Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccccc1Nc1ccccc1N
Yield: 99.3 %

Procedure:
2-isopropyl-N-(2-nitrophenyl)aniline (22.7 g, 89 mmol) and 10% palladium on carbon (0.6 g) were mixed with 150 mL of ethanol under nitrogen in a plastic coated hydrogenation vessel. The mixture was put on a par hydrogenator and reacted under 40 psi of hydrogen until there is no pressure drop. The catalyst was filtered off through a Celite bed. The solvent was evaporated. The product was used for the next step without further purification. 20 g of desired product was obtained.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:35]=[O:36])[N:19](COCC[Si](C)(C)C)[C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:6])=[O:5])([CH3:3])[CH3:2]>C(O)C.O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:35]=[O:36])[NH:19][C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C=O)n(COCC[Si](C)(C)C)c3-c3ccccc3)cc21
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C=O)[nH]c3-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 10 %

Procedure:
Add to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(trimethylsilylethoxymethyl)-2-(formyl)-5-(phenyl)-imidazolyl)-benzimidazole (100 mg, 0.185 mmol) in ethanol (4 mL) HCl (37%, 4 mL) and stir at room temperature for 4 hours. Dilute the mixture with water (20 mL) and wash with EtOAc (3×10 mL). Add to the aqueous phase NaOH (15%) until pH=6-7 and extract the mixture with EtOAc (3×20 mL). Dry (MgSO4) the combined organic layers and concentrate in vacuo. Purify the residue in solid phase extraction (SPE) cartridge (Oasis™) and then by HPLC to obtain a white solid, 8 mg, 10% yield. MS(ES+): m/z=410 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:32])=[CH:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:21][CH2:20][CH:19]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH:18]12.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([N:17]3[CH2:21][CH2:20][CH:19]4[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:24][CH:18]34)[N:5]([CH2:4][CH:3]=[C:2]([CH3:32])[CH3:1])[C:9]=2[CH:10]=1
Reactant: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc(N)cc21
Yield: 95 %

Procedure:
A solution of 49 mg (0.11 mmol) of tert-butyl 1-[1-(3-methylbut-2-enyl)-6-nitro-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate in 7.5 ml of ethanol was added dropwise to a suspension of 62 mg (1.11 mmol) of iron and 11 mg (0.20 mmol) of ammonium chloride in 0.75 ml of water, and the mixture was boiled at reflux for 3 hours. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. The 43 mg of the desired product thus obtained were used in the next stage without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]([OH:10])=[O:9])=O.[N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1.ClCCCl.[BH4-].[Na+]>C(O)(=O)C.C(OCC)(=O)C.CO.CN(C=O)C>[N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][CH2:1][C:3]3[CH:4]=[N:5][NH:6][C:7]=3[C:8]([OH:10])=[O:9])=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cn[nH]c1C(=O)O
Reactant: Nc1ccc2nccnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1[nH]ncc1CNc1ccc2nccnc2c1
Reaction time: 16 h
Yield: 104.6 %

Procedure:
To a suspension of product (4-B) (100 mg, 0.71 mmol) and quinoxalin-6-amine (104 mg, 0.71 mmol) in a solution of 1,2-dichloroethane (DCE, 5 mL) and DMF (5 mL) was added acetic acid (5 drops) at rt. The reaction mixture was then stirred for 16 h. MeOH (5 mL) was added, followed by NaBH4 (100 mg, 2.63 mmol). The reaction mixture was stirred at rt for another 30 min. The solution was diluted with ethyl acetate (30 mL); washed with 5% citric acid (10 mL) and brine (20 mL); dried over Na2SO4; and concentrated to give crude product (5-B) (200 mg, 99%) as a yellow solid. LC-MS (M+H)+=270.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-6-chloro-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (82) and 3-fluorobenzyl bromide according to General Procedure B. Yield 207 mg (37%), MP 186° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.16 (m, 4H), 3.92 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.24 (s, 2H), 7.07 (m, 3H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.30 (m, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H); EIMS: 555 (M+1). Anal. (C27H24ClFN4O4S) C, H, N.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.O1CCOC[CH2:15]1>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
HCl in dioxane (4M, 61.1 mL) was added to a solution of 3-(4-bromophenyl)propanoic acid in methanol (60 mL) at room temperature. The reaction was stirred 18 h and then concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using a 0-50% ethyl acetate-n-heptane gradient to afford 5.1 g of product as a colorless oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[C:8]2[C:6]([OH:7])=[O:5])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(OCC(=O)Cn2c(C(=O)O)cc3ccccc32)cc1
Temperature: 25 °C

Procedure:
0.046 g (0.096 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-2-carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 1.49 g (13.6 mmol) trifluoroacetic acid. Having stirred at room temperature for 1½ hours, concentration to dryness is carried out on the rotary evaporator. Two dissolution steps in toluene and respective concentration on the rotary evaporator leave as a crude product a yellowish solid which is recrystallized from petroleum ether/ethyl acetate (67:33) and yields the product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:8]>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN1CCC[C@H]1C(=O)Nc1cccc(N)c1
Reaction time: 3 h

Procedure:
To a solution of (S)-1-methyl-N-(3-nitrophenyl)pyrrolidine-2-carboxamide (crude from step 1) in MeOH (5 ml) was added Pd/C (50 mg), charged with H2 (1 atm), after stirring for 3 h, Pd/C was filtered off and the filtrate was concentrated to give (S)-N-(3-aminophenyl)-1-methylpyrrolidine-2-carboxamide (350 mg).
Reaction SMILES: ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@H:35](O)[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Br)(Br)(Br)[Br:51]>CCOC(C)=O>[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@@H:35]([Br:51])[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Br
Temperature: -17 °C

Procedure:
Anhydrous dichloromethane (5.6 L) was charged into a reactor and cooled to −22° C. or below. Triphenylphosphine (205.4 g, 0.783 mol) was added to the cold solvent and the suspension was stirred to form a solution. The lactol (2, 209.4 g, 0.559 mol) in solid form was added to the cold solution and stirred for 15 mins. Carbon tetrabromide (278.2 g, 0.839 mol) was added portion-wise while maintaining the temperature of the solution between −22° C. to −20° C. under a flow of nitrogen gas (approx. 30 min). After finishing the addition of CBr4, the temperature was slowly raised to −17° C. over 20 mins. The reaction was judged to be >95% complete by TLC (Rfs 0.61 (α), 0.72 ((β), 0.36 lactol; 20% EtOAc in hexanes). The reaction solution was immediately transferred to a vessel containing 230 g of flash chromatography grade silica gel (40-63 microns). The stirred mixture was immediately passed through a pad of silica gel (680 g) in a 2.5 L sintered glass Buchner funnel. The filtrate was concentrated under reduced pressure to about 800 mL and the ratio of α/β isomers of the crude product was 10:1 as determined by 1H-NMR. (CDCl3) δ=6.35, (s, α C1-H), 6.43, (d, β C1-H). The residue was purified by plug column chromatography using 2.1 kg of silica gel in a 6 L sintered glass Buchner funnel and eluted (via suction) with a stepwise gradient elution of 1%, 5%, 8% 12% EtOAc in hexane (ca 4 L each) to remove non-polar impurities followed by 12%, 25% EtOAc in hexane (6 L total) to elute the product. The product containing fractions were combined into two fractions, concentrated under reduced pressure, dried under vacuum (0.1 mmHg, ambient temp., 20 h) to colorless oils. Main fraction (197 g, 89% α/β=20:1). The alpha isomer crystallized from a small portion of the oil upon standing at 0° C. for several weeks to give large, thin plates, mp 59-61° C. The pure beta isomer crystallized from a mixture of alpha and beta product oil from an earlier less selective run to give needles, mp 77-79° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[C:22](=[O:25])[CH2:23][CH3:24])[CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH2:26][CH3:27])[C:22](=[O:25])[CH2:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:1][C:2]=12)#[N:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCC(=O)N(CC)c1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: CCC(=O)N(CC)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Yield: 81.5 %

Procedure:
A mixture of 0.54 g of 3-amino-4-pyrazolecarbonitrile and 1.37 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylpropanamide in 50 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed through a pad of hydrous magnesium silicate and hexane was added to the refluxing filtrate. The mixture was then cooled and the solid collected, giving 1.3 g of the desired product, mp 161°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH2:29][C:30](=[O:31])[NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:6]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CNC(=O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23]([C:24](N[C@H](C(O)=O)CCC(O)=O)=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.CC1NC(=O)C2C(=CC3CCC(N(C4C=CC(C(O)=O)=CC=4)CC#C)C=3C=2)N=1.[F:66][C:67]1[C:72]([OH:73])=[C:71]([F:74])[C:70]([F:75])=[C:69]([F:76])[C:68]=1[F:77]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23]([C:24]([O:73][C:72]5[C:71]([F:74])=[C:70]([F:75])[C:69]([F:76])=[C:68]([F:77])[C:67]=5[F:66])=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C#CCN(c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Agent: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21

Procedure:
Using an analogous procedure to that described in section (3) of Example 5 p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with pentafluorophenol to give pentafluorophenyl p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoate.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(F)nc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(F)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 75.3 %

Procedure:
6-Fluoro-3-hydroxypyridine (10 mg), 4-chloro-6,7-dimethoxyquinoline (59 mg), and 4-dimethylaminopyridine (32 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 3.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:9]2=[O:13])=[CH:6][CH:7]=1
Reactant: COc1ccc(OCCCOCCCCCBr)cc1
Reactant: O=C1NCCN1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCOCCCCCN2CCN(c3ccc(Cl)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-chlorophenyl)-2-imidazolidinone (0.10 g, 0.53 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 27.3 mg, 0.80 mmol). The mixture was stirred at room temperature for 30 min and then cooled in ice bath. 1-{3-[(5-Bromopentyl)oxy]propoxy}-4-methoxybenzene (0.18 g, 0.53 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. 5 mL saturated aqueous NH4Cl solution and 10 mL dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 6) as a white solid (0.16 g, 68%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][S:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.O>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17][N:18]([CH2:33][CH2:34][S:35][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[CH2:19][CH2:20]1
Reactant: BrCCSc1cccs1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCN(CCSc2cccs2)CC1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 0.46 g of ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate in 10 mL of N,N-dimethylformamide, 0.37 g of potassium carbonate and 0.31 g of 2-((2-bromoethyl)thio)thiophene were added, and the mixture was stirred at 50 to 70° C. for 2 hours 10 minutes. The reaction mixture was cooled to room temperature, then, water and ethyl acetate were added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol 50:1 to obtain 0.39 g of ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 15 h
Yield: 96.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-nitrobenzene (4 g, 18.2 mmol) and tert-butylamine (4.78 mL, 45.5 mmol, 2.5 eq) in EtOH (80 mL) is stirred for 15 h at 85° C., allowed to cool and concentrated. The residue purified by silica gel column chromatography (Hex/EtOAc, 1:0→99:1) to afford 4.8 g of the title compound as an orange solid: ESI-MS: 273.0/275.0 [M+H]+; tR=5.68 min (System 1); TLC: Rf=0.49 (Hex/EtOAc, 9:1).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[CH:50]=[CH:49][C:41]([C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:40][N:39]=1>>[C:45]([NH:44][C:42](=[O:43])[C:41]1[CH:49]=[CH:50][C:38]([C:18]2[CH:17]=[CH:16][C:15]([C@@H:13]([N:9]3[CH2:8][CH2:7][C@:6]([CH2:5][C:2]([C:3]#[N:4])([CH3:36])[CH3:1])([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:11][C:10]3=[O:12])[CH3:14])=[CH:20][CH:19]=2)=[N:39][CH:40]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: CC(C)(C)NC(=O)c1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC(C)(C)C)cn2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 6-bromo-N-tert-butylnicotinamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.323 min, m/z=539.3; 1H NMR (CDCl3) 1.35 (s, 3H), 1.49 (s, 3H), 1.53 (s, 9H), 1.56 (m, 3H), 2.18 (m, 2H), 2.33 (m, 1H), 2.49 (m, 2H), 2.93 (m, 1H), 5.70 (m, 1H), 6.00 (m, 1H), 6.98 (d, 2H), 7.38 (m, 5H), 7.34-7.40 (m, 5H), 7.69-7.74 (m, 3H), 8.13 (m, 1H), 9.00 (s, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH:23](=[C:25]([C:30](OC)=[O:31])[C:26]([O:28][CH3:29])=[O:27])[CH3:24]>CO>[CH3:29][O:28][C:26]([CH:25]1[C:30](=[O:31])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:22])[CH:9]([CH3:11])[CH3:10])=[N:21][CH:23]1[CH3:24])=[O:27]
Reactant: CC=C(C(=O)OC)C(=O)OC
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)N(Cc2ccccc2)C(C(NC(=O)OC(C)(C)C)C(C)C)=NC1C
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (7.08 g, 23 mMol) in MeOH (15 mL) was added Dimethyl ethylidenemalonate (3.64 g, 23 mMol). The reaction was slowly heated to 110° C. allowing the MeOH to distill off. The reaction was stirred for 5 h at 110° C. then allowed to cool to RT. Purification by flash chromatography (25% EtOAc, hexane) gave the title compound (6.37 g, 64%) as an oil: ˜(3:1) mixture of diastereomers by LCMS; MS (ES) m/e 432.2 and 432.4 (M+H)+.