Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[NH:26])[CH:18]=2)[CH:13]=[C:12]([CH2:28][C:29]([OH:31])=[O:30])[C:11]1=[O:32])[CH3:9].[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[NH:26])[CH:18]=2)[CH2:13][CH:12]([CH2:28][C:29]([OH:31])=[O:30])[C:11]1=[O:32])[CH3:9]
Reactant: [H][H]
Reactant: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCCNC(=N)N)cc21
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN1C(=O)C(CC(=O)O)Cc2ccc(OCCCNC(=N)N)cc21
Reaction time: 72 h
Yield: 14.2 %

Procedure:
A solution of [1-ethyl-7-(3-guanidino-propoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]-acetic acid trifluoroacetate (400 mg, 0.87 mmol) in 20 ml of methyl alcohol and 0.4 g of 10% Pd/C was hydrogenated under 50 psi of hydrogen for 3 days. The reaction mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo to a residue which was dissolved in 10 ml of hot acetic acid and hydrogenated over 0.4 g of 10% Pd/C for 3 days. The reaction mixture was filtered through diatomaceous earth and the filter cake washed with hot methyl alcohol. The combined filtrates were evaporated in vacuo to a residue of oil and solid. The residue was purified by chromatography on a reverse phase column to afford 57 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:20]([O:21][CH3:22])[CH3:19])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
The product from Example 71A (18 g, 72.96 mmol) in DCM at room temperature was treated with N,O-dimethylhydroxylamine hydrochloride (7.83 g, 80.26 mmol) slowly. The mixture was cooled to 0° C., stirred for 30 minutes, and treated with triethylamine (25.47 mL, 182.41 mmol) dropwise. The mixture was allowed to warm to 25° C., stirred for 16 hours, and treated with DCM (150 mL). The mixture was washed with saturated NaHCO3, brine, and water. The organic phase was dried, filtered, and the filtrate evaporated under reduced pressure to provide the title compound as a pale yellow solid (18.65 g, 95% yield). 1HNMR (300 MHz, CDCl3) δ 3.36 (s, 3H), 3.56 (s, 3H) 6.98 (d, 2H, J=8.9 Hz), 7.33-7.46 (m, 5H), 7.76 (d, 2H, J=8.9 Hz); MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-].[Na+].[I:15]I>CCO.O>[I:15][C:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1ccn2cncc2c1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1ncn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of imidazo[1,5-a]pyridine (0.50 g, 4.23 mmol) in EtOH (8 mL) and water (4 mL) was added sodium bicarbonate (1.07 g, 12.7 mmol) followed by iodine (1.61 g, 6.35 mmol). The dark maroon-brown heterogeneous reaction mixture was stirred at room temperature overnight then quenched with aqueous 10% Na2S2O3, diluted with water and extracted with EtOAc (3×). The combined organics were washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/hexanes to afford 649 mg (63%) of 1-iodo-imidazo[1,5-a]pyridine as a light brown solid (light sensitive). 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.13 (s, 1H), 7.92 (d, J=6.8 Hz, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.80 (dd, J=9.4, 6.8 Hz, 1H), 6.56-6.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1ccccc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 91.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.065 g (90%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-2-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[CH3:24][C:25]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:26]=1[CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1C>>[CH3:24][C:25]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:26]=1/[CH:27]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2C)c(C)c1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: Cc1ccc(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c(C)c1

Procedure:
Phthalimide 29 was coupled with 2,4-dimethylmethylbenzyltriphenylphosphonium bromide and purified by flash chromatography (20 to 50% EtOAc-hexanes gradient) to give (E)-2-(3-(3-(2,4-dimethylstyryl)phenyl)propyl)isoindoline-1,3-dione as an oil. Yield (0.3974 g, 92%), trans-/cis-isomer ratio 1.2:1. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.80-7.88 (m, 4H), 6.80-7.55 (m, 7H), 6.62 (d, J=12.0 Hz, 1H), 6.57 (d, J=12.0 Hz, 1H), 3.63 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.37 (s, 3H), 2.27 (s, 3H), 1.95 (quint, J=7.2 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[CH:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][O:32][C:46]([CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)=[O:47])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCCC1
Yield: 25.3 %

Procedure:
To a solution (15 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (550 mg) synthesized in the same manner as in Example 1 in dichloromethane was added pyridine (0.287 ml), cyclohexanecarbonyl chloride (0.158 ml) with stirring under ice-cooling and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the to mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:3), and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography, and concentrated to dryness under reduced pressure to give the title compound (yield 172 mg, 25.3%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](CNCc1ccc(Cl)cc1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-chlorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=<100%, [M+H]+=427.
Reaction SMILES: C([C:4]1([CH:11]=[C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])[CH2:9][C:7](C(=O)C)([OH:8])[CH:6]1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[CH:30]([CH3:32])[CH3:31])[OH:5])(=O)C.N>>[CH:30]([C:29]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:6]1[C:7]([OH:8])=[CH:9][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:11][C:4]=1[OH:5])([CH3:32])[CH3:31]
Reactant: CCCCCC(C)C(C)C1=CC(O)(C(C)=O)C(c2cnccc2C(C)C)C(O)(C(C)=O)C1
Agent: N
Product: CCCCCC(C)C(C)c1cc(O)c(-c2cnccc2C(C)C)c(O)c1

Procedure:
2-[4-Isopropyl-3-pyridyl]-5-(3-methyl-2-octyl)resorcinol was prepared by treating 1,3-diacetyl-2-[4-isopropyl-3-pyridyl]-5-(3-methyl-2-octyl)resorcinol with ammonia according to the procedure of Example 5.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C(Cl)Cl>[OH:12][CH:10]([CH3:11])[CH2:9][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: CC(=O)CCC(=O)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(O)CCC(=O)c1ccccc1
Yield: 88.9 %

Procedure:
A 100-ml stainless steel autoclave purged with nitrogen in advance was charged with 5 g (0.0284 mol) of 5-phenyl-2,5-pentanedione and 10 ml of methanol. A solution of 0.2 g (0.142 mmol) of [RuI(p-cymene)((R)-T-BINAP)]I3 in 2 ml of methylene chloride was added thereto, thereby conducting reaction at a reaction temperature of 50° C. for 40 hours under a hydrogen pressure of 50 kg/cm2. After distilling off the solvent, the residue was purified by column chromatography on a silica gel using a developing solvent of hexane/ethyl acetate (5/1) to obtain 4.5 g of (-)-4-hydroxy-1-phenylpentane-1-one (yield: 90.0%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].Cl>O1CCCC1.O.CO>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)[C:3]([OH:20])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(OC)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
A solution of 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.04 g, 3.73 mmol) in tetrahydrofuran/water/methanol (9.3 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution (3.73 mL, 3.73 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid (707.8 mg, 71.3%) as a white solid: mp 149-151° C.; EI-HRMS m/e calcd for C15H19F O3 (M+) 266.1318 found 266.1317.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:33])[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[O:15])=[CH:5]1)([CH3:3])[CH3:2].[ClH:34].CO>>[ClH:34].[NH2:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:14](=[O:15])[C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:33])[CH2:18][CH2:19]1
Reactant: CC(C)n1cc(C(=O)C(=O)NC2CCN(CCNC(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: CO
Product: CC(C)n1cc(C(=O)C(=O)NC2CCN(CCN)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The title compound was prepared according to general procedure D described in Scheme 2. tert-Butyl 2-(4-(2-(1-isopropyl-1H-indol-3-yl)-2-oxoacetamido)piperidin-1-yl)ethylcarbamate (132 mg, 0.29 mmol) was treated with 3 N HCl in MeOH (2 mL, 1.2 mmol) and stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure to afford the title compound as a pink solid (106 mg, 100%), which was used without further purification in the sulfonamide formation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:20][C:21]#[C:22][CH:23]([CH3:25])[CH3:24])[CH:4]=1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1C=CC=CC=1.[Pd].C([O-])([O-])=O.[Ca+2]>[CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:20][CH:21]=[CH:22][CH:23]([CH3:25])[CH3:24])[CH:4]=1
Reactant: COc1cccc2c(=O)c3c(OC)cc(OC#CC(C)C)cc3oc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: c1ccc2ncccc2c1
Product: COc1cccc2c(=O)c3c(OC)cc(OC=CC(C)C)cc3oc12
Reaction time: 2 h
Yield: 75.5 %

Procedure:
5% Pd/CaCO3 poisoned with lead (Lindlar's catalyst) (1.37 g, 0.642 mmol) was added to a solution of (104) (2.17 g, 6.42 mmol) and quinoline (3.5 mL) in benzene (200 mL). The reaction flask was evacuated, and then backfilled with H2 from a balloon. The reaction was stirred under H2 for 2 h. (The reaction can be monitored by the 1HNMR of small aliquots which have been filtered through celite and concentrated, observing the disappearance of the alkyne proton or the appearance of the olefin protons.) After 2 h, more Pd catalyst was added (0.5 g) and the reaction was stirred 1.5 h more under H2. The reaction was filtered through a pad of celite, washed with EtOAc (300 mL) and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), washed with 2M HCl (4×200 mL) and sat. NaHCO3, dried (Na2SO4), and concentrated under reduced pressure to yield 1.65 g (76%) of a yellow solid. (LH-63-17)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[C:20]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].ClC(OCC)=O.C(=O)([O-])[O-].[Ba+2]>FC(F)(F)S(O)(=O)=O.O>[Cl:29][C:25]1[CH:26]=[CH:27][C:28]2[C:13](=[C:10]3[CH2:11][CH2:12][N:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8][CH2:9]3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[CH2:21][CH2:22][C:23]=2[CH:24]=1
Reactant: CCOC(=O)N1CCC(C(=O)c2ncccc2CCc2cccc(Cl)c2)CC1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (1-ethoxycarbonyl-4piperidinyl)[3-[2-(3-chlorophenyl)ethyl]-2pyridinyl]methanone hydrochloride (0.5 g, 1.25 mmol) (prepared by reacting the corresponding 1-methyl-H-piperidinyl compound with ethvl chloroformate) in 1.5 mL of trifluoromethane sulfonic acid is stirred at ambient temperature for 24 hours. The reaction is diluted with ice and water, neutralized with barium carbonate, and the product extracted into ethvl acetate. The solvent is removed and following purification of the residue by silica gel chromatography, 8-chloro-6,11-dihydro-11-(1- ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:27].[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[C:50]2([OH:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][C:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)([OH:56])[CH2:51][CH2:52]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[C:8]1=[O:27]
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccc(F)cc3F)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3F)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(2,4-difluoro-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.38 (silica gel, 20% methanol/ethyl acetate).
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:24][CH:23](O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)[CH:12]=[CH:13][CH:14]=1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(F)c1)O2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylsilane (960 μl) was added slowly into a solution of 2-(3-fluorophenyl)chroman-4,6-diol (195 mg) in dichloromethane (4 ml). Trifluoroacetic acid (1.9 ml) was then added dropwise into a reaction mixture and it was stirred at room temperature for 5 hours. The reaction mixture was poured on ice-water and extracted with dichloromethane. The residue was evaporated under reduced pressure with toluene to obtain 2-(3-fluorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 8.78 (s, 1H), 7.43 (m, 1H), 7.28-7.25 (m, 2H), 7.14 (m, 1H), 6.66 (d, 1H, J 8.5 Hz) 6.52 (dd, 1H, J 8.5, 2.7 Hz), 6.49 (d, 1H, J 2.7 Hz), 5.03 (dd, 1H, J 9.9, 2.1 Hz), 2.86 (m, 1H), 2.63 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH2:12][N:13]1[C:21]2[C:20](=[O:22])[NH:19][C:18](=[O:23])[N:17]([CH3:24])[C:16]=2[N:15]=[CH:14]1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][O:11][CH2:9][CH3:10])[CH:14]=[N:15][C:16]=2[N:17]([CH3:24])[C:18]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)n(Cc1ccccc1)c(=O)n2C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
205 g (1.2 mol) of benzyl bromide were added to a suspension of 224 g (1 mol) of 7-ethoxymethyl-3-methylxanthine and 165 g of potassium carbonate in 1000 ml of dimethylformamide and the mixture was then stirred overnight at 90° C. The reaction solution was filtered hot, the filtrate was concentrated under reduced pressure and the residue was dried to constant weight in a bulb tube at 1 mbar and 60° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:36][C:35]1[CH:37]=[CH:38][C:32]([S:29]([O:19][C@@H:18]2[CH2:17][C:16]3[C@@:22]([CH3:23])([C@@H:24]4[C@@H:13]([CH2:14][CH:15]=3)[C@@H:12]3[CH2:11][CH2:10][C@H:9]([C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[C@@:27]3([CH3:28])[CH2:26][CH2:25]4)[CH2:21][CH2:20]2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 g (0.129 mmol) of cholesterol are dissolved in 250 ml of pyridine and cooled to about 5° C. with ice/water. Under argon, 49 g (0.258 mol) of tosyl chloride are added in portions thereto. When the addition is complete, the mixture is stirred for a further 15 minutes with cooling. The ice-bath is then removed and the mixture is stirred for 2 days at room temperature to complete the reaction. The resulting fine suspension is poured onto 1.2 liters of ice-water and stirred for 30 minutes. The precipitate is filtered off with suction, washed thoroughly with H2O and dried under a high vacuum at 40°. The substance, which still contains a large amount of pyridine hydrochloride, is dissolved in CH2Cl2 and the organic phase is washed twice with water, once with 1N hydrochloric acid and again with water. After drying over Na2SO4 and concentration in a rotary evaporator, the residue is recrystallised from CH2Cl2 /hexane, yielding cholesteryl tosylate; m.p. 130°-131°.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](O)=[O:22])[C:17]=3[CH:24]=2)[C:3]1=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].N12CCCN=C1CCCCC2.Cl>O1CCCC1.C(Cl)Cl.C(O)(=O)C>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:22])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)NS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (0.400 g, 1.08 mmol) in tetrahydrofuran is treated with 1,1'-carbonyldiimidazole (0.260 g, 1.58 mmol), stirred at room temperature for 30 minutes, refluxed for 2 hours, cooled to room temperature, treated dropwise with a solution of methanesulfonamide (0.130 g, 1.37 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.230 g, 1.50 mmol), stirred at room temperature for 3 hours, and poured into 0.5 N hydrochloric acid. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a methylene chloride/acetic acid solution (10:1) gives the title product as a white solid (0.350 g, 72%, mp 241-243° C.).