1)([N:29]1C=CN=C1)=O>C(Cl)Cl>[NH2:29][C:1]([C@H:4]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:7][N:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:5]1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(OC)c(OC3CCCC3)c2)C1
Solvent: ClCCl
Product: COC(=O)N1C[C@@H](C(N)=O)[C@H](c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a solution of trans-3-carboxy-4-(3-cyclopentoxy-4-methoxyphenyl)-1-(methoxycarbonyl)pyrrolidine (1.5 g, 4.1 mmol) in 11 mL of CH2Cl2 at 0° C. was added 1,1'-carbonyldiimidazole (736 mg, 4.5 mmol) in portions. The cooling bath was removed, and the solution was stirred at room temperature for 20 min. Ammonia gas was passed over the stirring solution for 4 min, and stirring was continued an additional 15 min. The solution was diluted with CH2Cl2 and poured into 1M H3PO4. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to a pale yellow foam. Silica gel chromatography (8:1:1, CH2Cl2 :ethyl acetate:methanol) provided trans-3-aminocarbonyl-4-(3-cyclopentoxy-4-methoxyphenyl)-I-(methoxycarbonyl)pyrrolidine as a white solid (1.1 g, 76%), m.p. 130°-32° C. Anal. Calcd for C19H26N2O5 : C, 62.97; H, 7.23; N, 7.73. Found: C, 63.03; H, 7.28; N, 7.65.