Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cu][C:11]#[N:12]>CN(C=O)C.CCOC(C)=O.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[N:12])=[C:3]([CH3:9])[CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(N)ncc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)ncc1C#N
Temperature: 200 °C
Yield: 32 %

Procedure:
A mixture of 5-bromo-4-methyl-2-pyridinamine (0.50 g, 2.7 mmol) and copper (I) cyanide (0.263 g, 2.9 mmol) in DMF (12 mL) was heated at 200° C. for a total of 1.75 h in a microwave reactor. The reaction mixture was diluted with EtOAc and water. The resulting thick dark precipitate was filtered off. The filtrate was extracted with EtOAc (×3) and the combined extracts were dried and concentrated to give a dark yellow solid (0.115 g). The filter cake was and washed with 1:1 DCM/MeOH (1 L) which was concentrated to give a second batch of dark yellow solid (0.047 g). The filter cake was washed with 2M NH3 in MeOH (200 mL) which was concentrated to give a dark green solid (0.533 g). These 3 batches of solids were purified by column chromatography using 0-100% EtOAc/hexane as the eluent to give the title compound as a white solid (total yield: 0.213 g). δH (CDCl3, 400 MHz) 8.28 (1H, s), 6.36 (1H, s), 4.87 (2H, br.s), 2.40 (3H, s). MS (ES): MH+ 134.1.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[C@H:10]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=1)[CH3:7].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>O1CCCC1.C(OCC)C>[CH2:6]([O:8][C:9]1[C@H:10]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:12]([O:15][CH2:16][CH3:17])[C@@H:13]([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[N:14]=1)[CH3:7]
Reactant: BrCCCCBr
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC1=N[C@H](CCCCBr)C(OCC)=N[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.5 %

Procedure:
n-butyllithium (13.3 mL of a 1.6 M solution in hexanes,21.3 mmol) was added to a solution of (2S)-2,5-dihydro-3,6-diethoxy-2-isopropyl pyrazine (Schöllkopf reagent)(4.30 g, 20.3 mmol) in tetrahydrofuran (THF) over the course of five minutes. The solution was maintained at −78° C. for 15 minutes after which 1,4-dibromobutane (9.75 mL, 81.2 mmol) was added in a single portion. After 2.5 hours at −78° C. the reaction was allowed to warm to room temperature and diluted with diethyl ether (100 mL). The organic phase was washed with water (100 mL), brine (100 mL) and then dried with magnesium sulfate (MgSO4). Following filtration and concentration most of the residual 1,4-dibromobutane was removed under high vacuum. The remaining oil was purified by silica gel chromatography (2% ethyl acetate in hexanes) to provide 5 (3.7 g, 57%) as a colorless liquid;[α]25D−1.13° (c=4.5, CHCl3); IR (thin film) 2957, 1689, 1456, 1364, 1304, 1230, 1144, 1038 cm−1; 1H NMR(300 MHz, CDCl3) δ4.04-4.18 (m, 4H) 3.94-4.02 (m, 1H) 3.90 (t, J=3.9, 1H) 3.39 (t, J=6.9, 2H) 2.21-2.32 (m, 1H) 1.68-1.92 (m, 4H) 1.33-1.47 (m, 2H) 1.274 (t, J=7.2, 3H) 1.268 (t, J=7.2, 3H) 1.03 (d, J=6.9, 3H) 0.70 (d, J=6.9, 3H); 13C NMR (100.6 MHz, CDCl3) d 163.12, 163.05, 60.72, 60.48, 55.09, 33.60, 33.11, 32.66, 31.80, 23.22, 19.03, 16.6, 14.34, 14.31; Mass Spectrum (FAB+) 347.1 (MH+).
Reaction SMILES: C[As]([NH:4][C@@H:5]([CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:15][SH:16])=[O:12])[C:6]([OH:8])=[O:7])C.[CH3:24][As:25](N(SSN([As](C)C)[C@H](C(O)=O)CCC(=O)N)[C@H](C(O)=O)CCC(=O)N)[CH3:26].C[As]([As](C)C)C>ClCCl>[CH3:24][As:25]([CH3:26])[S:16][CH2:15][C@@H:14]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[NH:13][C:11](=[O:12])[CH2:10][CH2:9][C@@H:5]([C:6]([OH:8])=[O:7])[NH2:4]
Reactant: C[As](C)N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: C[As](C)N(SSN([C@@H](CCC(N)=O)C(=O)O)[As](C)C)[C@@H](CCC(N)=O)C(=O)O
Agent: C[As](C)[As](C)C
Solvent: ClCCl
Product: C[As](C)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylarsinoglutathione is made using an adapted of Chen (Chen, G. C., et al. Carbohydrate Res. (1976) 50: 53-62) the contents of which are hereby incorporated by reference in their entirety. Briefly, dithiobis(dimethylarsinoglutamine) is dissolved in dichloromethane under nitrogen. Tetramethyldiarsine is added dropwise to the solution and the reaction is stirred overnight at room temperature under nitrogen and then exposed to air for 1 h. The mixture is then evaporated to dryness and the residue is washed with water and dried to give a crude solid that is recrystallized from methanol to give S-dimethylarsinoglutathione.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:21])([CH3:20])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2].[Mg].Br[CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:20])([CH3:21])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:18])[CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(COCCCBr)cc1
Reactant: CC1(C)C=C(n2ccc(C=O)cc2=O)c2cc(C#N)ccc2O1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COCCCC(O)c2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Forty milliliters of an anhydrous tetrahydrofuran solution containing 1.53 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-formyl-1-pyridinyl)-2H-benzo[b]pyran, obtained in Example 25, is added at 0° C. to a Grignard reagent solution prepared from 0.19 g of magnesium and 1.94 g of 1-bromo-3-p-methoxybenzyloxy propane in 5 ml anhydrous tetrahydrofuran, and the resulting mixture is reacted first at that temperature for 10 minutes and then at room temperature for one hour. After stopping the reaction by adding a saturated aqueous solution of ammonium chloride, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/1 mixture of ethyl acetate/methylene chloride as a developing solvent. Thus, 1.43 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-4 -p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH:14]=[CH2:15])=[CH:7][C:8]([CH2:12][OH:13])=[N:9][C:10]=1[Cl:11])C=C>C1CCC([P+](C([P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)C2C=CC=CC=2)(C2CCCCC2)C2CCCCC2)CC1.Cl[Ru]Cl>[Cl:11][C:10]1[N:9]=[C:8]([CH2:12][OH:13])[CH:7]=[C:6]2[CH:14]=[CH:15][CH2:1][O:4][C:5]=12
Reactant: C=CCOc1c(C=C)cc(CO)nc1Cl
Agent: Cl[Ru]Cl
Agent: c1ccc(C([P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Product: OCc1cc2c(c(Cl)n1)OCC=C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
[5-(Allyloxy)-6-chloro-4-vinylpyridin-2-yl]methanol (225 mg, 1.0 mmol) is combined with bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (16.5 mg, 0.02 mmol) in 5 ml CH2Ci2 and the reaction is stirred 4 h at RT. The volatiles are removed in vacuo and the residue is chromatographed over 15 g SiO2 (230-400 mesh) eluting with 40% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 175 mg (89%) of (8-chloro-2H-pyrano[2,3-c]pyridin-6-yl)methanol as a tan solid. MS for C9H8ClNO2 (EI) m/z: 197 (M)+.
Reaction SMILES: CN1CCCC1=O.O.[Li+].[Li+].SCC([O-])=O.SCC([O-])=O.[CH2:21]([N:28]1[CH2:35][CH:34]2[O:36][CH:30]([CH2:31][N:32](S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[CH2:33]2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CC(O)C.C1(C)C=CC=CC=1>[CH2:21]([N:28]1[CH2:35][CH:34]2[O:36][CH:30]([CH2:31][NH:32][CH2:33]2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC3CN(Cc4ccccc4)CC(C2)O3)cc1
Agent: Cl
Agent: O=C([O-])CS
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: c1ccc(CN2CC3CNCC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 117.3 %

Procedure:
1-Methyl-2-pyrrolidinone (10 mL) was added to mercaptoacetic acid di-lithium salt monohydrate (from part (a) above, 1.21 g, 10 mmol) and the mixture was stirred for 10 minutes at room temperature. 3-Benzyl-7-(4-nitrophenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane (2 g, 5 mmol, see Example 2 above) was added and the mixture stirred at room temperature under nitrogen for 2.5 hours. Toluene (8 mL) and 2-propanol (15 mL) were added to the bright orange reaction solution. The internal temperature was adjusted to 40-45° C. A solution of hydrogen chloride in 2-propanol (10 mL, approx. 4M) was added dropwise whilst maintaining the above internal temperature range. Stirring was continued for 30 minutes in this temperature range. A white precipitate formed and the mixture was cooled slowly to room temperature with stirring. The mixture was stirred overnight and then cooled in an ice/water bath to 7° C. The precipitate was collected by filtration, washed with 2-propanol (2×5 mL) and sucked dry on the filter to give the title compound as a white powder (1.28 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH:23]1(CBr)[CH2:25][CH2:24]1>>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:23]4[CH2:25][CH2:24]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: BrCC1CC1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Yield: 88.6 %

Procedure:
Naltrexone can be produced from noroxymorphone by various direct and indirect alkylation methods. One method is by direct alkylation of noroxymorphone with cyclopropylmethylbromide. This process has been disclosed in general terms by Rice in WO 91/05768. Sanofi-Avensis (WO 2008/034973) describes a process for obtaining naltrexone in 88.6% yield by reacting noroxymorphone hydrochloride with cyclopropylmethylbromide in dimethylacetamide in the presence of sodium hydrogen carbonate. Cilag (WO 2008/138605) describes N-alkylation of noroxymorphone with cyclopropylmethylbromide in N-methyl-pyrrolidone in the presence of sodium hydrogen carbonate. Mallinckrodt (WO 2010/039209) describes N-alkylation of noroxymorphone with cyclopropylmethylbromide in the presence of a protic solvent. Specific examples in WO 2010/039209 describe the addition of water, isopropanol or ethanol as the protic solvent.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[Cl:37][C:38]1[CH:46]=[C:45]2[C:41]([CH2:42][CH2:43][NH:44]2)=[CH:40][CH:39]=1>ClCCCl>[Cl:37][C:38]1[CH:46]=[C:45]2[C:41]([CH2:42][CH2:43][N:44]2[C:9]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)=[CH:40][CH:39]=1
Reactant: Cc1cc2c(=O)[nH]cnc2cn1
Reactant: Clc1ccc2c(c1)NCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
6Methyl-pyrido[3,4-d]pyrimid-4one (200 mg, 1.24 mmol), polymer-supported triphenylphosphine (2.06 g of 3.0 mmol Pig resin, 6.20 mmol) and anhydrous carbon tetrachloride (1.20 mL, 12.40 mmol) were combined in 1,2-dichloroethane (6 mL). The mixture was heated to 60° C. under an atmosphere of dry N2(g) for 18 hours. 6-Chloroindoline (1.1 eq.) was added and heating was continued at 60° C. for another 18 hours. The triphenyphosphine-bearing resin was filtered off and washed several times with chloroform. The filtrate and washings were concentrated in vacuo and preparative reversed-phase (C18) chromatography utilizing a gradient of 15% to 70% MeCN/pH4.5, 50 mM NH4OAc followed by lyophilization of the appropriate fractions afforded the title product (30%) as its free-base: MP: 232-234° C.; LC-MS: 297 (MH+); anal. RP-HPLC: 4.33 minutes.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:16]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:17]([C:30](ON1C(=O)CCC1=O)=[O:31])[CH2:18][CH2:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.CO>CN(C=O)C>[NH:16]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:17]([C:30]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:31])[CH2:18][CH2:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(=O)O

Procedure:
Boc-Val-Val-OH (40.5 g, 128 mmol) was treated with 1.8 l of 4N HCl in THF for 60 minutes. Evaporation to remove excess acid and solvent followed by treatment with ether provided 34.5 g of HCl.H-Val-Val-OH as a white amorphous powder. It was treated with Boc-Glu(OBzl)-OSu (55.6 g, 128 mmol) in 1 liter DMF for 24 hours in the presence of 54 ml Et3N. The reaction mixture was filtered to remove some insoluble material and the filtrate evaporated to dryness. The remaining oily residue was taken up in EtOAc (1.5 l) and washed with 5% HOAc (2×) followed by water (3×). The organic layer was dried (Na2SO4) and evaporated to dryness to give a colorless clear oil which did not crystallize. It was thus dissolved in 3.2 l of ether and treated with cyclohexylamine (CHA) (17 ml) until the pH (moist pH paper) of the mixture was 7.5. The solid salt obtained was collected and recrystallized from MeOH and ether: Yield, 58.9 g (72.7%); mp 158°-;60°; [α]D25 = -33.41° (c 1, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]12[CH2:14][CH:13]1[C:12](=[O:15])[O:11][C:10]2=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:10](=[O:11])[CH:9]3[CH:13]([CH2:14]3)[C:12]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: Nc1cccc(Br)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1C2CC2C(=O)N1c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
3-Bromophenylamine (2.78 g, 16.2 mmol) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (2.0 g, 17.8 mmol) were suspended in 90 mL dichloromethane. The reaction was stirred at 50° C. for 3 h. The reaction was cooled to room temperature and 1,1′-carbonyldiimidazole (3.14 g, 19.4 mmol) was added in portions. The reaction was heated again to 50° C. and stirred overnight then cooled to room temperature and the solvent was evaporated. The residue was redissolved in 90 mL 1,2-dichloroethane and additional 1,1′-carbonyldiimidazole (1.13 g, 7.0 mmol) was added. The reaction mixture was heated at reflux for 2.5 h then cooled to room temperature. The solvent was evaporated and the product was crystallized from isopropyl alcohol to give 4.25 g (99%) of 3-(3-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione as a white solid.
Reaction SMILES: [CH:1](=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[C:4]1([CH:2]([CH3:3])[CH2:1][NH:21][C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C=O)c1ccccc1
Reactant: N[C@H]1CCCc2ccccc21
Product: CC(CN[C@H]1CCCc2ccccc21)c1ccccc1

Procedure:
Hydratropaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 192 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (7.9 ml) is added to the bottle, and L-aminopropanol (7.0 ml) is added thereto. The above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.2 g). The yield is about 74.0%.
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2[N:18]=[CH:19][C:20]3[N:21]([C:22]([C:25]45[CH2:32][CH2:31][C:28]([NH:33][S:34]([CH:37]6[CH2:39][CH2:38]6)(=[O:36])=[O:35])([CH2:29][CH2:30]4)[CH2:27][CH2:26]5)=[N:23][N:24]=3)[C:16]=2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].I[CH3:41]>CN(C=O)C>[CH3:41][N:33]([C:28]12[CH2:27][CH2:26][C:25]([C:22]3[N:21]4[C:16]5[CH:15]=[CH:14][N:13]([S:3]([C:6]6[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=6)(=[O:4])=[O:5])[C:17]=5[N:18]=[CH:19][C:20]4=[N:24][N:23]=3)([CH2:30][CH2:29]1)[CH2:32][CH2:31]2)[S:34]([CH:37]1[CH2:38][CH2:39]1)(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N(C)S(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
A round bottom flask was charged with sodium hydride (60% dispersion in mineral oil, 0.013 g, 0.33 mmol) and DMF (1 mL) to give a white suspension. The suspension was cooled to about 0° C. followed by the addition of a solution of N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.15 g, 0.27 mmol, Example #7, Step C) in DMF (2 mL). The reaction mixture was stirred for about 15 min and iodomethane (0.06 g, 0.41 mmol) was added. The reaction mixture was stirred at about 0° C. for about 30 min, warmed to room temperature, and stirring was continued for about 2 h. The solvent was removed under reduced pressure. The residue was dissolved in DCM (5 mL) then purified by flash silica gel chromatography using EtOAc as the eluant to give N-methyl-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.068 g, 45%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.35 min; LC/MS m/z 555 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:14]1.Br>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH2:14]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Oc1ccc(C2CCCNC2)cc1
Agent: Br
Solvent: CC#N
Product: Oc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (47 mg, 0.20 mmol), 4-(piperidin-3-yl)phenol.HBr (53 mg, 0.20 mmol) and KHCO3 (84 mg, 0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 6.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of DCM and MeOH as eluent to give 6 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[CH3:36])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+].Cl>O1CCCC1.CO.O>[Br:35][C:27]1[C:28]2[S:29][C:30]([CH3:34])=[C:31]([CH3:33])[C:32]=2[C:20]([C:16]2[CH:15]=[C:14]([CH3:36])[C:13]([O:12][C@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3]([OH:37])=[O:2])=[C:18]([CH3:19])[CH:17]=2)=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid methyl ester (3.1 g, 5.4 mmol) in tetrahydrofuran (125 mL) and methanol (41 mL) at room temperature was added dropwise aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h at room temperature the reaction mixture was placed in the freezer for 18 h. The reaction was removed from the freezer and allowed to stir at room temperature. More aqueous potassium hydroxide (19.5 mL of a 1N solution, 19.5 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 9.5 h. Concentration under reduced pressure gave a residue which was diluted with water (1 L). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1, and extracted with diethyl ether (700 mL). The diethyl ether layer was washed twice with water (500 mL), and then dried (Na2SO4). Concentration under reduced pressure and chromatography on silica gel (treated with 2% phosphoric acid in methanol) with petroleum ether:ethyl acetate (90:10, then 86:14) gave the title compound as a white solid foam (1.9 g, 64%): Opt. Rot. [a]25/D=+33.38° (10.035 mg/mL, MeOH); NMR (DMSO-d6): δ12.90 (broad singlet, 1H), 8.17 (d, 1H), 7.63 (ddd, 1H), 7.50-7.43 (m, 2H), 7.36-7.23 (m, 5H), 6.97 (s, 2H), 4.71 (t, 1H), 3.25 (d, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.54 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 558/560; Anal. Calc. for C31H27BrO3S: C, 66.55; H, 4.86; N, 0.00. Found: C, 65.91; H, 5.05; N, 0.09; Analytical HPLC indicates a major component (99.5%).
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1>C(Cl)CCl>[Cl:1][C:9]1[C:8]([OH:11])=[CH:7][CH:6]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:10]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: ClCl
Solvent: ClCCCl
Product: Oc1ccc(C(F)(F)F)cc1Cl
Yield: 71 %

Procedure:
Chlorine gas is passed through a flow meter into a solution of α,α,α-trifluoro-p-cresol (4.05 g. 0.025 mole) in ethylene dichloride (200 ml.) at 0° C. until the theoretical volume has been absorbed. The solvent is stripped off and the residue distilled to give 2-chloro-α,α,α-trifluoro-p-cresol (3.5 g. 71%) b.p. 80°-82° C. at 33 mm.