Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]3[CH2:16][CH2:15]3)=[N:10][NH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH:14]1([C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:12]3[NH:13][C:26](=[O:27])[CH:25]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:11]3[N:10]=2)[CH2:16][CH2:15]1
Reactant: Nc1[nH]nc(C2CC2)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=c1cc(-c2ccc(F)cc2)n2nc(C3CC3)c(-c3ccc(Cl)cc3)c2[nH]1
Temperature: 25 °C

Procedure:
4-(4-Chlorophenyl)-3-cyclopropyl-1H-pyrazol-5-amine (121 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (0.095 mL) are stirred overnight in a pyridine (7 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 75 mg of the target compound. 1H NMR (CDCl3, 300 MHz): δ 10.15 (br, 1H), 8.02 (m, 2H), 7.42 (m, 4H), 7.18 (m, 2H), 4.08 (br, 1H), 1.80 (m, 1H) 0.89 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 68b (5 g, 0.02 mol) in THF (100 mL) was added a 1 M THF solution of NaHMDS (22.6 mL, 22.6 mmol) at 0° C. under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then cooled to 0° C. and iodomethane (3.19 g, 22.5 mmol) was added dropwise. The ice-water bath was removed and stirring was continued for an additional hour at room temperature. The reaction mixture was then treated with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68c as brown oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C11H13BrO2: 256.0 (M). found: 256.0.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH:8]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH2:9]>O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[CH2:9][CH2:8][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: OCCNCCO
Reactant: C=CP(=O)(OCC)OCC
Solvent: O
Product: CCOP(=O)(CCN(CCO)CCO)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of diethanolamine (2.1 g, 20 mmol), H2O (50 ml) and diethyl vinylphosphonate (3.3 g, 20 mmol) was stirred at room temperature overnight. The solvent was evaporated and the residue codistilled with ethanol. The residue was purified by chromatography on silica gel (CHCl3-MeOH) to obtain diethyl 2-(bis(2-hydroxyethyl)amino)ethylphosphonate, yield 5.03 g (93%). This intermediate (3.4 g, 12.6 mmol) was dissolved in CH2Cl2 (50 ml), a catalytic amount of dimethylaminopyridine was added followed by Et3N (1.2 ml) and then tritylchloride (3.5 g, 14.5 mmol) dissolved in CH2Cl2 (30 ml) was added drop-wise. The reaction mixture was stirred overnight at room temperature and solvent evaporated. The residue was purified by column chromatography on silica gel (CHCl3-MeOH) to afford diethyl 2((2-hydroxyethyl)(2-(trityloxy)ethyl)amino)ethylphosphonate as yellowish oil (6.01 g, 93%). To a solution of triphenylphosphine (6.3 g, 24 mmol) in dry THF (100 ml) cooled to −30° C. under argon atmosphere diisopropylazadicarboxylate (DIAD, 4.4 ml, 23 mmol) was added slowly. The mixture was stirred for 30 minutes and this preformed complex was added to 2-amino-6-chloropurine (3.8 g, 22.6 mmol), dry THF (70 ml) and diethyl 2-((2-hydroxyethyl)(2-(trityloxy)ethyl)amino)ethylphosphonate (5.72 g, 11.2 mmol) at −30° C. under argon. The resulting mixture was slowly warmed to room temperature and stirred for 48 h. Then water (30 ml) was added and the mixture was heated at 80° C. for 30 h. Solvent was evaporated the residue was codistilled with toluene or ethanol and the crude mixture purified by chromatography on silica gel (MeOH—CHCl3). This intermediate was dissolved in trifluoroacetic acid (aqueous, 75%, 20 ml) and stirred overnight. The solvent was evaporated and the residue codistilled with water (3×) and ethanol. After chromatography on silica gel (MeOH—CHCl3) the diethyl 9-[(N-(2-hydroxyethyl)-N-(2-phosphonoethyl))-2-aminoethyl]guanine was obtained in 50% yield (2.25 g).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.Cl.C([O:35][C:36](=[O:48])[CH2:37][NH:38][CH:39]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1)C>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([NH:11][C@H:12]([C:14]([N:38]([CH:39]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1)[CH2:37][C:36]([OH:48])=[O:35])=[O:16])[CH3:13])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOC(=O)CNC1Cc2ccccc2C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A solution of 22.3 g of N-carbobenzoxy-L-alanine and 14 ml of triethylamine in 200 ml of tetrahydrofuran is cooled to -10° C., and 13.1 ml of isobutyl chlorocarbonate is added dropwise in portions with stirring. After stirring for 30 minutes, a solution of 24.1 g of N-(indan-2-yl)glycine ethyl ester hydrochloride and 14 ml of triethylamine in 200 ml of chloroform is added dropwise at -10° C. to -5° C. After standing overnight at room temperature, the reaction mixture is washed in sequence with water, aqueous sodium hydrogen carbonate, 10% hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the residue is dissolved in 100 ml of methanol, 75 ml of 2N sodium hydroxide is added, and the mixture is stirred at room temperature for 2 hours. Then, the mixture is made acidic with 10% hydrochloric acid to separate the resulting oil, which is extracted with 500 ml of ethyl acetate. The extract washed with water and dried, and the solvent is distilled off under reduced pressure to give 25 g of N-carbobenzoxy-L-alanyl-N-(indan-2-yl)glycine as an oil. This is dissolved in 50% ethanol and subjected to catalytic reduction in the presence of 4 g of 10% palladium-carbon. When the hydrogen absorption has ceased, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure. Addition of 50 ml of methanol to the residue yields 11 g of L-alanyl-N-(indan-2-yl)glycine as colorless needles melting at 180°-182° C.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][S:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9]>C(OCC)C>[CH3:4][S:5][C:6]1[CH:7]=[C:8]([NH:9][C:2]#[N:1])[CH:10]=[CH:11][CH:12]=1
Reactant: N#CBr
Reactant: CSc1cccc(N)c1
Solvent: CCOCC
Product: CSc1cccc(NC#N)c1
Temperature: 24 °C
Reaction time: 12 h
Yield: 31.8 %

Procedure:
A solution of cyanogen bromide (1.42 g, 13.4 mmol) in anhydrous diethyl ether (8 mL) was added slowly to a stirred solution of 3-(methylthio)aniline (2.72 mL, 21.4 mmol) in anhydrous diethyl ether at 4° C. After the addition, the reaction mixture was stirred at 24° C. for 12 hours and became a brown solution with a white precipitate. The precipitate was filtered off; the filtrate was washed with aqueous HCl (1 M, 3×15 mL) in ether and the organic layer extracted with brine (10 mL). Then the ether solution was dried over MgSO4, filtered, and concentrated in vacuo to yield a thick liquid. The crude product was further purified by column chromatography (SiO2, a gradient of hexanes/CH2Cl2/EtOAc) to afford 3-(methylthio)phenyl cyanamide (0.7 g, 49% yield) as a white solid: m.p. 64-65° C.;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:18]=[CH:17][S:16][C:15]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>>[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:18]=[CH:17][S:16][C:15]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: NS(=O)(=O)c1sccc1NS(=O)(=O)CCc1ccc(Br)cc1
Product: CC(C)(C)C#Cc1ccc(CCS(=O)(=O)Nc2ccsc2S(N)(=O)=O)cc1
Yield: 18 %

Procedure:
The title compound was synthesized as described for Example 210 in 18% yield, starting from 3-[2-(4-bromo-phenyl)-ethanesulfonylamino]-thiophene-2-sulfonic acid amide and 3,3-dimethyl-1-butyne. Purification by column chromatography, using 50% ethyl acetate in hexanes as the eluent, followed by purification by preparative HPLC.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]=[CH:10]2.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]=[CH:10]2
Reactant: COc1ccc2c(=O)occc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1occc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of boron tribromide (1M in dichloromethane, 130 mL) was added to a solution of 6-methoxyisochromen-1-one (9.3 g) in dichloromethane (300 mL) at 0° C., and the mixture was stirred at room temperature for 16 h. After addition of sodium carbonate solution, the mixture was washed with ethyl acetate, and the aqueous phase was acidified with 2N HCl, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel. The product with the molecular weight of 162.15 (C9H6O3) was obtained in this way; MS (ESI): 163 (M+H+).
Reaction SMILES: NC(N)=O.[C:5]([NH:9][C:10]([C:12]1[S:41][C:15]2[N:16]=[C:17]([S:39][CH3:40])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([O:29]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH:21]=3)[C:14]=2[C:13]=1[NH2:42])=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH3:43][O:44][C:45]1[C:46]([NH2:51])=[CH:47][CH:48]=[CH:49][CH:50]=1>>[C:5]([NH:9][C:10]([C:12]1[S:41][C:15]2[N:16]=[C:17]([S:39][CH3:40])[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([NH:51][C:46]4[C:45](=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:44][CH3:43])=[O:29])[CH:21]=3)[C:14]=2[C:13]=1[NH2:42])=[O:11])([CH3:6])([CH3:8])[CH3:7]
Reactant: COc1ccccc1N
Reactant: CSc1nc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Agent: NC(N)=O
Product: COc1ccccc1NC(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.75 h

Procedure:
The urea coupling of tert-Butyl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 20, 142 mg) with ortho-anisidine (159 mg) was performed according to the methods described in example 21. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCCCCC.C([Li])CCC.C(OC([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=O)(C)(C)C.[OH-].[Na+]>C(OCC)C.O>[F:12][C:4]1[CH:3]=[C:2]([C:34]2([OH:37])[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2cc(F)cc(C(F)(F)F)c2)CCNCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
5-Bromo-3-fluorobenzo trifluoride (APOLLO Co., 9.0 g) was dissolved in diethyl ether (110 ml), and the mixture was cooled to −78° C. An n-butyllithium hexane solution (2.71 M, 17.5 ml) was added to this solution, and the mixture was stirred at −78° C. for 1 hr. Then, 1-(tert-butoxycarbonyl)-4-piperidone (6.71 g) was added. The reaction temperature was then warmed to 0° C., and the mixture was further stirred for 1 hr. After completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). Then, the residue was dissolved in 1,4-dioxane (150 ml), and 10% aqueous sulfuric acid (10 ml) was added thereto. The mixture was stirred with heating at 70° C. for 2 hr. After completion of the reaction, the reaction system was basified (pH=9) with an 1N aqueous sodium hydroxide solution, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[3-fluoro-5-(trifluoromethyl)phenyl]piperidin-4-ol (9.89 g, yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:10]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:27]2[C:32](=[O:33])[NH:31][C:30](=[O:34])[CH:29]=[N:28]2)[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1C(=O)c1ccc(F)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-{3-chloro-4-[3-(4-fluoro-benzoyl)-4-methoxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (1.1 g) in dichloromethane (30 mL) was added a solution of 1M boron trichloride in dichloromethane (11 mL) and the resulting suspension was stirred at ambient temperature for 4 h. Ice was added to the reaction and the resulting mixture was stirred for 30 min, extracted with ethyl acetate, the organic phase dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (30% THF/hexanes) to afford the title compound of Step B, 0.94 g. MS Calc.:467.8 Found:467.8.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[N:6]3[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CON(C)C(=O)c1nc2cccc(C)n2c1Br
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: C1COCCO1
Solvent: O
Product: CON(C)C(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Temperature: 95 °C
Yield: 81.1 %

Procedure:
A solution of 3-bromo-N-methoxy-N,5-dimethylimidazo[1,2-a]pyridine-2-carboxamide (0.48 g, 1.6 mmol), (3,5-difluorophenyl)boronic acid (0.33 g, 2.1 mmol), and sodium carbonate (0.26 g, 2.4 mmol) in 1,4-dioxane (10 mL) and water (1.9 mL) was degassed with nitrogen and treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol). The reaction mixture was degassed with nitrogen and heated at 95° C. for 19 h. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude solid. Purification by flash column chromatography gave the desired product (0.43 g, 80%). LCMS for C17H16F2N3O2 (m+H)+: m/z=332.1.
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].[C:23](OCC=C)(=O)[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:23]=[CH:24][CH2:1][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]([CH2:9][CH2:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: C=CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 80 °C

Procedure:
In one embodiment, allylation of noroxymorphone with allyl acetate is accomplished by combining noroxymorphone with triethylamine (3 equivalents), toluene (50 mL) and tetrakis(triphenylphosphine)palladium[0] (0.1 equivalent), and heating the mixture at 80° C. for 64 hours. The mixture is cooled to a temperature of about 20° C. and filtered through a plug of CELITE and the filtrate was concentrated under reduced pressure. Naloxone is isolated from the concentrated filtrate using normal extractive procedures.
Reaction SMILES: [C:1]([CH:3]([O:11][N:12]=[C:13]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:4][CH2:5][C:6]([O:8]CC)=[O:7])#[N:2].[OH-].[Na+]>O1CCOCC1>[C:1]([CH:3]([O:11][N:12]=[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)CCC(C#N)ON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=NOC(C#N)CCC(=O)O)c2ccc(OC)cc2)cc1
Yield: 97.8 %

Procedure:
3.96 g of the 4,4'-dimethoxybenzophenone O-(1-cyano-3-ethoxycarbonylpropyl)oxime was dissolved in 20 ml of dioxane and 3 ml of a 5N aqueous solution of caustic soda was added thereto. Then the mixture was allowed to react at 60° C. for five hours. After the completion of the reaction, the reaction mixture was acidified and extracted with ethyl acetate. Thus 3.6 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25]([OH:27])=O)(=[O:21])=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:25](=[O:27])[C:24]2[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:20])=[O:21])[CH:23]=2)=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CNc1cnccc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50), followed by preparative HPLC using a gradient of methanol:water (10:90 to 95:5). Colorless foam (44%). MS (ESI): m/z=483.099 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([Mg]Br)[CH3:14].CCOCC>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CC[Mg]Br
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nc(SC)nc(Cl)c1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom flask was added 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (300 mg, 1.363 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to −78° C. Ethylmagnesium bromide in ether (3.0 M, 0.454 mL, 1.363 mmol) was added and the reaction mixture was allowed to stir for 1 hour at room temperature. LCMS indicated the reaction was complete. The reaction mixture was quenched with a few drops saturated aqueous NH4Cl and allowed to warm to room temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 12 g, 20-100% EtOAc/hexane gradient) to give the title compound as a pasty yellow solid. ESI-MS m/z [M+H]+ calc'd for C8H8ClN3S, 214. found 214.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14](=[S:16])[NH2:15])=[CH:5][N:4]=1.CO[CH:19](OC)[CH2:20]Br>C(O)C.Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]2[S:16][CH:19]=[CH:20][N:15]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(C(N)=S)c(-c2cccs2)n1
Reactant: COC(CBr)OC
Agent: Cl
Solvent: CCO
Product: CSc1ncc(-c2nccs2)c(-c2cccs2)n1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
2-(Methylthio)-4-(thiophen-2-yl)pyrimidine-5-carbothioamide (0.3 g, 1.12 mmol) suspended in ethanol (2 mL) was treated with bromoacetaldehyde dimethylacetal (0.158 mL, 1.34 mmol). The reaction was stirred at reflux overnight. No product formtion was obverved by thin layer chromatography in 20% ethyl acetate/hexanes. Another equivalent of bromoacetaldehyde dimethylacetal was added to the reaction in addition to a few drops of concentrated hydrochloric acid and the reaction kept at reflux for another 3 h. The reaction was cooled down to room temperature and the volatiles removed in vacuo. A solution of saturated sodium bicarbonate was added to the residue, which was extracted with dichloromethane. The organic layer was dried with sodium sulfate and purified by flash chromatography using a gradient of 20 to 60% of ethyl acetate in hexanes. The product was obtained as a brown solid (0.18 g). MS (M+H)+ 292.
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][O:25][CH3:26])[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:28][C:29]1[N:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=1>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][O:25][CH3:26])[C:18]([NH:35][C:32]1[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][N:33]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: Cc1cnc(N)cn1
Reactant: COC[C@@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: COC[C@@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.170 mL, 1.28 mmol) was added to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-((R)-1-methoxypropan-2-yloxy)propanoic acid (Intermediate Y10) (250 mg, 0.85 mmol) in DCM (5 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. A solution of 5-methylpyrazin-2-amine (140 mg, 1.28 mmol) in DCM (5 mL) was added to the reaction mixture and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL), extracted with DCM (2×25 mL), the combined organic layers were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 90% ethyl acetate in isohexane to afford the product (170 mg, 51.8%). 1H NMR (400 MHz, DMSO) δ 0.01 (d, 6H), 0.80 (s, 9H), 0.91 (d, 3H), 2.35 (s, 3H), 3.09-3.23 (m, 5H), 3.47-3.63 (m, 3H), 4.35-4.40 (m, 1H), 8.20 (s, 1H), 9.09 (s, 1H), 9.63 (s, 1H); m/z (ESI+) (M+H)+=384.43; HPLC tR=2.99 min.