Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-isohexyl-6-methylpiperidine (1.4 g, 5.50 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 70 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-isohexenyl-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 164.2-167.0° C.; 1H NMR (250 MHz) δ 9.44 (s, 2H), 5.71 (s, 2H), 4.18 (s, 1H), 3.56 (s, 1H), 2.0-1.5 (m, 12H), 0.94 (dd, 6H); 13C NMR (62.7 MHz) δ 135.7 (s), 123.6 (s), 48.4 (s), 47.9 (s), 36.9 (s), 28.9 (s), 28.4 (s), 28.2 (s), 22.5 (s), 22.1 (s), 17.6 (s), 17.2 (s) ppm. FT-IR (neat): 3429, 3165, 2940, 1620, 1550, 1478, 1400, 1354, 1097, 890. Elemental Analysis for C2H24NCl: C, 66.17%; H, 11.13%; N, 6.43%. Found: C, 66.25%; H, 11.05%; N, 6.50%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([O:22]CC2C=CC=CC=2)=[N:13][C:12]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].C(Cl)Cl>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14](=[O:22])[NH:13][C:12]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCOc1c(-c2ccc(Cl)c(Cl)c2)nc(OCc2ccccc2)c2cc(F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(=O)c2cc(F)ccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
{2-[1-Benzyloxy-3-(3,4-dichloro-phenyl)-7-fluoro-isoquinolin-4-yloxy]-ethyl}-carbamic acid tert-butyl ester (85 mg, 0.15 mmol) was treated with trifluoroacetic acid/DCM=1:10 (4.5 mL) and stirred for 8 hs at RT. The reaction mixture was then concentrated under reduced pressure. The resulting crude was taken up with diethyl ether and filtered, thus affording 55 mg of the title compound (76% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[O:22]=[C:23]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH2:24][CH2:25][C:26](O)=[O:27].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:26](=[O:27])[CH2:25][CH2:24][C:23](=[O:22])[C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)CCC(=O)c1cccs1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCC(=O)c1cccs1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 55.8 %

Procedure:
(S)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl amine (0.200 gm, 0.00068 moles) was taken up in 1:1 THF-water mixture (20 ml). To this was added 4-oxo-4 (2-thienyl)butanoic acid (0.125 gm, 0.00068 moles) and HOBt (0.091 gm, 0.00068 moles). The resulting mixture was cooled to 0° C. and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.142 gm, 0.00074 moles) was added and the resulting mixture was allowed to warm to room temp and then stirred for 24 hr. The reaction mixture was concentrated, 15 ml of saturated sodium bicarbonate was added, stirred for 15 min and then extracted with ethyl acetate. The ethyl acetate layer was separated and the solvent evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20 gm). The column was eluted with mixture of ethyl acetate:hexane, and finally with ethyl acetate. The combined fractions were concentrated to give the title compound (0.175 gm, 56%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.N12CCN(CC1)CC2>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][C:23]3[NH:1][C:2]4[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=4[C:22]=3[CH2:21]2)=[CH:18][CH:19]=1
Reactant: O=C1CCN(c2ccc(F)cc2)CC1
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Temperature: 110 °C
Reaction time: 3.5 h
Yield: 39.4 %

Procedure:
A solution of methyl 4-amino-3-iodobenzoate (0.5 g, 1.8 mmol), 1-(4-fluorophenyl)piperidin-4-one (1.05 g, 5.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.61 g, 5.4 mmol) and palladium (II) acetate (20 mg, 0.09 mmol) in DMF (10.0 mL) was degassed, filled with argon (3×) and allowed to stir at 110° C. for 3.5 h. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (40 mL) and water (40 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), filtered and concentrated. Column chromatography (25% EtOAc/hexane) provided, upon trituration with ethyl ether, methyl 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (23 in Scheme 1(k)) as a yellow solid (0.23 g, 39%). 1H NMR (CDCl3, 300 MHZ) 8.17 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 3H), 7.09 (t, J=8.1 Hz, 2H), 4.53 (s, 2H), 3.96 (s, 3H), 3.73 (t, J=5.6 Hz, 2H), 3.12 (br s, 2H) ppm; MS (ES) 325 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[CH:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:32]2[CH2:33][CH2:34][N:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:30][CH2:31]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: C1CCC(N2CCNCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CCCCC2)CC1
Temperature: 65 °C
Yield: 74.3 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 1-cyclohexylpiperazine (0.068 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (94 mg, 74%). LCMS calculated for C21H27ClN3O (M+H)+: m/z=372.2; Found: 372.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2([CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH:21]4[CH2:24][CH:19]3[C:20]4([CH3:26])[CH3:25])[CH2:12][CH2:11]2)[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1.[CH3:33][NH2:34].CCO>O.CCOC(C)=O.[I-].[Na+]>[CH3:26][C:20]1([CH3:25])[CH:19]2[CH2:24][CH:21]1[CH2:22][CH2:23][CH:18]2[CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][C:8]2([N:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:34][CH3:33])[C:9]2=[O:10])[CH2:15][CH2:14]1
Reactant: CC1(C)C2CCC(CCN3CCC4(CC3)C(=O)N(CCCCl)CN4c3ccccc3)C1C2
Reactant: CN
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CNCCCN1CN(c2ccccc2)C2(CCN(CCC3CCC4CC3C4(C)C)CC2)C1=O
Temperature: 70 °C
Reaction time: 72 h
Yield: 52.2 %

Procedure:
The crude spiro compound (23) (162.8 g; 0.36 mol) was dissolved in methylamine/EtOH solution (Fluka, 8M; 1154 ml; 9.23 mol). Sodium iodide (2.16 g; 0.014 mol) was added and the solution was stirred at 70° C. under N2-atmosphere for 3 days. After cooling the reaction mixture was diluted with water and EtOAc (500 ml each). The aqueous layer was extracted with EtOAc (3×800 ml). The organic layer was washed with brine (500 ml). After drying on Na2SO4 the solvent was evaporated to yield a yellow oil. This oil was purified by column chromatography (SiO2; CH2Cl2/MeOH 90:10; containing 1% 7N NH3/MeOH) to yield 30 g of (24) with a purity of 93% (according to HPLC/MS) and 85 g of (24) with a purity of 96% (115 g; 0.25 mol; 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.Cl.[CH3:17][C:18]1([NH2:24])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:24][C:18]1([CH3:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: CC1(N)CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)CCOCC1
Yield: 84 %

Procedure:
A solution of 6-bromo-4-chloro-3-nitroquinoline (1 g, 3.48 mmol), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (1.055 g, 6.96 mmol) and triethylamine (1.939 mL, 13.91 mmol) in DMF (10 mL) was heated to 100° C. for 1 h in a sealed tube in the microwave reactor. The mixture was allowed to cool then poured into stirred water (50 mL) and the resulting yellow precipitate was collected by filtration and dried under vacuum to afford the desired material (1.070 g, 84%) as a yellow solid. This was used without further purification. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.40 (3H, s), 1.78 (2H, dt), 1.89 (2H, ddd), 3.51-3.64 (4H, m), 7.80 (1H, s), 7.91 (1H, d), 8.01 (1H, dd), 8.48 (1H, d), 9.18 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=366, 368.
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[C:21]([C:44]([F:47])([F:46])[F:45])=[CH:22][C:23]2[O:28][C:27]([CH3:35])([CH2:29][O:30][CH2:31][CH:32]3[CH2:34][O:33]3)[C:26](=[O:36])[N:25]([CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:24]=2[CH:43]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].[O-:48][CH2:49][CH3:50].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:49]([O:48][CH2:34][CH:32]([OH:33])[CH2:31][O:30][CH2:29][C:27]1([CH3:35])[C:26](=[O:36])[N:25]([CH2:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:24]2[CH:43]=[C:20]([C:18]([N:4]([CH:1]([CH3:2])[CH3:3])[C@@H:5]3[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6]3)=[O:19])[C:21]([C:44]([F:47])([F:45])[F:46])=[CH:22][C:23]=2[O:28]1)[CH3:50]
Reactant: COCCCCN1C(=O)C(C)(COCC2CO2)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(O)COCC1(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2N(CCCCOC)C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3R)-3-(isopropyl{[4-(4-methoxybutyl)-2-methyl-2-[(oxiran-2-ylmethoxy)methyl]-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-amino)piperidine-1-carboxylate (113 mg) in tetrahydrofuran (1 ml) was added sodium ethoxide (0.1 ml, 20% ethanol solution), and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. To the obtained residue was added acetic acid (1 ml), and the mixture was stirred at 50° C. for one hour. The solution was cooled to room temperature, and thereto was added ethyl acetate, and the organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].[Cl:9][S:10](O)(=[O:12])=[O:11]>CCCCCCC>[F:1][C:2]1[C:3]([I:8])=[CH:4][C:5]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1ccccc1I
Reactant: O=S(=O)(O)Cl
Solvent: CCCCCCC
Product: O=S(=O)(Cl)c1ccc(F)c(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoroiodobenzene (0.58 mL, 5.0 mmol) was added dropwise to chlorosulfonic acid (1.66 mL, 25 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was poured into ice and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to obtain a crude residue. The crude residue was dissolved in heptane (100 mL) and the suspension was filtered. The filtrate was concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Cl>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Temperature: 25 °C

Procedure:
100 cm3 of toluene was added to 170 cm3 (0.6 mol) of 70% toluene solution of NaAlH2 (OC2H4OCH3)2. 133 g (0.50 mol) of 4-(trans-4'-propylcyclohexyl) benzoic acid chloride was added drop-wise to the solution while stirring at a rate to moderately reflux the toluene solution and the mixture was stirred over a warm water bath at a temperature of 88°-90° C. for 5 hours. The solution was cooled to room temperature and 500 cm3 of concentrated hydrochloric acid diluted by twice its volume was added drop-wise. The toluene layer was separated out and the aqueous layer was extracted three times with 100 cm3 of toluene. The toluene layers were combined and washed with 10% hydrochloric acid and water. The toluene was distilled off under reduced pressure and the residue was distilled under reduced pressure (150° C./2.5 mmHg) to yield 114 g (0.49 mol) of 4-(trans-4'-propylcyclohexyl) benzyl alcohol.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH2:7][CH2:8][CH2:9][O:10]C2CCCCO2)[NH:5][C:4](=[O:17])[CH2:3]1>C(O)(=O)C.C1COCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:5][C:4](=[O:17])[CH2:3][CH:2]1[CH3:1]
Reactant: CC1CC(=O)NC1CCCOC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CC(=O)NC1CCCO

Procedure:
A mixture of the title compound of EXAMPLE 234 is treated with acetic acid:THF:water (4:2:1), and concentrated. The resulting material is purified by column chromatography to yield the title material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Cl.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[CH2:7][CH2:8][C:9]1=[O:12]
Reactant: CN(C)CCCl
Reactant: O=C1CCc2cccc(F)c2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCN1C(=O)CCc2cccc(F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Fluoro-3,4-dihydroquinolin-2(1H)-one (2.31 g, 13.98 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (4.03 g, 27.9 mmol) and potassium carbonate (11.78 g, 85.3 mmol) were combined in a round bottom flask containing a stirbar. The flask was purged with argon and DMF was added. The white suspension was stirred overnight at room temperature. The mixture was then diluted with ethyl acetate and washed with water (5×), then brine (2×). The organic phase was then dried, filtered and concentrated, then chromatographed on silica gel using EtOAc eluent. Yield: 2.86 g, 86%. 1H NMR 7.0 Hz), 4.09 (t, 2H, J=7.0 Hz), 6.98 (m, 3H). ESI-MS: 237 (MH+, 29), 192 (100). (CDCl3) δ 2.24, (s, 6H), 2.51 (t, 2H, J=7.0 Hz), 2.59 (t, 2H, J=7.0 Hz), 2.87 (t, 2H, J=
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>ClCCl.CCCCCC>[Cl:15][C:16]1[C:17]([CH3:25])=[C:18]([C:19]([N:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]2)=[O:20])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(Cl)cccc1C(=O)Cl
Reactant: O=C1CNCCN1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1C(=O)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Oxopiperazine (1.5 g, 14.98 mmol, commercially available from e.g. Sigma-Aldrich) was suspended in dry dichloromethane (DCM) (40 mL), cooled in an ice bath before adding triethylamine (3.13 mL, 22.47 mmol), followed by 3-chloro-2-methylbenzoyl chloride (I130) (2.97 g, 15.73 mmol) in Dichloromethane (DCM) (15 mL) dropwise over 15 mins. The reaction mixture was then stirred for 16 hours at RT, under argon. Solvent removed under reduced pressure. Residue partitioned between DCM (100 ml) and water (60 ml). Layers separated and aqueous layer extracted with DCM (2×50 ml). Combined extracts were washed with saturated sodium bicarbonate solution (70 ml), brine (70 ml), dried (Na2SO4), filtered and evaporated to afford an off-white solid. Solid was stirred in n-hexane (50 mL) at 55° C. for 30 mins, before filtering and drying in the vacuum oven at 40° C. for 18 hours to afford the desired product in 3.39 g as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:1]3[CH2:2][CH2:3][C:4]4([O:11][C:10]5[C:12]6[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=5[S:8][CH2:7]4)=[CH:16][CH:15]=[CH:14][CH:13]=6)[CH2:5][CH2:6]3)=[CH:25][CH:26]=2)[CH:34]=[N:33]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCc1ccc(-c2cn[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccc(-c4cn[nH]c4)cc3)CC1)O2
Temperature: 70 °C
Reaction time: 16 h
Yield: 2.2 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.15 g, 0.5 mmol) in anhydrous acetonitrile (5.0 mL) was added 4-[4-(bromomethyl)phenyl]-1H-pyrazole (0.24 g, 1.0 mmol) followed by potassium carbonate (0.20 g, 1.5 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was filtered to remove all the solids and the solvent removed under vacuum. The crude product was purified by reverse phase HPLC to give the desired product as a purple solid (0.005 g, 2.3%). M.p.=190-192° C.; 400 MHz 1H NMR (CDCl3) δ: 8.1 (d, 1H), 7.9 (s, 1H), 7.8 (d, 1H), 7.6-7.7 (m, 4H), 7.5 (t, 1H), 7.4 (d, 2H), 6.5 (s, 1H), 3.6 (s, 2 h), 2.9 (s, 2 h), 2.8 (d, 2H), 2.5 (t, 2H), 2.1 (d, 2H), 1.9 (t, 2H); LCMS: 458 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)[CH2:6]2>C(O)C>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)[CH2:6]2
Reactant: CN1C2C=C(c3cccc([N+](=O)[O-])c3)CC1CC2
Solvent: CCO
Product: CN1C2CCC1CC(c1cccc(N)c1)C2
Reaction time: 2 h

Procedure:
8-Methyl-3-(3-nitrophenyl)-8-azabicyclo[3.2.1]oct-2-ene (D10) (0.146 g, 0.598 mmol) was dissolved in ethanol (25 ml) and was hydrogenated at atmospheric pressure in the presence of 10% PdC (0.1 g) at 50° C. After 2 h, the reaction mixture was allowed to cool to room temp. and hydrogenation was continued for a further 16 h. The reaction mixture was then filtered through kieselguhr and the filter pad was washed with ethanol. The filtrate was then evaporated under reduced pressure to give the title compound as a pale yellow oil, which was dried in vacuo (0.104 g, 81%).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[SH:34])([CH2:26][CH3:27])[CH3:25].N1CCCCC1>ClCCl>[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8])([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)c1ccccc1S
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCC(C)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 2-sec-butylbenzenethiol, and 2.1 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 67°-68° C.). 1H NMR (DMSO-d6) δ 0.82 (q, 3 H), 1.09 (t, 3 H), 1.46-1.61 (m, 2 H), 2.26 (m, 2 H), 2.35 (m, 1 H), 2.62 (m, 1 H), 2.98 (m, 1 H), 3.47 (q, 2 H), 5.90 (t, 1 H), 6.56 (t, 1 H), 6.94 (t, 1 H), 7.07-7.18 (m, 4 H), 7.25 (m, 2 H), 7.45 (m, 5 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Br:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[CH:16][CH:15]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.5 eq), 4-bromophenol (1.0 eq) and PPh3 (1.5 eq) in anhydrous THF under nitrogen was added DIAD (1.5 eq) dropwise at 0° C. The reaction was stirred at rt. for 48 h., quenched with water, and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product.