Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][OH:24])[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28].[H-].[Na+].O>CS(C)=O>[C:1]1([CH2:7][O:8][CH2:9][CH:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]([CH2:23][O:24][CH2:26][C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])[O:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN(CCC)C(=O)CCl
Reactant: OCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)COCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A mixture of 4.9 g (0.015 mole) of 6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinemethanol and 2.84 g (0.016 mole) of 2-chloro-N,N-dipropylacetamide are dissolved in 100 ml of dry DMSO and the mixture stirred at room temperature under nitrogen. Slowly, 0.88 g of sodium hydride (0.0183 mole, 50% oil dispersion) is added to the DMSO mixture and the reaction allowed to stir at ambient temperature (22°). After stirring for 10 minutes, an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1/2 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted and washed with 6×300 ml portions of water. The product is then extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 6×300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is removed in vacuo yielding the crude product as a dark oil. The resulting oil is purified on a neutral Alumina III column (200 g), eluting with 2% methanol/chloroform, yielding 4.6 g (69%) of the desired product, 2-[[6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinyl]methoxy]-N,N-dipropylacetamide.
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:9](O)[CH3:10].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:9][CH3:10])=[O:6]
Reactant: CC(=O)CCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CCC(C)=O

Procedure:
100 g (0.86 mol) of 4-oxopentanoic acid, 150 g of ethanol and 1 ml of sulfuric acid in 200 ml of benzene were refluxed until water separation in the Dean-Stark trap ceased. The cooled reaction mixture was washed with water, sodium carbonate solution and again with water and then dried under reflux with the Dean-Stark trap. When removal of the water phase was complete, the solvent was removed by distillation and the residue was distilled under reduced pressure. Boiling point 85-87° C./16 mm Hg, yield 105.5 g (85%).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23]C)=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[CH3:27])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1-c1ccc(C(=O)O)nc1)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.47 mL, 1.42 mmol) was added to a THF (2 mL) and MeOH (1 mL) solution of methyl 5-(5-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)(methyl)amino)methyl)phenyl)picolinate (226 mg, 0.47 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[N+:24]([O-:26])=[O:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
To a solution of 3-(benzyloxy)phenol (1.145 g, 5.72 mmol) and 2,5-dichloronitrobenzene (1.154 g, 6.01 mmol) in 15 mL of DMSO was added cesium carbonate (3.72 g, 11.4 mmol). The reaction was heated to 70° C. under argon for one hour, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown oil.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](/[CH:29]=[CH:30]\[C:31]#[N:32])=[N:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[C:31]([NH2:32])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)=[N:27][CH:28]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Reactant: N#C/C=C\c1ccc(Cl)cn1
Product: Nc1cc(-c2ccc(Cl)cn2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):323 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-(5-chloro-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>ClCCl>[Cl:1][CH2:2][CH2:3][C:4]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: c1ccsc1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)c1cccs1
Temperature: -5 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Chloropropionyl chloride (12 mL, 130 mmol) in dry dichloromethane (50 mL) was added dropwise at −5° C. to a stirred suspension of aluminium chloride (18.8 g, 141 mmol) in dry dichloromethane (100 mL). The resulting suspension was allowed to stir at −5° C. for 10 mins before a solution of thiophene (10 g, 118 mmol) in dry dichloromethane (50 mL) was added dropwise. The resulting orange solution was stirred at −5° C. for 1 hr before being carefully dropped onto crushed ice (200 g). The organic phase was separated and dried (MgSO4), the solvent was then passed through a pad of celite/charcoal to remove any colour. Removal of the solvent in vacuo resulted in the title compound as a colourless oil (20 g, 100%); δH (300 MHz, CDCl3) 7.75 (1H, d, Ar), 7.68 (1H, d, Ar), 7.15 (1H, m, Ar), 3.90 (2H, t, J=7 Hz, CH2), 3.38 (2H, t, J=7 Hz, CH2).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C1COCCN1
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(N6CCOCC6)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4 S,4 aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and morpholine.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (0.906 g, 22.67 mmol) in dimethylformamide (50.0 mL), is added ethyl 2-[[4-methoxybenzenesulfonyl]amino]acetate (4.13 g, 15.11 mmol) and 4-methoxybenzyl chloride (2.17 mL, 15.87 mmol), and the reaction is stirred overnight at room temperature. The reaction is cooled to 0° C., quenched with 1N hydrochloric acid, and extracted well with ether. The combined organic layers are washed with brine, dried (Na2SO4), and the solvent is evaporated. The product is recrystallized from ether/hexanes to give ethyl 2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)=[CH:17][C:10]=23)=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:32][O:31][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[CH:17][C:10]=12)[C:1]#[N:2]
Reactant: COc1cc(C#N)ccc1-c1ccnc2[nH]c(C3CCCN(C(=O)OC(C)(C)C)C3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C#N)ccc1-c1ccnc2[nH]c(C3CCCNC3)cc12

Procedure:
A solution of Example 137A (75 mg, 0.17 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (1 mL) for 10 minutes and was concentrated. The residue was purified by reverse phase HPLC, eluted with 10-70% acetonitrile in 0.1% trifluoroacetic acid/water to afford the title compound. LCMS: 333.11 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.80 (m, 2H) 1.88 (d, 1H) 2.11 (d, 1H) 2.77-2.89 (m, 1H) 3.02-3.12 (m, 1H) 3.14-3.22 (m, 1H) 3.29 (d, 1H) 3.81 (s, 3H) 6.05 (d, 1H) 7.07 (d, 1H) 7.54 (s, 2H) 7.67 (s, 1H) 8.21 (d, 1H) 8.70 (d, 1H) 8.87 (s, 1H) 11.83 (s, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:27])([C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH:12]([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:29].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[OH:1][C:2]([CH3:27])([C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:29])=[O:18]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCCCC(F)(F)C(C)(O)C=CC1CCC(=O)N1CC(O)CCCCCO
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(F)(F)C(C)(O)C=CC1CCC(=O)N1CC(=O)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of 19 (37 mg, 0.09 mmol) in dimethylformamide (1 mL) containing pyridinium dichromate (165 mg, 0.45 mmol) was stirred at room temperature overnight. It was then poured into water and extracted with ether three times. The combined ether layer was washed with water and dried over magnesium sulfate. Removal of the solvent in vacuo gave 11.6 mg of 7-[2-(3-hydroxy-3-methyl-4,4-difluoro-1-octen-1-yl)-5- oxopyrrolidin-1-yl]-6-oxo-heptanoic acid (20). IR (CH2Cl2): 3600-2800 (br), 1730, 1690 cm-1 ; PMR (CDCl3); δ5.85-5.62 (m, 2H), 4.33-3.65 (m, 3H), 2.50-1.20 (m, 21H), and 0.92 (t, 3H); MS: m/z 385.2048 (M+ --H2O), calcd. for C20H29NO4F2, 385.2064.
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:12](N(CC)CC)[CH3:13]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(O)C>[Cl:11][C:3]1[C:2]([CH:12]=[CH2:13])=[CH:9][CH:8]=[C:7]([F:10])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(F)ccc(Br)c1Cl
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1ccc(F)c(C#N)c1Cl

Procedure:
3-Bromo-2-chloro-6-fluorobenzonitrile (15.4 g, 65.6 mmol), potassium vinyl trifluoroborate (17.6 g, 131 mmol), triethylamine (18.3 mL, 131 mmol) and PdCl2(dppf)-CH2Cl2 adduct (2.68 g, 3.28 mmol) were added to ethanol (75 mL) then degassed and heated at reflux for 3 h. The reaction was diluted with ethyl acetate and washed with brine, dried and evaporated to dryness. The product was purified by chromatography through a 330 g ISCO Redi-Sep column with 10% ethyl acetate/hexane solvent system to yield 2-chloro-6-fluoro-3-vinylbenzonitrile.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].ICCCCI.O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]1=[O:10]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Agent: ICCCCI
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2ccccc2C12CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2 was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N,N′N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), the combined organic layers were washed with dilute HCl (pH 1) and water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:4) to afford the subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 1H NMR (CDCl3) δ1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J7.5, 1.0Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([SH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:27](Cl)(=[O:30])(=[O:29])[NH2:28]>ClCCl>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][C@@H:6]([SH:8])[CH2:7][C@H:3]1[CH2:2][NH:1][S:27](=[O:30])(=[O:29])[NH2:28])=[O:10])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CN
Reactant: NS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNS(N)(=O)=O
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a solution of (2S,4S)-2-aminomethyl-1-allyloxycarbonyl-4-mercaptopyrrolidine (2.80 g: ca. 13.14 mmole) in dichloromethane (66 ml) at -50° C., triethylamine (4.02 ml: 28.91 mmole) and trimethylchlorosilane (3.76 ml: 28.91 mmole) are added dropwise over 15 minutes. The mixture is stirred at the same temperature for 20 minutes. To the reaction mixture triethylamine (0.92 ml: 6.57 mmole) and a solution of sulfamoyl chloride (19.37 mmole) in dichloromethane (6.8 ml) are added dropwise over 20 minutes at -70° C., and the mixture is stirred for 30 minutes. To the reaction mixture triethylamine (3.84 ml: 27.59 mmole) is again added over 1 hour at -50° C. The reaction mixture is kept at the same temperature overnight and concentrated in vacuo. The residual oil is purified by silica gel chromatography (ethyl acetate) to give (2S,4S)-1-allyloxycarbonyl-2-(sulfamoylamino)methyl-4-mercaptopyrrolidine (2.64 g). Yield: 68%. White powder.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].Br[CH2:11][CH2:12][Cl:13].[OH-].[Na+]>>[Cl:13][CH2:12][CH2:11][O:3][C:2]1[C:1]([O:8][CH3:9])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccccc1O
Reactant: ClCCBr
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1OCCCl
Temperature: 100 °C
Yield: 96.4 %

Procedure:
Guaiacol (6.2 g, 50 mmol) and 1-bromo-2-chloro-ethane (8.4 mL, 100 mmol) were mixed thoroughly and heated at 100° C. for 30 minutes. Then, 31 ml of 1.6 N NaOH aqueous solution was added into the mixture to bring the pH to about 7.0. After cooling, the mixture was extracted with chloroform. The chloroform layer was partitioned with 20% NaOH aqueous solution, water and saturated NaCl aqueous solution in sequence. The organic portion was dried with anhydrous sodium sulfite and evaporated to dryness to obtain O-(2-chloroethyl)guaiacol (18) (9 g; yield 96%). Rf 0.67 (chloroform with saturated ammonia water); IR (KBr) νmax 2934 (m), 1593 (s), 1504 (s), 1455 (s), 1254 (s), 1224 (s), 1178 (s), 1125 (s), 1028 (m) cm−1; 1H NMR (CDCl3, 400MHz): δ 6.94 (4H, m), 4.26 (2H, t, J=6.3Hz), 3.85 (3H, s, 2-OMe), 3.81 (2H, t, J=6.3Hz).
Reaction SMILES: Br[C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:19][CH2:18][C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:6]=1)=O.[NH2:27][C:28]1[C:29]([OH:35])=[N:30][CH:31]=[N:32][C:33]=1[NH2:34].Cl>CCO>[NH2:34][C:33]1[C:28]2[N:27]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:19][CH2:18][C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH2:16][CH2:17]4)[CH2:14][CH2:13][CH2:12]5)=[CH:7][CH:6]=3)[C:2]([CH3:26])([CH3:25])[O:35][C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: COC(=O)CC12CCCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Reactant: Nc1ncnc(O)c1N
Agent: Cl
Solvent: CCO
Product: COC(=O)CC12CCCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of methyl {5-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[3.2.2]non-1-yl}acetate (Intermediate 24; 80 mg, 0.19 mmol) in absolute EtOH (20 mL) was added 5,6-diaminopyrimidin-4-ol (30 mg, 0.21 mmol) followed by 1M HCl (0.21 mL). The suspension was heated under gentle reflux (80° C.) overnight then allowed to cool, the solvent removed and the residue treated with 2M NaOH (2 mL). The aqueous phase was extracted into EtOAc (3×50mL), the organic extracts were combined, dried (MgSO4) and concentrated to leave a pale yellow gum. This was purified on a 12 g Crawford silicycle cartridge, loading in DCM and eluting with 0-5-10% MeOH-DCM, giving the title compound as a pale yellow gum (55 mg, 0.123 mmol, 65%); 1H NMR (CDCl3) 1.41-1.61 (14H, m), 1.71 (6H, s), 2.07 (2H, s), 3.61 (3H, s), 7.11 (2H, d), 7.51 (2H, d), 8.14 (1H, s); MS m/e MH+ 449.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br:43]N1C(C)(C)C(=O)N(Br)C1=O>CCCCCC>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]([Br:43])[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 80 °C

Procedure:
A mixture of 0.260 g. (0.0005 mole) of [1α,3β,24S]-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.25 g. of sodium bicarbonate, 0.096 g. (0.00033 mole) of 1,3-dibromo-5,5-dimethylhydantoin, and 13 ml. of hexane was heated at reflux (80° C.) for 1 hr and cooled. The mixture was filtered and the solids were triturated with hexane and filtered. The combined filtrates were evaporated to dryness to yield [1α,3β,7ξ,24S]-7-bromo-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:28]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc(NCc2ccccc2)cc1

Procedure:
The title compound is prepared from N-(4-aminophenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamide dihydrochloride (Example 181) and benzaldehyde according to the method described in Example 177. Melting Point: 84-106° C. (dec.) (diethylether-ethyl acetate)
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C@H:37]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH:36][C@H:37]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Boc-D-Trp(CHO)-OH (2.99 g), TsOH.H-Phe-OBzl (3.85 g, and HOBT (1.22 g) were dissolved in a mixed solvent of methylene chloride (60 ml) and DMF (15 ml). To this solution was added WSC (1.53 g) under ice cooling, and the reaction mixture was stirred for 3 hours at the same temperature. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was washed successively with diluted sodium hydrogencarbonate solution (twice), water, 0.5N hydrochloric acid, and saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether (1:1), which was filtered, washed with diisopropyl ether, and dried to give Boc-D-Trp(CHO)-Phe-OBzl (4.95 g).