Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:35].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:25][C:24]([S:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:16](=[O:36])[CH2:17]3)(=[O:23])=[O:22])=[CH:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(-c4ccc(Cl)cc4)s3)CC2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-2-piperazinone (115 mg) were added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give crude crystals of 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride. A mixture of the obtained 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride and chloropyridine hydrochloride (85 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1 N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane: methanol containing 10% ammonia solution 10:1) to give colorless solid of the title compound (42 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][N:24]=[C:25]=[O:26]>>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:12][N:13]([C:25](=[O:26])[NH:24][CH2:23][C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[Cl:15])[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC12CNC2
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCc1ccc(Cl)cc1Cl)C2

Procedure:
In analogy to the experimental procedure of example 8) 1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of 1-benzyl-1,6-diaza-spiro[3.3]heptane was converted using 2,4-dichloro-1-isocyanatomethyl-benzene instead of (3-isocyanato-propyl)-benzene into the title compound which was used directly in the next step without further purification.
Reaction SMILES: [Cl-].C([NH+](CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[NH:22][N:11]=[N:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(F)cc1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Cc2nnn[nH]2)cc1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A mixture of triethylammonium chloride (4.14 g, 30 mmol) and sodium azide (1.95 g, 30 mmol) was treated with a solution of (4-fluorophenyl)acetonitrile (1.35 g, 10 mmol) in toluene (14 ml) and the mixture was stirred and heated at 100° C. for 5 h. The cooled mixture was treated with water (10 ml) and the mixture separated. The aqueous phase was stirred and treated dropwise with concentrated hydrochloric acid until the product had precipitated from solution. The precipitated product was filtered off, washed with water and dried to yield the title compound as a white solid (1.27 g, 72%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH2:10]>CO>[N:1]1([CH:2]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:3][CH2:4][C:5]([OH:10])=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O
Solvent: CO
Product: O=C(O)CCC(n1ccc2ccccc21)n1ccc2ccccc21
Temperature: 35 °C
Reaction time: 24 h

Procedure:
282 mg of indole (2.4 mmol) were dissolved in 10 ml of CH3OH and 5 ml of H2O; 102 mg of semisuccinic aldehyde (1 mmol) and 240 mg of dysprosium triflate-(CF3SO3)3Dy-(0.393 mmol) were added. The resulting solution was stirred at 35° C. for 24 hours. At the end of that period the methanol was removed under vacuum and the residue was extracted with ethyl acetate (3×50 ml). The organic extracts were pooled, washed with a small amount of water, dried on anhydrous Na2SO4, filtered and concentrated to dryness. The end product was isolated and purified chromatographically on an SiO2 column, using a hexane:isopropyl alcohol gradient ranging from 9:1 to 8:2.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C>C(O)(=O)C>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:12]2([C:1]#[N:2])[CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: Cc1ccc(N)cc1
Reactant: O=C1CCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(NC2(C#N)CCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
Sodium cyanide (0.147 g, 3 mmol) was added to a mixture of p-toluidine (0.214 g, 2 mmol) and cyclobutanone (0.21 g, 3 mmol) in 90% acetic acid (3 ml). The reaction mixture was stirred at room temperature for 12 h and then 20 ml of ethyl acetate was added. The organic layer was washed with water (3×10 ml), dried over magnesium sulfate and concentrated under vacuum to dryness to yield 1-(4-methylphenyl)aminocyclobutanenitrile, 7a (0.343 g, 1.84 mmol, 92%) as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+].CCOCC>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCCCc1ncccn1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCOCCCCc1ncccn1
Reaction time: 20 h

Procedure:
A mixture of 2-pyrimidinebutanol (1.31 g), 1,6-dibromohexane (5 ml), 50% aqueous sodium hydroxide solution (5 ml) and TAB (140 mg) was vigorously stirred under nitrogen at 23° for 20 h. Ether (25 ml) and water (20 ml) were added, the organic phase separated, washed with brine (20 ml), dried and evaporated in vacuo. The residue was purified by FCC. Elution with hexane and hexane-ether (9:1) followed by ether afforded the title compound as a colourless oil (1.67 g)
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=C[C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[C:31](=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:31][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cccnc3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 3-pyridinylboronic acid (71 mg, 0.577 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(pyridin-3-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.68 (d, 1H), 8.1 (d, 1H), 7.9 (m, 1H), 7.8 (m, 1H), 7.3 (s, 1H), 6.9-7.1 (m, 2H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 2.8-3.3 (m, 9H), 2.22-2.4 (m, 5H).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[N:7]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:17]1([C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]([CH2:5][C:1]#[N:2])[N:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1nc(-c2ccccc2)oc1-c1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(-c2ccccc2)oc1-c1ccccc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
To a suspension of potassium cyanide (67.1 mg, 0.999 mmol) in DMSO (2 mL) was added dropwise at RT a solution of 4-(chloromethyl)-2,5-diphenyloxazole (245 mg, 908 μmol) in DMSO (3 mL) over a period of 5 min. The reaction mixture was stirred at RT for 2 h and at 45° C. for another 3 h. The reaction mixture was cooled to RT, poured into water (25 mL) and extracted with ethyl acetate (2×75 mL). The organic phases were washed with water (2×20 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 245 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (189 mg, 726 μmol, 79.9%).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH3:29]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.[CH3:61][O:62][C:63](=[O:66])[CH2:64][NH2:65]>C1COCC1.CN(C=O)C>[OH:2][C:3]1[CH:20]=[C:19]([C:21]([NH:65][CH2:64][C:63]([O:62][CH3:61])=[O:66])=[O:23])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:29])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:27])([CH3:28])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)CN
Reactant: COc1cc(C(=O)O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cc(O)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.7 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methylmorpholine (0.20 mL, 3.0 mmol) and glycine methyl ester hydrochloride (0.18 g, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give methyl 2-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]formamido}acetate (92) (0.10 g, 42%) as a white solid. 1H NMR (CDCl3): δ 8.16 (s, 1H), 7.81 (d, 1H), 7.71 (d, 1H), 7.18 (m, 1H), 4.24 (m, 2H), 3.32 (m, 3H), 2.30 (d, 1H), 1.76-1.00 (m, 16H), 0.97 (s, 3H), 0.88 (s, 3H), 0.84 (s, 3H). MS m/z 478 (C25H35NO6S+H+).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[F:10][C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14]I.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:11]([F:17])([F:16])[CH2:12][CH2:13][CH2:14][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: FC(F)(F)CCCI
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)C1CCN(CCCC(F)(F)F)CC1
Yield: 106.8 %

Procedure:
Prepared from isonipecotamide (0.422 g, 3.3 mmol), 4,4,4-trifluorobutyliodide (0.82 g, 3.4 mmol) and potassium carbonate (0.47 g, 3.4 mmol) according to the procedure used for Example 8 (Step A) to give 0.84 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1)[CH3:2].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+]([O-])=O.[N+:20](C1C=CC=CC=1)([O-:22])=[O:21]>C(Cl)Cl.[Cu]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(I)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cu]
Solvent: ClCCl
Product: CCc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
Copper lining powder (75g) was added portionwise over 30 minutes to a stirred mixture of 1-ethyl-4-iodobenzene (34.8g, 0.15 mole) and 2-bromo-1-nitrobenzene (30.3g, 0.15 mole) in nitrobenzene (250 ml) at 160°. After stirring for a further 3 hours at 160° C the solution was cooled, diluted with methylene chloride and filtered. Methylene chloride was distilled, nitrobenzene was steam-distilled, and the product was isolated in ether, and distilled to give 4-ethyl-2-nitrobiphenyl, b.p. 120°-130° C/0.1mm.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)nccc23)c1F
Yield: 12.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-6, 70 mg, 0.23 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 129 mg, 0.45 mmol), oxalyl chloride (85 mg, 0.68 mmol), DMF (1 drop) and DIPEA (89 mg, 0.69 mmol) in CH2Cl2 (3 mL) to afford 17 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.21 (br t, 1H), 8.10-8.01 (m, 2H), 7.81-7.67 (m, 6H), 7.47-7.36 (m, 2H), 4.34 (m, 2H), 1.15 (s, 9H); MS [M+H]+: 574.09.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]([C:24]5[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=5)[CH2:22][CH2:21][CH:20]4[C:31]4[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:38][O:39][C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.CO>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([CH:23]2[N:19]([C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[N:12][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][CH:9]=4)=[CH:18][CH:17]=3)[CH:20]([C:31]3[CH:32]=[CH:33][C:34]([NH:35][C:44](=[O:45])[C@@H:43]([NH:42][C:40](=[O:41])[O:39][CH3:38])[CH:47]([CH3:49])[CH3:48])=[CH:36][CH:37]=3)[CH2:21][CH2:22]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(C2CCC(c3ccc(N)cc3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)Nc1ccc(C2CCC(c3ccc(N)cc3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of Example 108B (70 mg, 0.142 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (26.2 mg, 0.150 mmol) in anhydrous DMSO (1.5 mL), added HATU (58.6 mg, 0.150 mmol) and diisopropylethylamine (0.050 mL, 0.285 mmol), and stirred dark yellow solution at 25° C. for 15 min. Diluted the reaction with MeOH (1.5 mL) and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova Pak HR C18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H2O/AcCN to 25:75 0.1% TFA in H2O/AcCN, then 10 min to 100% AcCN at 20 mL/min. Pure fractions were concentrated by rotary evaporation (water bath 35°) to a small volume, partitioned between 20% iPrOH/CHCl3 (50 mL), and sat'd aq NaHCO3 (15 mL), separated layers, dried organic extract over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to afford the title compound as a light yellow solid (48 mg, 52%). 1H NMR showed the material to be ˜3:1 trans:cis mixture; MS (ESI+) m/z 649 (M+H)+, 1297 (2M+H)+.
Reaction SMILES: [CH:1]([OH:40])([CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:39])([F:38])[F:37])([F:35])[F:34])([F:32])[F:31])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23])[CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4].[C:41]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH:1]([O:40][C:41]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:47])([CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4])[CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:37])([F:39])[F:38])([F:34])[F:35])([F:31])[F:32])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23]
Reactant: CN(CC(O)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CN(CC(CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OC(=O)CCC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A 250 mL three necked round bottom was charged with [C4F9SO2N(CH3)CH2]2CHOH (6.8 g; 10 mmole), succinic anhydride 1.0 g; 10 mmole) 4-dimethylaminopyridine (0.1 g) and toluene (100 mL). The ensuing mixture was stirred at 100° C. overnight, the toluene removed using a rotary evaporator, leaving a white solid residue that was triturated with toluene-hexane to yield [C4F9SO2N(CH3)CH2]2CHOC(O)C2H4COOH (5.2 g)
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O.O=[As](O[As](=O)=O)=O.S(=O)(=O)(O)O>O.N>[Br:1][C:2]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[C:5]2[C:3]=1[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: Cc1cc(N)c(Br)c(C)c1C
Reactant: OCC(O)CO
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Solvent: O
Product: Cc1c(C)c(Br)c2ncccc2c1C
Temperature: 100 °C

Procedure:
2-Bromo-3,4,5-trimethylaniline (10.4 g), glycerol (4 equiv) and arsenic oxide (0.75 equiv) were stirred and heated to 100° C. Concentrated sulfuric acid (60% w/w of the glycerol) was added to the mixture dropwise. After heating at 130° C. for 4 hr, the cooled mixture was diluted with water and neutralised with aqueous ammonia. The solid was filtered off, washed with water and dried in air. Purification by column chromatography over alumina with dichloromethane elution gave 8-bromo-5,6,7-trimethylquinoline as a white solid, mp 180° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.50 (3H,s); 2.61 (3H,s); 2.74 (3H,s); 7.37-8.98 (3H,m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.O>C1COCC1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: BrCC1CC1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1cc(Br)ccc1OCC1CC1
Temperature: 70 °C
Reaction time: 40 h
Yield: 82.8 %

Procedure:
To 5-bromo-2-hydroxybenzaldehyde (1.00 g, 4.97 mmol, 1.00 equiv) and K2CO3 (3.44 g, 24.9 mmol, 5.00 equiv) in THF (10 mL) in an oven-dried round-bottom flask fitted with a reflux condenser under a N2 atmosphere at 23 ° C. was added (bromomethyl)cyclopropane (1.01 g, 0.724 mL, 7.46 mmol, 1.50 equiv). The reaction mixture was warmed in an oil heating bath at a temperature of 70 ° C. and heated at reflux with vigorous stirring for 40 hours. The reaction mixture was cooled to 23 ° C. and poured into H2O (30 mL) in a separatory funnel. CHCl3 (30 mL) was added, the funnel was shaken and the organic phase collected. The aqueous phase was then extracted with CHCl3 (2×30 mL). The combined organic phases were washed with brine (30 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 2-7% EtOAc in hexanes (v/v) to afford 1.05 g of the title compound as a colorless solid (83% yield). Rf=0.30 (hexanes/EtOAc 19:1 (v/v)). NMR Spectroscopy: 1H NMR (600 MHz, CDCl3, 23 ° C., δ): 10.45 (s, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.58 (dd, J=8.9, 2.6 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 3.91 (d, J=7.2 Hz, 2H), 1.32-1.26 (m, 1H), 0.71-0.63 (m, 2H), 0.41-0.34 (m, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 188.7, 160.5, 138.3, 130.9, 126.5, 115.0, 113.5, 73.9, 10.1, 3.4. HRMS-FIA (m/z): calcd for C11H11BrNaO2[M+Na]+, 276.9840; found, 276.9820.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-])=O.[CH2:19](N)[CH2:20][CH2:21][CH3:22].O.[N+:25](C1C=C(C=CC=1NCCCC)C(C1C=CC=CC=1)=O)([O-:27])=[O:26]>C1(C)C=CC=CC=1>[N+:25]([N:16]([CH2:19][CH2:20][CH2:21][CH3:22])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:2]=1)[C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([O-:27])=[O:26]
Reactant: CCCCN
Reactant: CCCCNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN(c1cccc(C(=O)c2ccccc2)c1)[N+](=O)[O-]
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-3-nitrobenzophenone (13.08 g.; 0.05 mole) and n-butylamine (10.97 g.; 0.15 mole) are refluxed and stirred for 4 hours. To the reaction mixture is added water (300 ml.) and toluene (200 ml.) and the toluene layer collected and dried over magnesium sulfate. The toluene solution is filtered and the toluene removed under vacuum to afford 11.4 g. of 3-nitro-4-n-butylaminobenzophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:18])[CH2:13][O:14][CH2:15][CH2:16]Cl)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C:12]2=[O:18])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1cc(NC(=O)COCCCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Nc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
22.2 5.2 g (0.016 mol) of N-(3-amino-4-nitrophenyl)-2-(2-chloroethoxy)acetamide are suspended in 250 ml of acetonitrile, and 6.6 g (0.02 mol) of caesium carbonate are added. The mixture is stirred at room temperature for 18 h. The batch is poured into about 250 ml of water and extracted 3× with 200 ml of ethyl acetate each time. The entire organic phases are dried using anhydrous sodium sulfate, filtered, and the solvent is stripped off in a Rotavapor to a residual volume of about 150 ml. The crystals deposited during evaporation in the rotary evaporator are separated off and dried, giving 4-(3-amino-4-nitrophenyl)morpholin-3-one, HPLC-MS [M+H]+ 238.1.