Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[C:7](OC(=O)C)(=[O:9])[CH3:8].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([O:5][CH2:4][C@H:3]([CH3:6])[CH2:2][Br:1])(=[O:9])[CH3:8]
Reactant: C[C@@H](CO)CBr
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](C)CBr
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
5 g of (S)-(+)-3-bromo-2-methyl-1-propanol (32.6 mmol) were stirred in 5 ml of pyridine at room temperature. 3.67 g of acetic anhydride (35.9 mmol) were added and the reaction mixture was stirred for 3 h at 70° C. Stirring was continued for 16 h at room temperature. 30 ml of water and 40 ml of ethyl acetate were added. The organic layer was separated and washed with a further portion of water, then dried over magnesium sulfate, filtered, and evaporated under reduced pressure, whereby 4.34 g of the title compound were obtained.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][Si](C(C)(C)C)(C)C)[C:25](Br)=[CH:24][C:23]=2[CH2:37][CH3:38])[C:12]=1[CH2:39][CH2:40][CH3:41].[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1B(O)O.C(=O)([O-])[O-].[Na+:55].[Na+]>O1CCCC1.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>[Na+:55].[CH2:37]([C:23]1[CH:24]=[C:25]([C:44]2[O:43][CH:47]=[CH:46][CH:45]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38]
Reactant: CCCc1c(OCCCOc2cc(O[Si](C)(C)C(C)(C)C)c(Br)cc2CC)cccc1Oc1ccccc1C(=O)OC
Reactant: OB(O)c1ccco1
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: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccco3)cc2CC)cccc1Oc1ccccc1C(=O)[O-]
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 2-(3-{3-[4-bromo-5-(tert-butyldimethylsilanyloxy)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (1.05 g, 1.60 mmol), furan-2-boronic acid (0.358 g, 3.20 mmol), tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.160 mmol), and 2 M aqueous sodium carbonate solution (8 mL) in tetrahydrofuran (20 mL) was heated at reflux for 18 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 0.8 g (94%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.90 (d, J=9 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J=8 Hz, 1H), 7.21 (s 1H), 7.13 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 6.52 (m, 3H), 6.44 (d, J=9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.67 (t, J=8 Hz, 2H), 2.59 (q, J=7 Hz, 2H), 2.32 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.18 (t, J=7 Hz, 3H), 0.91 (t, J=7 Hz, 3H); MS ES− m/z=589 (p+AcO−). Anal. Calcd for C32H34O7: C, 72.43; H, 6.46. Found: C, 72.21; H, 6.15.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4](=[O:16])(=[O:15])[NH:3]1.[CH3:17][Mg]Br.O>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4](=[O:16])(=[O:15])[NH:3]1
Reactant: C=CCN1c2ccccc2C(C)NS1(=O)=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1c2ccccc2C(C)(C)NS1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Aminoacetophenone(5.6 g, 41.5 mmol)and sulfamide (4 g, 41.5 mm) were added to diglyme (70 ml, dried over 4A molecular sieves) and the solution heated under nitrogen at 150° C. After 1 hour a solid forms but heating was continued for 2 hours in total. After cooling, ether was added followed by 2N sodium hydroxide which dissolved the solid formed. The aqueous phase was collected, diluted with ethanol and (prop-2-en-1-yl) bromide (8 ml) added, stirring being continued overnight. After concentration under vacuo the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried, over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a yellow oil, 3,4-dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 3,4-Dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(2.4 g, 10 mmol) was dissolved in dry tetrahydrofuran (40 ml) under nitrogen and the solution cooled to -78° C. in an acetone/dry ice bath. Methyl magnesium bromide (5 ml, 3M solution in ether) was added at this temperature and kept for 30 minutes when it was allowed to come to room temperature. After stirring for 2 hours, water was added and the solution concentrated. Partitioning between ethyl acetate and dilute HCl(aq) and collection of the organic extracts followed by drying, filtering and removal of solvent gave a product showing 75% conversion to product. Column chromatography eluting with ethyl acetate/hexane gave product, 3,4-dihydro-4,4-dimethyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. This compound (1.85 g, 7.3 mmol) was dissolved in N-methylpyrrolidine (30 ml) under nitrogen and sodium hydride (350 mg) was added at room temperature resulting in a vigorous effervescence. After the gas evolution had subsided (30 minutes), methyl iodide (300 mg) was added and the solution stirred overnight. The reaction was poured onto water and extracted with ethyl acetate(3×50 ml). Organic phase was washed with water (2×100 ml), dried, filtered and vacced to an oil, 3,4-dihydro-1-(prop-2-en-1-yl)-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(#N)C.ClCCl>[CH2:16]([N:18]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCNCC
Reactant: COc1ccc(OCCCl)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
4-(2-chloroethoxy)-1-methoxy-2-nitrobenzene (0.15 g, 0.67 mmol) was dissolved in acetonitrile (1 ml). Excess diethylamine (1.5 ml, 17.7 mmol) was added and the reaction heated in the microwave (T=120° C., 40 min) to complete conversion. The reaction mixture was diluted with dichloromethane, then washed with 5M sodium hydroxide and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as an orange oil.
Reaction SMILES: [CH2:1]([C:8]1([CH3:20])[C:12]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:11]=2[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>ClCCl.CN(C=O)C>[I:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:17]([C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([CH3:20])[CH2:9][O:10][C:11]=2[CH:16]=1)=[O:19]
Reactant: CC1(Cc2ccccc2)COc2cc(C(=O)O)ccc21
Reactant: Nc1ccccc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Cc2ccccc2)COc2cc(C(=O)Nc3ccccc3I)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (80 mg, 0.3 mmol) and 2-Iodoaniline (72 mg, 0.33 mmol) in dichloromethane (3 mL) and DMF (2 mL) were added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol) and then a solution of N,N-diisopropylethylamine (58 mg, 78 μL, 0.45 mmol, mL) in DMF (1 mL). The reaction mixture was stirred at ambient temperature for 18 h. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (MgSO4), and concentrated to give the amide which is purified by flash chromatography (AcOEt/heptane: 4/6). The column was chosen too small and a bigger column was chosen (AcOEt/heptane: 4/6) to afford 22 mg of the desired amid as a pale yellow solid (16%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.N#N.[C:22](=[S:24])=[S:23].[CH3:25]I>CO>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:22](=[S:24])[S:23][CH3:25])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CI
Reactant: S=C=S
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC(=S)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 97.1 %

Procedure:
To a stirred solution of 150 g (795 mmole) of 4-nitrobenzylamine hydrochloride and 243 ml (176 g, 1.75 mole) of triethylamine in 780 ml of methanol was added gradually (under N2) a solution of 54 ml (68.9 g, 906 mmole) of carbon disulfide in 300 ml of methanol. The internal temperature was maintained below 30° C. during the addition, which took 75 minutes. After an additional hour at room temperature, the reaction mixture was cooled to -10° C. in an ice-MeOH bath as a solution of 50 ml (113 g, 795 mmole) of methyl iodide in 125 ml of methanol was gradually added over about 20 minutes. The cooling bath was removed, and the mixture was allowed to stir at room temperature for 2 hours. It was then concentrated in vacuo to a volume of approximately 500 ml and partioned between 2 L of ether and 2 L of 0.2 N HCl. The ethereal phase was washed with 2 L of saturated aqueous NAGl, dried over. MgSO4, filtered and concentrated to give a yellow solid. Trituration with petroleum ether and drying afforded 187 g (97%) of methyl N-(4-nitrobenzyl)dithiocarbamate, mp 106°-107° C., satisfactory purity by TLC in 2:1 hexane EtOAc; mass spectrum (FAB) m/e 243 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([F:13])[C:3]=1[CH2:4][OH:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[C@H:23]([CH2:30][CH3:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([F:13])[C:3]=1[CH2:4][O:5][C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])[CH2:22][C@H:23]1[CH2:30][CH3:31])=[O:28]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: CCOc1cc(F)c(CO)c(Cl)c1
Product: CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 94 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-ethoxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (418 mg; 94%); MS (ISP): 462.4 (M+NH4)+.
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH:7]=O.[CH3:27][NH2:28].[BH4-].[Na+].O>CO.CO.CCOC(C)=O>[CH3:27][N:28]1[CH2:7][CH2:6][CH2:5][CH:4]([C:9]2[N:13]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:3]1=[O:26]
Reactant: CN
Reactant: COC(=O)C(CCC=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2C2CCCN(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a magnetically stirred solution of (+/−)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-5-oxo-pentanoic acid methyl ester 35c (0.085 g, 0.253 mmol) in methanol (1 mL) at room temperature under Ar atmosphere was added a 40% aqueous solution of methyl amine (MeNH2) (0.021 mL, 0.253 mmol). The reaction mixture was stirred for 1 h at room temperature. NaBH4 (0.019 g, 0.506 mmol) was added at room temperature. After 30 min, water (30 mL) was added, and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic layers were dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (EtOAc, then 4:96 MeOH/EtOAc as eluent) which gave the title compound (0.03 g, 31%) as a white solid. The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude product. 1H NMR (400 MHz, CDCl3) δ 1.99 (m, 3H), 2.11 (m, 1H), 2.31 (s, 3H), 2.38 (s, 3H), 3.05 (s, 3H), 3.41 (m, 1H), 3.53 (m, 1H), 4.25 (m, 1H), 6.99 (d, J=9.1 Hz, 1H), 7.22 (m, 3H), 7.46 (s, 1H), 7.53 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 18.9, 21.5, 23.1, 26.1, 35.4, 39.7, 50.3, 117.4, 119.1, 121.5, 121.7, 127.0, 129.1, 129.3, 132.4, 137.5, 143.9, 144.4, 168.7. Mass spectrum m/e 335 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9](=[O:14])[NH:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CC([O-])(C)C.[K+].CS(O[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])(=O)=O.O>C1COCC1>[F:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][N:10]1[CH:11]=[CH:12][N:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[C:9]1=[O:14]
Reactant: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Reactant: CN1CCN(c2ncc[nH]c2=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-methyl-1-piperazinyl)-2(1H)-pyrazinone (obtained in Step 2 above; 0.5 g, 2.6 mmol) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temp, HPLC showed only 50% conversion. The reaction solution was then heated to 60° C. overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried (Na2SO4) and concentrated to yield 1.08 g of the crude product as a yellow oil. Purification by chromatography on silica gel [eluent: 2% MeOH in CHCl3+NH3 (g)] gave the title compound as a yellow oil, which solidified upon cooling. Yield: 304 mg (32%). HPLC purity: 100%. MS m/z 369 (M+H)+. HRMS m/z calcd for C17H19F3N4O2 (M)+ 368.1460, found 368.1462.
Reaction SMILES: [F:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[NH2:8][C:9]1[C:10]([Cl:18])=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:12][NH2:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[NH2:8][C:9]1[C:10]([Cl:18])=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:12][NH:13][C:3](=[O:4])[C:2]([CH3:7])([F:1])[CH3:6]
Reactant: NCc1ccc(Cl)c(N)c1Cl
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoroisobutyric acid (555 mg, 5.2 mmol), 3-amino-2,4-dichloro-benzylamine (1.00 g, 5.2 mmol), TBTU (1.85 g, 5.8 mmol), TEA (1.82 mL, 13 mmol) and THF is stirred at rt overnight. The mixture is concentrated, stirred with sat. aq NaHCO3-solution and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[S:4][C:3]=1C(O)=O.CN1CCNCC1.CN1CCCC1=O.CCOC(C)=O>O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][CH:3]=[C:2]([NH2:1])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Nc1cc(-c2ccc(Br)cc2)sc1C(=O)O
Agent: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1csc(-c2ccc(Br)cc2)c1
Temperature: 160 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
3-amino-5-(4-bromophenyl)thiophene-2-carboxylic acid (11.21 mmol), N-methyl piperazine (11.21 mmol) and N-methylpyrrolidinone (13.5 mL) were mixed together The reaction mixture was stirred at 160° C. for 5 hours and cooled down to room temperature. EtOAc and water were added, organics were separated, dried over Na2SO4, concentrated under reduced pressure and filtrated over silica (DCM/MeOH). Diisopropyl ether was added to the crude material and the residue obtained was filtered to give Intermediate IX.1 as a beige solid in 44% yield, which was characterized by the following spectroscopic data: MS (ESI, EI+) m/z=255 (MH+).
Reaction SMILES: [O:1]1[CH:3]([CH:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH3:20])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2]1.C([N:23](CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].C(O)(C)C>C(=O)(OC)OC>[Cl:28][CH2:29][C:30]([NH:23][CH2:2][CH:3]([OH:1])[CH:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCOc1ccccc1OC(c1ccccc1)C1CO1
Reactant: CCN(CC)CC
Solvent: COC(=O)OC
Solvent: CC(C)O
Product: CCOc1ccccc1OC(c1ccccc1)C(O)CNC(=O)CCl
Temperature: 8 °C
Reaction time: 1 h

Procedure:
(2RS,3RS)-1,2-Epoxy-3-(2-ethoxyphenoxy)-3-phenylpropane (47.7 g) and dimethyl carbonate (700 mL) were stirred to form a white slurry. Triethylamine (52 mL) was added and the mixture cooled to 6-10° C. using an ice/H2O bath, a solution of chloroacetyl chloride (13.8 mL) in dimethyl carbonate (50 mL) was added over a 30 minute period keeping the temperature between 4-10° C. The mixture was stirred for 1 hour. The mixture was washed with 500 mL of H2O and then with 500 mL of 3% aqueous NaCl solution. The organic layer was concentrated under vacuum at 40° C. to yield a dark oil. Isopropanol (500 mL) was added and the mixture again concentrated to remove any residual dimethyl carbonate, yielding the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].CO>CN(C)C=O.O>[CH:22]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[CH:23][CH3:24]
Reactant: C=CCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC=COc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 136 h
Yield: 71.6 %

Procedure:
5.0 grams (25.0 mmole, 1.0 eq.) of 4-benzyloxyphenol was dissolved in 100 ml of N,N-dimethylformamide. 10.4 grams (75.0 mmole, 3.0 eq.) of potassium carbonate and 3.25 ml (37.5 mmole, 1.5 eq.) of allyl bromide were added to the reaction and it was stirred at 80° C. for 3 hours and at room temperature for another 136 hours. The reaction mixture was diluted with water and extracted 3× with 60 ml of ethyl acetate. The combined organics were dried over sodium sulfate, filtered, evaporated and pumped on high vacuum overnight. The title compound (4.3 grams, 72% yield) was isolated by recrystallization from methanol.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH:24]1([C:27]2[O:31][C:30]([NH2:32])=[N:29][N:28]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[O:31][C:30]([NH:32][C:8]([CH:10]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:17][C:16]4[C:11]3=[CH:12][CH:13]=[CH:14][CH:15]=4)=[O:9])=[N:29][N:28]=2)[CH2:26][CH2:25]1
Reactant: Nc1nnc(C2CC2)o1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Product: O=C(Nc1nnc(C2CC2)o1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 246-248° C. and MS: m/e=333.1 (M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine [J.Med.Pharm.Chem. 5, 617(1962)].
Reaction SMILES: [NH2:1][CH:2]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([Cl:16])[CH:3]1[OH:17]>FC(F)(F)C(O)=O>[ClH:16].[NH2:1][CH:2]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][C:3]1=[O:17]
Reactant: NC1Cc2c(ccc3ccccc23)C(Cl)C1O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NC1Cc2c(ccc3ccccc23)CC1=O
Yield: 38.8 %

Procedure:
3-Amino-1-chloro-1,2,3,4-tetrahydro-2-phenanthrenol (103 mg) in trifluoroacetic acid (10 ml) was refluxed for 3 hours. The green mixture was evaporated and the residue was taken up in methanol and acidified with a solution of hydrochloric acid in diethyl ether. The evaporation residue was treated with charcoal in methanol. Filtration gave a clear solution which was evaporated to yield the crude compound as a solid (99 mg). Recrystallization from ethanol/diethyl ether afforded the title compound (40 mg) as a white solid, m.p. 247° C. (dec.).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[N:41][C:40]([C:43]2([C:46]#[N:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:42]=[N:41][C:40]([C:43]4([C:46]#[N:47])[CH2:44][CH2:45]4)=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N#CC1(c2ccc(Cl)nn2)CC1
Product: C[C@@H](c1ccc(-c2ccc(C3(C#N)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 51 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-chloro-pyridazin-3-yl)-cyclopropanecarbonitrile following a procedure analogous to that described in Example 1. Yield: 51% of theory; LC (method 2): tR=3.42 min; Mass spectrum (ESI+): m/z=497 [M+H]+.