Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([O:36]C)=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].Cl>C1COCC1.[OH-].[Na+]>[C:1]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
The methyl 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate (0.9 g, 1.7 mmol) was dissolved in THF (15 mL) and 1 N NaOH (8 mL). The reaction was stirred (50° C., 5 h), and then acidified to pH 3 with 2 N HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine and dried over MgSO4. The crude material was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.40 g of 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoic acid as a yellow solid. [M+H]+=521.3. Mass calculated for C31H40N2O5=520.66. found: [M−H]+=519.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)O1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:26]4[N:30]([C:31]5[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=5)[N:29]=[CH:28][CH:27]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(C(F)(F)F)cc2)OC1(C)C
Product: Fc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound, white solid (37 mg, 26%), MS (ISP) m/z=423.6 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate E) (0.1 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(4-trifluoromethyl-phenyl)-1H-pyrazole (intermediate P) (0.15 g, 0.45 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:28](=[O:30])[CH3:29])[N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Solvent: ClCCl
Product: CC(=O)n1nc(C(=O)NC2CN(C)CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (1.0 g) in dichloromethane (10 ml), acetic anhydride (0.56 g) is added; and the mixture is stirred at 25° C. for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.92 g) as an oil. The free base thus obtained is converted to the fumarate 1/4 hydrate of the title compound in a usual manner, m.p. 166-168° C. (recrystallized from ethanol).
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH3:10])[N:5]1[CH2:11][CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]1[O:23][C:24]2[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:15].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH3:10][C@H:6]1[CH2:7][CH2:8][CH2:9][C@@H:4]([CH3:3])[N:5]1[CH2:11][CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]1[O:23][C:24]2[CH:30]=[C:29]([O:31][CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:15]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccc(O)cc2o1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2nc(N3CCCC[C@H]3C(=O)NCCN3[C@H](C)CCC[C@@H]3C)oc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride as a 60% dispersion in oil (6 mg) was added to a solution of (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-hydroxy-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (54.5 mg) [see Preparation 39] in dimethylformamide (2 ml) at 0° C. After 5 minutes 2-iodopropane (0.014 ml) were added. The reaction mixture was stirred at room temperature for 4 hours, after which time sodium hydride (3 mg) followed by 2-iodopropane (0.007 ml) was added. The mixture was stirred for a further 18 hours, after which time the solvent was removed and the residue partitioned between water and diethyl ether. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 97:3.5:0.5, by volume, dichloromethane/methanol/0.88 aqueous ammonia solution to afford (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-isopropoxy-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (24 mg) as a brown solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[H-].[K+]>O1CCCC1>[I:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:18]#[N:19])=[C:7]2[S:4][CH2:3][CH:2]([CH3:5])[CH3:1]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CC(C)CS
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CSc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 2-methyl-propane-1-thiol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of tetrahydrofuran to give 6-iodo-4-isobutylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 369(MH+).
Reaction SMILES: NC1N(C2C=CC(OC)=CC=2)C(C2C=CC=C(NS(C)(=O)=O)C=2)[N:5]=[C:4]2[O:27]C=C[C:3]=12.C(O[C:34](=[O:36])[CH3:35])(=O)C.[C:37]1(C)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:4]([NH:5][C:37]1[CH:38]=[CH:39][C:40]([C:34](=[O:36])[CH3:35])=[CH:41][CH:42]=1)(=[O:27])[CH3:3]
Reactant: Cc1ccccc1
Reactant: COc1ccc(N2C(N)=c3ccoc3=NC2c2cccc(NS(C)(=O)=O)c2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Yield: 960 %

Procedure:
To a suspension of 4-aminoacetophenone 1 (74 g, 547 mmol) in toluene (700 mL), acetic anhydride (56 mL 593 mmol) was added dropwise at room temperature. Soon after added all of acetic anhydride, the reaction mixture became a clear solution and then rapidly began to make a white precipitation. The precipitation were filtrated and washed with a small amount of toluene then dried under reduced pressure to afford 2 as a white solid (93 g, 960% yield): MS(ES) m/e 178 [M+H].
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[C:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:4]2[C:5](=[O:17])[C:6](=[O:16])[C:7]=2[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CS(C)=O
Product: O=c1c(Nc2ccccc2O)c(Nc2ccccc2-c2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-aminobiphenyl (36.3 mg, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 357.2 (M+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1>>[Br-:1].[Br-:1].[CH2:2]([N+:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1
Reactant: BrCCCCCCCCCCCCBr
Reactant: c1ccc2cnccc2c1
Product: [Br-]
Product: c1ccc2c[n+](CCCCCCCCCCCC[n+]3ccc4ccccc4c3)ccc2c1
Temperature: 65 °C

Procedure:
1,12-Dibromododecane (mmol) was added to a solution (30 mL) of isoquinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting off-white solid was isolated. 1H NMR (300 MHz, DMSO-D6) δ 10.06 (1H, d, C1-H), 8.78 (1H, d, C3-H), 8.58 (1H, d, C8-H), 8.48 (1H, d, C4-H), 8.35 (1H, d, C7-H), 8.25 (1H, t, C5-H), 8.07 (1H, t, C6-H), 4.70 (2H, t, C′1-CH2), 2.0 (2H, m, C′2-CH2), 1.75 (1H, m, C′3-CH2), 1.15-1.40 (7H, m, C′3-6-CH2).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=2[F:33])[O:15][CH2:14]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C@@H:22]2[C:21]3[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=3[F:33])[O:15][CH2:14][C@H:13]2[CH2:12][O:11][CH2:10][CH2:9][OH:8])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1COCCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)[C@@H]1c2c(F)ccc(F)c2OC[C@H]1COCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-Benzyloxy-ethoxymethyl)-4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman (0.4 g, 0.79 mmole) was dissolved in 10 ml EtOAc and Pd(OH)2 was added. Hydrogen was introduced via a balloon. The reaction was stirred at room temperature for 30 minutes. The catalyst was filtered and residue was used in next step without purification. Yield: 0.32 g, 97%. 1H NMR (CDCl3 400 MHz δ 7.73 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.03 (m, 1H), 6.41 (m, 1H), 4.90 (dd, J=8.8 and 2.9 Hz, 1H), 4.57 (s, 1H), 4.39 (td, J=11.7 and 1.5 Hz, 1H), 3.68 (br, 2H), 3.41-3.54 (m, 3H), 2.30 (t, J=9.5 Hz, 1H), 3.15 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:37])[NH2:36])=[CH:31][CH:30]=1.[OH-].[Na+].C(O)C.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:36])[NH2:37])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3ccccc3)ccc21

Procedure:
0.52 g (0.93 mmol) of 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and 0.4 g (0.01 mol) of sodium hydroxide are stirred in 5 ml water and 10 ml ethanol for three hours at ambient temperature. Then the mixture is diluted with water and adjusted to pH 4 with glacial acetic acid. The crystalline precipitate is suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12]1)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=N[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N>CN(C=O)C>[C:37]([CH2:38][NH:43][C:16]([CH:13]1[CH2:14][CH2:15][CH:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:12]1)=[O:18])#[N:36]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CCC(S(=O)(=O)c2ccccc2Cl)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CCC(S(=O)(=O)c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(2-chloro-benzenesulfonyl)-cyclopentanecarboxylic acid (0.25 g, 1.0 eq) in DMF (4.0 mL) was treated with DIPEA (0.22 mL, 1.5 eq) and HATU (0.39 g, 1.2 eq). The mixture was stirred at RT for 15 min, then a solution of aminoacetonitrile hydrochloride (0.12 g, 1.5 eq) and DIPEA (0.22 mL, 1.5 eq) in DMF (1 mL) was added. The resulting solution was stirred at RT overnight and then purified by preparative HPLC. The title compound was obtained as a light yellow gum (0.10 g, 37%). MS (ESI): m/z=327.1 [M+H]+.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:27]=[CH:26][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:25][CH:23]([CH3:24])[CH2:22][CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:27][CH:26]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CC(C)CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 24.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-isopentyl-1-piperidinecarboxamide formate (0.40 g, 1.05 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.427 g, 1.05 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.194 g, 0.26 mmol).
Reaction SMILES: [CH2:1]([C:4]1[C:13](OCC=C)=CC=C2[C:5]=1CCC(=O)N2)[CH:2]=C.[CH2:19]([C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]2)=[CH:24][C:23]=1[O:33][CH2:34][CH:35]=[CH2:36])[CH:20]=[CH2:21].[H-].[Na+].[H][H].C(Cl)C=C(C)C>CN(C)C=O.O>[CH2:34]([O:33][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:22]=1[CH:19]=[CH:20][CH3:21])[N:29]([CH2:2][CH:1]=[C:4]([CH3:13])[CH3:5])[C:28](=[O:32])[CH2:27][CH2:26]2)[CH:35]=[CH2:36]
Reactant: C=CCOc1cc2c(cc1CC=C)NC(=O)CC2
Reactant: [H][H]
Reactant: C=CCOc1ccc2c(c1CC=C)CCC(=O)N2
Agent: CC(C)=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc2c(cc1C=CC)N(CC=C(C)C)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
80 Grams of the mixture of 5-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone and 7-allyl-6-allyloxy-3,4-dihydro-2(1H)-quinolinone obtained in Example 16 was dissolved in 300 ml of dimethylformamide, then 15 g of 60% oily sodium hydride was added little by little thereto at room temperature and stirred at 25° to 40° C. until generation of hydrogen gas was ceased. After the reaction mixture was cooled to room temperature, 35 g of prenyl chloride was added thereto and stirred at 50° C. for 2 hours, further stirred at room temperature for 8 hours. After finished the reaction, the dimethylformamide was removed by distillation under reduced pressure to obtain the residue. To the residue was added water and extracted with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to obtain pale yellow oily product. This oily product was subjected to separation and purification by means of a silica gel flush chromatography, by using a mixed solvent of ethyl acetate:n-hexane (1:10 to 1:2) as the eluent, there was obtained 29 g (28.3%) of 6-allyloxy-3,4-dihydro-1-prenyl-7-(1-propenyl)-2(1H)-quinolinone.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]3[C:16]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:17][CH:18]=[CH:19][N:20]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:42]>>[ClH:42].[ClH:42].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]3[C:16]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[N:17][CH:18]=[CH:19][N:20]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2ccc3c(c2)OCCO3)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1cnc(N2CCNCC2)c(OCCOc2ccc3c(c2)OCCO3)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
To a solution of the product obtained in Step 2 (0.43 g, 0.94 mmol) in CH2Cl2 (2 mL) was added CF3COOH (1.5 mL) at room temperature. The solution was stirred at room temperature for 5 h and evaporated to dryness. The residue was dissolved in EtOAc. The solution was washed with 25% aqueous NaOH and dried over K2CO3. A solution of HCl in Et2O was dropped into the solution until no more precipitate formed. The precipitate was collected, washed with ethyl ether, and dried in vacuum to give 251 mg (62%) of the title product: mp 158-160° C. MS m/z 358 (M)+. HRMS m/z calcd for C18H22N4O4 (M)+ 358.1641, found 358.1647.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:38]C(=O)OC(C)(C)C)[C:15]([NH:17][C@H:18]2[C@@H:22]([OH:23])[C@H:21]([N:24]3[CH:32]=[N:31][C:30]4[C:25]3=[N:26][CH:27]=[N:28][C:29]=4[N:33]([CH3:35])[CH3:34])[O:20][C@@H:19]2[CH2:36][OH:37])=[O:16])=[CH:9][CH:8]=1)=[N+:2]=[N-:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:34][N:33]([C:29]1[C:30]2[N:31]=[CH:32][N:24]([C@@H:21]3[O:20][C@H:19]([CH2:36][OH:37])[C@@H:18]([NH:17][C:15]([C@@H:14]([NH2:38])[CH2:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=4)=[O:16])[C@H:22]3[OH:23])[C:25]=2[N:26]=[CH:27][N:28]=1)[CH3:35].[NH2:38][C@@H:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[CH:8][CH:9]=1)[C:15]([NH:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[N:33]([CH3:35])[CH3:34])[O:20][C@@H:19]1[CH2:36][OH:37])=[O:16]
Reactant: CN(C)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](NC(=O)[C@H](Cc2ccc(OCCN=[N+]=[N-])cc2)NC(=O)OC(C)(C)C)[C@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](NC(=O)[C@@H](N)Cc2ccc(OCCN=[N+]=[N-])cc2)[C@H]1O
Product: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N(C)C)ncnc43)O[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Boc-Puromycin analog 4A (392 mg, 0.63 mmol) was dissolved in a 1:1 TFA (5 mL) and CH2Cl2 (5 mL) mixture and then stirred at room temperature for 30 min. Volatiles were evaporated in vacuo and the residue was dissolved into CH2Cl2. The solution was poured into a suspension of saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, step-wise gradient from 2-15% MeOH in CH2Cl2) to afford Puromycin analog 5A (151 mg, 46%) as a white solid. 1H NMR (600 MHz, DMSO-d6): δ 8.45 (1H, s), 8.24 (1H, s), 8.06 (1H, br), 7.17 (2H, d, J=8.4 Hz), 6.87 (1H, d, J=8.4 Hz), 6.14 (1H, d, J=4.8 Hz), 5.98 (1H, d, J=2.4 Hz), 5.14 (1H, t, J=5.4 Hz), 4.42-4.52 (2H, m), 4.14 (2H, t, J=5.4 Hz), 3.92-3.97 (1H, m), 3.10-3.80 (12H, m), 2.92 (1H, dd, J=13.8, 5.4 Hz), 2.55 (1H, dd, J=13.8, 9.0 Hz), 1.72 (2H, br); 13C NMR (150 MHz, DMSO-d6): δ 174.8, 156.5, 154.3, 151.8, 149.6, 137.9, 131.1, 130.3, 119.6, 114.2, 89.4, 83.6, 79.1, 73.2, 66.7, 61.0, 56.3, 50.0, 49.6, 40.1; MS (ESI, m/z): 527 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[N:32][CH:33]=[C:34]([Br:39])[CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:39][C:34]1[CH:35]=[C:36]2[C:31](=[N:32][CH:33]=1)[N:30]=[C:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1)[CH:38]=[CH:37]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccc3cc(Br)cnc3n2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc3cc(Br)cnc3n2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(6-bromo-[1,8]naphthyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[N:43]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:42][N:41]=[C:40]2[O:51][CH:52]=[CH:53][C:39]=12.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:37][C:38]1[N:43]([C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:10](=[O:12])[CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:48][CH:49]=2)[CH2:42][N:41]=[C:40]2[O:51][CH:52]=[CH:53][C:39]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: COc1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CC(=O)Nc2ccc(N3CN=c4occc4=C3N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The carboxylic acid of choice (3-methoxyphenyl acetic acid, 0.055 mmol) and 0.055 mmol of HBTU were dissolved in 0.5 mL amine-free DMF. To this solution was added dropwise a solution of 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) in 0.5 mL DMF. The resulting solution was treated with 0.024 mL of N,N-diisopropylethylamine. The system was stirred at room temperature overnight and then was concentrated to dryness in a Speedvac system, reconstituted in 1 mL DMSO and purified by prep HPLC to give the title compound. MS(ES) m/e 375 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH2:11]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:12][CH3:13].[Si](C#N)(C)(C)C.[N:29]1([C:34](N2C=CN=C2)=[O:35])C=CN=[CH:30]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:19]([C:18]4[CH:21]=[CH:22][C:15]([O:14][CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]=4)[CH2:30][NH:29][C:34]3=[O:35])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCOc1ccc(C=O)cc1
Agent: C[Si](C)(C)C#N
Product: CCCOc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-propoxybenzaldehyde (0.632 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA 0.558 mL, 4 mmol), di-(imidazol-1-yl)methanone (0.648, 4 mmol) as described in method 2. Yield: 0.135 g (10.0%); MS m/z 337.0 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 0.90-0.93 (m, 3H); 1.61-1.70 (m, 2H); 3.08-3.12 (m, H); 3.81-3.87 (m, 3H); 5.49-5.53 (m, H); 6.85 (d, 2H, J=8.3 Hz); 7.19 (s, H); 7.25 (d, 2H, J=8.7 Hz); 7.55 (dd, H, 3J=9.1 Hz, 4J=2.1 Hz); 7.62 (d, H, J=9.1 Hz); 7.86 (d, H, 4J=2.1 Hz); 9.21 (s, H), HPLC (λ=214 nm, [B]: rt 9.00 min (99%).