Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[S:14][CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[CH:19]=[N:18][CH:17]=1.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([S:14][CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH3:23])[CH:19]=[N:18][CH:17]=3)=[N:4][C:5]=2[CH:10]=1
Reactant: CCCn1cncc1CSc1nc2cc([N+](=O)[O-])ccc2n1C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1cncc1CSc1nc2cc(N)ccc2n1C
Yield: 19.3 %

Procedure:
An aqueous solution of 1-methyl-5-nitro-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazole (700 mg), reduced iron (0.6 g) and anhydrous calcium chloride (1.18 g) in 85% ethanol (15 ml) was stirred for 1 day under nitrogen atmosphere at 105° C. The mixture was allowed to be at room temperature, the insolubles were filtered off, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (methanol:ethyl acetate=1:8) to give 5-amino-1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazole (123 mg) as brown oil.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[C:16]([O:19][CH2:20][CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH2:23]1)(=[O:18])[CH3:17]>CN(C)C=O>[Si:8]([N:25]1[CH:22]([CH2:21][CH2:20][O:19][C:16](=[O:18])[CH3:17])[CH2:23][C:24]1=[O:26])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(=O)OCCC1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
Triethylamine (Et3N) (2.96 ml, 21.2 mmol) and t-butyldimethylsilyl chloride (3.059 g, 20.3 mmol) are added to an ice-cold stirring solution of 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g, 19.3 mmol) in anhydrous dimethylformamide (DMF) (20 ml). A white precipitate appears immediately. The cooling bath is removed and the mixture is stirred at 25° C. (room temperature) for 5 mins. The mixture is diluted with benzene (200 ml), washed with H2O (5×80 ml) and brine, dired with MgSO4, filtered, and evaporated under reduced presure to afford N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (5.078 g) as an off white solid: ir(neat) 5.75, 8.08, 8.41, 11.92, and 12.18 cm-1 ; nmr (CDCl3) δ 0.25 (s, 6), 0.98 (s, 9), 1.97 (m, 2), 2.05 (s, 3), 2.67 (dd, 1), 3.20 (dd, 1) 3.62 (m, 1), and 4.12 (t,2); mass spectrum m/e 214 (M+ -57) and 172.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:17]=[C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:19][CH:20]=3)[C:13]([C:29](N(OC)C)=[O:30])=[N:12]2)=[CH:8][CH:7]=1>C1COCC1.CCOC(C)=O.Cl>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[N:17]=[C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[S:19][CH:20]=3)[C:13]([C:29](=[O:30])[CH3:1])=[N:12]2)=[CH:35][CH:36]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(=O)N(C)OC)n2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(-c3csc(Oc4cccc(C)n4)n3)c(C(C)=O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
According to Scheme 5, Step 5: Methylmagnesium bromide 3 M (148 μmol, 49 μL) was added dropwise at room temperature to a solution of 1-(4-methoxybenzyl)-N-methoxy-N-methyl-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazole-3-carboxamide (99 μmol, 46 mg) in THF (0.5 mL) and the reaction mixture was stirred for 1 hour at room temperature. The reaction was diluted with EtOAc and with an aqueous solution of HCl 1M. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4, was filtered and was concentrated to yield 1-(1-(4-methoxybenzyl)-4-(2-(6-methylpyridin-2-yloxy)thiazol-4-yl)-1H-pyrazol-3-yl)ethanone (0.10 mmol, 42 mg, 100%) as a beige solid. The mixture was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[CH:28][C:29]([F:38])=[C:30]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:30]1[CH:31]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:27]=[CH:28][C:29]=1[F:38])(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)ccc1F

Procedure:
Example 107 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.30–8.13 (m, 1H), 8.09–7.95 (br, 1H), 7.47–7.26 (m, 3H), 7.08–6.87 (m, 3H), 6.75–6.54 (br, 1H), 3.30–3.07 (m, 4H), 2.59–2.44 (m, 3H), 2.44–2.33 (m, 2H), 2.33–2.19 (m, 2H), 1.99–1.69 (m, 16H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][SiH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].C([Br:26])C=C>Cl[Pd]Cl>[F:22][C:2]([F:1])([C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[CH2:3][CH2:4][Si:5]([Br:26])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)[SiH](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Reactant: C=CCBr
Agent: Cl[Pd]Cl
Product: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Temperature: 60 °C

Procedure:
In an oven-dried round-bottom flask equipped with a stir bar and cooled under N2, 3,3,4,4,5,5,6,6,6-nonafluorohexyldiisopropylsilane (10.1 g, 27.8 mmol) was dissolved in allyl bromide (20 mL), and PdCl2 (50 mg) was added. The solution was heated to 60° C. for 15 hr, then cooled, and concentrated via rotary evaporation. The resulting suspension was dissolved in pentane, filtered to remove residual catalyst, and then solvent was removed to yield (3,3,4,4,5,5,6,6,6-nonafluorohexyldiisopropylsilyl)bromide (12.1 g) as a pale brown liquid. The bromide was treated under anhydrous conditions with 1.2 eq. (based on initial silane) of ethynylmagnesium bromide and heated to 40° C. for 6 hr. The reaction was quenched with water and dilute sulfuric acid, pentane was added, and the organic layer was separated. The organic layer was washed with water (6×50 mL), dried over MgSO4, filtered, and concentrated via rotary evaporation. Further purification via flash chromatography using hexane yielded pure (3,3,4,4,5,5,6,6,6-nonafluorohexyldiisopropylsilyl)acetylene (9.90 g, 25.6 mmol, 92%) as a colorless liquid. Analysis of the product provided the following data: 1H-NMR (200 MHz, CDCl3) δ=2.4 (s, 1H), 2.2 (m, 2H), 1.1 (m, 14H), 0.8 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:17](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:18]>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([N:14]=[C:17]=[S:18])[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(-c2cccnc2F)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ncccc1-c1cc(N=C=S)ncn1
Reaction time: 1.5 h
Yield: 36.3 %

Procedure:
To a solution of 6-(2-fluoropyridin-3-yl)pyrimidin-4-amine (0.3 g, 1.577 mmol) in DMF was added NaH (0.126 g, 3.15 mmol). Stirring was continued for 1.5 h and 1,1′-thiocarbonyldipyridin-2(1H)-one (0.366 g, 1.577 mmol) was added. The mixture was stirred at rt for 2 h and purified on silica gel using 10-15% ethyl acetate in hexanes to give an orange solid (0.133 g, 0.573 mmol, 36%). MS (LC/MS) R.T.=2.48; [M+H]+=233.08.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:6][C:7]1[N:8]=[N:9][C:10]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccnc2)nn1
Temperature: 75 °C
Yield: 83.1 %

Procedure:
A mixture of imidazole (0.613 g, 8 mmol) and 3,6-dichloropyridazine (1.55 g, 10 mmol), K2CO3 (4.15 g) and DMF (15 mL) was heated at 70-80° C. overnight. After removal of DMF in vacuo, the residual solid was dissolved in CH2Cl2 (50 mL), washed with 1N Na2CO3 aq. solution, and dried (MgSO4). Separation using column chromatography (CH2Cl2/methanol 100:1) afforded 3-chloro-6-(imidazol-1-yl)pyridazine (1.2 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCO)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.7 %

Procedure:
Triethylamine (18.9 g, 136 mmol) was added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25 g, 113 mmol) in N,N-dimethylformamide (100 mL). 4-Aminobutan-1-ol (11.1 g, 124. mmol) was added with a syringe and the reaction mixture was allowed to stir under a nitrogen atmosphere at ambient temperature for 17 hours. A portion (85 mL) of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with water (2×50 mL) then with brine (75 mL), dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a solid. This material was recrystallized from ethyl acetate/hexanes to provide 15.07 g of 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butan-1-ol as yellow powder. An additional 5.70 g was isolated from the mother liquor.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:6]=[CH:7][C:8]1[C:14]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:13]=2[CH2:12][C:11]([CH3:22])=[N:10][N:9]=1.ClCCl.[B-][N+](C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:6]=[CH:7][C:8]1[C:14]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:13]=2[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=1
Reactant: COc1ccc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1OC
Agent: O=C([O-])[O-]
Agent: [B-][N+](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C=CC2=NNC(C)Cc3cc4c(cc32)OCO4)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of 2.04 g (5.6 mmoles) 1-(3,4-dimethoxystyryl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 40 ml of anhydrous dichloromethane 1.0 ml (8.4 mmoles) of borotrifluoride etherate is added under cooling with tap water, and 0.45 g (6.16 mmoles) of borane trimethylamine complex is added to it. The reaction mixture is stirred at 25° C. for 0.5 hour, and then 30 ml of 10% aqueous sodium carbonate solution are dropped to it under cooling with tap water, and the mixture is stirred further for 1 hour. The organic phase is separated, washed four times with 30 ml each of distilled water, dried and evaporated. The crystalline residue is suspended in 10 ml of ethanol, filtered, washed three times with 1 ml each of ethanol and dried at a temperature between 80° C. and 100° C. Thus 1.76 g of the desired product is obtained. M.p.: 166-168° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH:15]2[CH2:18][NH:17][CH2:16]2)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:17]2[CH2:18][CH:15]([O:14][C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:20][CH:19]=3)[CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Brc1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Fc1ccc(OC2CN(c3cccc(Br)c3)C2)cc1
Temperature: 100 °C
Yield: 29.1 %

Procedure:
To a solution of 1, 3-dibromobenzene (500 mg, 2.13 mmol) and 3-(4-fluorophenoxy)azetidine (357 mg, 2.13 mmol) in toluene (7 mL, 3 mmol) was added cesium carbonate (600 mg, 5.3 mmol) and degassed for 15 min. Pd2(dba)3 (97 mg, 0.106 mmol) and BINAP (66 mg, 0.106 mmol) were added and the mixture was heated in the microwave for 30 min at 100° C. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 1-(3-bromophenyl)-3-(4-fluorophenoxy)azetidine (200 mg, 30%) as a solid. Observed mass (M+1): 322.1.
Reaction SMILES: Cl.[C:2](=[N:5][OH:6])([NH2:4])[CH3:3].[H-].[Na+].[I:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=O)=[CH:12][CH:11]=1>O1CCCC1>[CH3:3][C:2]1[N:4]=[C:14]([C:13]2[CH:19]=[CH:20][C:10]([I:9])=[CH:11][CH:12]=2)[O:6][N:5]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(I)cc2)n1
Temperature: 65 °C
Yield: 29 %

Procedure:
Acetamidoxime hydrochloride (1.5 g) was added portionwise to an ice-cooled suspension of sodium hydride (1.18 g of a 60% dispersion in oil) in dry tetrahydrofuran (40 ml) under an atmosphere of argon. Molecular sieves (type 4A, 8-12 mesh) were added to the reaction mixture, followed by a solution of ethyl 4-iodobenzoate (3.73 g) in tetrahydrofuran (10 ml). The reaction mixture was heated at 65° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using a 70:30 (v/v) mixture of ethyl acetate/hexane as eluent to give 3-methyl-5-(4-iodophenyl)-1,2,4-oxadiazole (1.12 g) as a solid, m.p. 136°-137° C.; microanalysis, found: C, 38.2; H, 2.5; N, 9.5%; C9H7IN2O requires: C, 37.8; H, 2.47; N, 9.79%; NMR: 2.41(3H,s), 7.84(2H,d), 8.02(2H,d); m/z 287(M+H).
Reaction SMILES: [CH3:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([O:24][C:25](=[O:29])[CH:26](Br)[CH3:27])[CH3:23].CC#N>CC(C)=O.O>[CH2:22]([O:24][C:25](=[O:29])[CH:26]([N:6]1[C:5]2[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C)N1C(=O)COc2cc(C)c([N+](=O)[O-])cc21
Temperature: 70 °C
Yield: 112.6 %

Procedure:
To 7-methyl-6-nitro-4H-benzo[1,4]oxazin-3-one (50% purity; 0.870 g, 1.44 mmol) and K2CO3 (1.15 g, 8.36 mmol) in acetone (20 mL) was added 2-bromo-propionic acid ethyl ester (1.5 g, 8.36 mmol) and the mixture was heated at 70° C. for 5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo and the residue was dissolved in DCM (15 mL). The solution was washed with water (15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give a mixture of the title compound as a yellow solid (total 0.5 g crude, 48% desired product as indicated by HPLC at 254 or 220 nm), HPLC (Column: Ultimate XB-C18, 3 um, 50×3.0 mm; Mobile phase: MeCN (0.02% TFA) in water (0.04% TFA), from 30% to 90% within 7 min; Flow rate: 1.5 mL/min; Wavelength: 220 nm) Rt=3.42 min.), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.C(N(S(F)(F)F)CC)C.[C:32]([O:51][CH2:52][C@H:53]([CH2:74][O:75][P:76]([O:79][CH2:80][CH2:81][NH2:82])([OH:78])=[O:77])[O:54][C:55](=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(OCC)C>[C:32]([O:51][CH2:52][C@@H:53]([O:54][C:55](=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:74][O:75][P:76]([O:79][CH2:80][CH2:81][NH:82][C:18](=[O:20])/[CH:17]=[C:16](\[CH3:21])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])([OH:78])=[O:77])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN)OC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: CCN(CC)S(F)(F)F
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCNC(=O)/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of retinoic acid (250 mg, 0.83 mmol) in diethyl ether stirring (20 mL) at −78° C., a solution of (diethylamino)sulfur trifluoride (130 μl, 0.90 mmol) in cold ether (20 mL) was added through a syringe. The reaction mixture was taken out of the cold bath and the stirring was continued at room temperature for an additional 2 hr. At the end, the solvent was removed by rotary evaporation. The residue was redissolved chloroform (50 mL) in the presence of solid Na2CO3 (50 mg). To this solution was added 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (600 mg, 0.81 mmol) and the reaction mixture was stirred at room temperature for an additional 24 hrs. The solvent was removed by rotary evaporation. The residue was purified by silica gel chromatography with a dichloromethane/methanol gradient to yield Z)-(2R)-3-(((2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl dioleate (240 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 0.87 (t, 6H, CH3), 1.01 (s, 6H, CH3) 1.20-1.40 (m, 40H, CH2), 1.40-1.60 (m, 8H, CH2), 1.70 (s, 3H, CH3—C═C), 1.80-2.10 (m, 8H), 2.32 (m, 4H, CH2C(═O)), 3.50 (m, 2H), 3.92-4.18 (m, 5H), 4.35 (m, 2H), 5.20 (m, 1H, NHC(═O)), 5.31 (m, 4H, CH═CH), 5.80-6.90 (m, 6H, CH═CH).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:24])=O.C1C=CC=CC=1>C(Cl)Cl>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([Cl:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
o-Phenylbenzoic acid (163 mg) was dissolved in 5 ml of methylene chloride, a catalytically effective amount of N,N-dimethylformamide was added dropwise, and 0.165 ml of oxalyl chloride was added dropwise. After 3 hours of stirring at room temperature, benzene was added and the solvent was evaporated to obtain o-phenylbenzoic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)Nc1ccc(C#N)cc1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 15.3 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), 4-aminobenzonitrile (7.68 mg, 0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (2 mg, 15.1%). 1H NMR (400 MHz, CD3OD) δ 0.90-1.03 (m, 3 H) 1.07-1.15 (m, 3 H) 2.59 (dt, J=11.24, 6.63 Hz, 1 H) 5.01 (d, J=19.45 Hz, 1 H) 5.21 (d, J=11.12 Hz, 1 H) 5.42 (d, J=19.45 Hz, 1 H) 7.64-7.66 (m, 1 H) 7.66-7.68 (m, 1 H) 7.80-7.82 (m, 1 H) 7.82-7.84 (m, 1 H) 7.86 (s, 1 H) 8.25 (s, 1 H). [M+H] calc'd for C21H18ClN5O2, 408; found, 408.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15])[CH2:8][NH:9][C:10]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2)=[O:11]
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1
Temperature: 25 °C

Procedure:
The product from Example 192A (4.4 mmol) in toluene (10 mL) was treated with 5-amino-3-methylisoquinoline (460 mg, 2.9 mmol) and DIEA (3 mL). The mixture was heated at 80° for 1.5 hours, cooled to room temperature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.77 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.70-7.81 (m, 3H), 7.38-7.53 (m, 3H), 7.19 (t, 1H, 6.1 Hz), 4.47 (d, 2H, J=5.8 Hz), 2.65 (s, 3H); MS (ESI+) m/z 378 (M+H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([C:21]([N+:24]([O-])=O)=[CH:22][CH:23]=2)[CH:15]=[CH:16][C:17](OC)=[O:18])[CH2:8][CH2:7]1)=[O:4].[H][H]>C(O)C.[C].[Pd]>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:21](=[CH:22][CH:23]=2)[NH:24][C:17](=[O:18])[CH2:16][CH2:15]3)[CH2:8][CH2:7]1)=[O:4]
Reactant: CCC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C=CC(=O)OC)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)NC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
1.25 Grams of methyl 3-[4-(N-methylacetylamino)-1-piperidyl]-6--nitrocinnamate was dissolved in 50 ml of ethanol, then 0.4 g of 10%-palladium carbon was added thereto, the reaction mixture was stirred until the absorption of hydrogen gas was stopped under conditions of at room temperature and normal pressure. The catalyst was removed by filtration, the filtrate was concentrated by evaporating the solvent, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane: methanol=50:1), then recrystallized from methanol-diethyl ether to yield 0.82 g of 6-[4-(N-methylacetylamino)-1-piperidyl]-3,4-dihydrocarbostyril. Light yellow needle-like crystals. Melting point: 195°-197° C.