Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(F)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (49 mg, 0.22 mmol) was dissolved in 3 mL of CH2Cl2, treated with 4-chlorophenylisocyanate (40 mg, 0.27 mmol), and stirred at room temperature overnight. The solvent was removed under reduced pressure, dissolved in DMSO (5 ml), and purified by preparative HPLC to afford Compound 27 as a white solid, 41 mg, 49% yield: LCMS m/z (%)=377 (M+H37Cl, 31), 375 (M+H15Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.77 (s, 1H), 8.67 (s, 1H), 7.66 (ddd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.60 (d, J=9.2 Hz, 2H), 7.54 (d, J=2.8 Hz, 1H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.39 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([F:17])[CH:10]=2)=[O:8])[C:3]2[CH:18]=[N:19][CH:20]=[CH:21][C:2]1=2.B(Br)(Br)Br.CCCCCC.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:17])[CH:10]=2)=[O:8])[C:3]2[CH:18]=[N:19][CH:20]=[CH:21][C:2]1=2
Reactant: COc1ccc(C(=O)N2CCOc3ccncc32)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: O=C(c1ccc(O)c(F)c1)N1CCOc2ccncc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 31.6 %

Procedure:
In a 10 ml flask, (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(3-fluoro-4-methoxy-phenyl)-methanone (30 mg, 0.104 mmol) was dissolved in dichloromethane and the mixture was cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (1.25 ml, 1.25 mmol) was added thereto and stirred at room temperature for 10 hours. n-hexane and water were added and then filtered to obtain solid. The resulting solid was purified by preparative LC-Mass using 0.05% TFA in acetonitrile and 0.05% TFA in water solvent. The fractions containing the product were collected and adjusted to pH 6 to 7 with saturated solution of sodium hydrogen carbonate. The organic layer was extracted with ethyl acetate. The combined organic layer was evaporated under reduced pressure to obtain the target compound 26 as white solid (9 mg, 28%).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:30])[C@@H:18]([N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[O:29]=[S:24]1(=[O:28])[CH2:25][CH2:26][CH2:27][N:23]1[C@@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][NH:8][CH2:12]2)[CH2:15][CH2:14]1)=[O:30]
Reactant: [H][H]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCCS1(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCCS1(=O)=O

Procedure:
(25)-N-[(3aS,4R,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl]-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methylpentanamide (265 mg, 0.611 mmol) from Example 220 Step D and ethanol (20 mL) were added to 20% Pd(OH)2 on carbon, wet (53.0 mg, 0.377 mmol) in a 50 mL pressure bottle and stirred for 48 hours under 30 psi hydrogen at 50° C. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give (2S)-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]pentanamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.89 (dd, J=6.6, 18.9, 1H), 4.55-4.50 (m, 1H), 4.42-4.31 (m, 1H), 3.99-3.91 (m, 1H), 3.44-3.39 (m, 1H), 3.34 (dd, J=2.8, 11.4, 0.5H), 3.29-3.25 (m, 2H), 3.21 (dd, J=5.4, 13.2, 1H), 3.13 (dd, J=7.7, 11.2, 0.5H), 2.99 (td, J=7.5, 10.8, 1H), 2.79 (dd, J=3.3, 10.9, 0.5H), 2.73 (dd, J=3.3, 10.9, 0.5H), 2.69-2.55 (m, 2H), 2.31-2.16 (m, 2H), 2.12-2.00 (m, 1H), 1.94-1.78 (m, 4H), 1.69 (dddd, J=5.2, 11.0, 16.7, 19.8, 2H), 1.49-1.29 (m, 1H), 0.88 (t, J=6.5, 3H), 0.83 (t, J=6.4, 3H); MS (ESI+) m/z 344 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:19]=[N:18][CH:17]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:20]3[CH:19]=[N:18][CH:17]=[N:16][CH:21]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl--phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrimidin-5-yl-benzaldehyde, of Preparation 26, using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3)δ 9.19 (s, 1H), 8.92 (s, 2H), 7.55 (m, 4H), 7.25 (m, 3H), 7.11 (d, 1H), 3.87 (s, 2H), 3.81 (s, 2H), 3.66 (s, 3H), 2.95 (t, 2H), 2.63 (t, 2H); MS 362 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: N
Reactant: CC(O)C#Cc1nc(Cl)c2ncn(C)c2n1
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C#Cc1nc(N)c2ncn(C)c2n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-2-ol (4.8 g, 20.34 mmol) in dioxane (30 ml) was added 30% w/w water solution of ammonia (60 ml). The reaction mixture was stirred overnight in an autoclave at 70° C. The solution was evaporated at atmospheric pressure at 50° C. and then under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 97/3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2([C:14](O)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C1COCC1.O>[CH3:32][N:33]([CH3:34])[C:14]([C:8]1([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[CH3:30])=[CH:23][CH:24]=3)[CH:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:15]
Reactant: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(=O)O)CCOCC3)c2)cc1
Reactant: CNC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1-c1ccc(COc2cc(F)cc(C3(C(=O)N(C)C)CCOCC3)c2)cc1
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
To a stirred suspension of 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylic acid (100 mg, 0.24 mmol), dimethylamine hydrochloride (98 mg, 1.2 mmol) and triethylamine (253 mg, 2.5 mmol) in THF (50 ml) at 0° C. was added diethyl cyanophosphonate (44 mg, 0.27 mmol). After 10 min, the reaction was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated. Purification of the residue was performed by column chromatography (silica-gel, 50 g; gradient polarity of eluant from dichloromethane to 5% methanol in dichloromethane) to give 117 mg of crude product as a colorless foam. Recrystallization from a mixture of isopropyl ether-ethyl acetate (1:1) to give the titled compound (51 mg, 50%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:52])([CH3:51])[CH2:48][O:49][CH3:50])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:52])([CH3:51])[CH2:48][O:49][CH3:50])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogen carbonate (0.74 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({2-ethyl-1-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 61%).
Reaction SMILES: CS(OC[C@H]1OC1)(=O)=O.[CH3:10][O:11][C:12]1[C:21]2[N:20]=[C:19]([NH2:22])[N:18]3[CH2:23][CH2:24][N:25]=[C:17]3[C:16]=2[CH:15]=[CH:14][C:13]=1[O:26][CH2:27][C@H:28]1[CH2:30][O:29]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[NH2:37][C:38]1[N:43]=[CH:42][C:41]([C:44](O)=[O:45])=[CH:40][N:39]=1>>[NH2:37][C:38]1[N:43]=[CH:42][C:41]([C:44]([NH:22][C:19]2[N:18]3[CH2:23][CH2:24][N:25]=[C:17]3[C:16]3[CH:15]=[CH:14][C:13]([O:26][CH2:27][C@@H:28]([OH:29])[CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:12]([O:11][CH3:10])[C:21]=3[N:20]=2)=[O:45])=[CH:40][N:39]=1
Reactant: Nc1ncc(C(=O)O)cn1
Reactant: C1COCCN1
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Agent: CS(=O)(=O)OC[C@@H]1CO1
Product: COc1c(OC[C@@H](O)CN2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21

Procedure:
Prepared using (S)-glycidyl methanesulfonate (Intermediate H, Step 1) in place of (R)-glycidyl methanesulfonate (Intermediate F, Step 1), and morpholine in place of piperidine in Step 1, and 2-amino-5-pyrimidinecarboxylic acid in place of nicotinic acid in Step 2 (75.0 mg, 71%): HPLC ret. time 0.81 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 3.14-3.38 (m, 4H), 3.44-3.52 (m, 2H), 3.69 (app t, J=12.0 Hz, 1H), 3.77/app t, J=12.1 Hz, 1H), 3.90-3.98 (m, 2H), 4.00 (s, 3H), 4.16-4.25 (m, 4H), 4.38-4.44 (m, 1H), 4.46-4.52 (m, 2H), 7.43 (d, J=9.1 Hz, 1H), 7.99 (d, J=9.1 Hz, 1H), 8.97 (s, 2H); mass spectrum m/z 497 ((M+1)+, 8.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:35]([CH3:37])[CH3:36]>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH:35]([CH3:37])[CH3:36])=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=C2Oc3cc(OC(C)C)ccc3C2=O)cc(OC)c1
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g, potassium carbonate 0.58 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to -obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for four hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 316.1 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:12]=[CH:13][C:14]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C([O:28][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=O)[CH:30]=1)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH3:17])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:13][C:14]=1[C:31]1[CH2:32][CH2:33][CH2:34][C:29](=[O:28])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC1=CC(=O)CCC1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 3.89 g. (10 mmoles) of 2-(3-benzyloxy-4-bromophenyl)-2-methyloctane in 10 ml. of tetrahydrofuran was slowly added to 360 mg. (14.4 mmoles) of 70-80 mesh magnesium metal. The resulting mixture was refluxed for 30 minutes and then cooled to 0° C. To this solution was slowly added a solution of 1.40 g. (10 mmoles) of 3-ethoxy-2-cyclohexen-1-one in 3 ml. of tetrahydrofuran. The reaction mixture was stirred for 30 minutes at 0° C. and then quenched by the addition of 20 ml. of 1 N sulfuric acid and heating on the steam bath for 30 minutes. It was then cooled and added to 200 ml. of ether-200 ml. of water. The organic extract was washed successively with 200 ml. of saturated sodium bicarbonate and 200 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product was purified via column chromatography on 170 g. of silica gel eluted with 1:1 ether:pentane to yield 2.5 g. (54%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](=[O:21])[CH3:20])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Br-:22].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>CC(O)=O.Br>[NH2:1][C:2]1[C:3]([C:19](=[O:21])[CH2:20][Br:22])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(C)=O)n2)CC1
Reactant: [Br-]
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)CBr)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.7 %

Procedure:
A solution of 1-(3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-yl)ethanone (510 mg, 1.627 mmol) in AcOH (2 mL) and HBr in AcOH (0.5 mL of 33% w/v, 2.039 mmol) was treated with pyridinium tribromide (544.5 mg, 1.708 mmol) and the mixture allowed to stir at ambient temperature for 2 hours. The reaction was poured into ether (50 mL), partitioned between EtOAc/water and extract with EtOAc (3×). The mixture was dried (MgSO4), filtered, evaporated down and the resultant residue was purified on silica gel by flash column chromatography (0-100% EtOAc/Petrol) to afford the title compound as a orange oil (68 mg, 11% Yield). 1H NMR (400.0 MHz, DMSO) d 1.23 (t, 3H), 3.12 (q, 2H), 3.31 (m, 4H), 3.52 (m, 4H), 4.86 (s, 2H), 7.21 (s, 1H), 8.34 (s, 1H) ppm; MS (ES+) 393.91
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][C:18](=[O:23])[CH:17]=[CH:16]2)=[O:7])[CH3:4].[C:24](O)(=O)[CH3:25].C([OH:30])C>>[OH:19][C:20]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][CH2:3][CH3:4])=[O:7])=[CH:14][C:15]=1/[CH:16]=[CH:17]/[C:18]([O:23][CH2:24][CH3:25])=[O:30]
Reactant: CCO
Reactant: CC(=O)O
Reactant: CCOC(=O)CCCCOc1ccc2oc(=O)ccc2c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1cc(OCCCCC(=O)OCC)ccc1O
Reaction time: 4 h

Procedure:
Sodium hydride (content: 62%; 60 mg) was gradually added to anhydrous ethanol (10 ml) and dissolved. A solution of the ester (314 mg; prepared in reference example 26) in anhydrous ethanol (1 ml) was added to the solution. The mixture was stirred for 4 hr. at 70° C. and then for 30 min at 80° C. Glacial acetic acid (210 mg) was added to the reaction solution with ice-cooling to stop the reaction. The solvent was removed from the reaction solution under reduced pressure. The residue was diluted with ether. The mixture was washed with water. Aqueous layer was removed. Ethereal layer was dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (122 mg) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[NH:12][CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[C:19]1(C)C=CC=C[CH:20]=1>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>[CH:19]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[NH:12][CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1)=[CH2:20]
Reactant: Cc1ccccc1
Reactant: Brc1ccc(N2NC=C(c3ccccc3)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc(N2NC=C(c3ccccc3)O2)cc1

Procedure:
2-(4-Bromophenyl)-5-phenyl-oxadiazole (2.0 g, 6.64 mmol) was dissolved in degassed toluene (30 ml). Pd(PPh3)4 (0.15 g, 0.133 mmol) and nBu3Sn(CHCH2)(2.11 g, 6.64 mmol) were added under dry nitrogen. The solution was refluxed for 4 hours, cooled, and evaporated to give a yellow solid. This solid was dissolved in toluene (20 ml), silica added (20 g) and the solvent removed in vacuo. This solid was placed on top of a short column of silica and flushed with hexane to remove nBu3SnBr, and the column then stripped with methanol. The methanol was evaporated, and the residue recrystallised from hexane to give white crystals of 2-(4-vinylphenyl)-5-phenyloxadiazole, (m.pt. 83-84° C., lit.ii 82-84° C.)1.1 g, 67%. 1H NMR (CDCl3, 300 MHz) δ 8.1-8.0 (m, 4H, aromatic CH), 7.6-7.6 (m,5H, aromatic CH), 6.77 (d of d, 3JHH 17.4 Hz and 10.8 Hz, ChCH2), 6.90 (d, 3JHH 17.4 Hz, CHCH2), (d of d, 3JHH 10.8 Hz, CHCH2).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@@H:6]([C:8]([OH:10])=O)[C@H:5]([C:11]([OH:13])=O)[CH2:4][C:3]=1[CH3:14].S(Cl)(Cl)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(OCC)C>[CH2:19]([N:21]([CH2:22][CH3:23])[C:8]([C@H:6]1[C@H:5]([C:11]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:13])[CH2:4][C:3]([CH3:14])=[C:2]([CH3:1])[CH2:7]1)=[O:10])[CH3:20]
Reactant: CCNCC
Reactant: CC1=C(C)C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)N(CC)CC
Reaction time: 2 h

Procedure:
To trans-1,2-dimethylcyclohexene-4,5-dicarboxylic acid (1.98 g 0.01 mol) heated to 80° C., was added thionyl chloride (2.38 g, 0.02 mol) over 1 hr. The mixture was kept at this temperature for a further two hours, then cooled and added dropwise to a diethyl ether solution (45 ml) of excess diethylamine (14.6 g, 0.2 mol) cooled to ice bath temperature. The solvent was removed to give the crude product as an oil which was not purified for use in the next stage.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[CH:5]1[CH2:15][O:16][CH:17]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1.C(N(CC)CC)C.[C:57]1([CH3:67])[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:3][CH2:2][O:1][S:63]([C:60]2[CH:61]=[CH:62][C:57]([CH3:67])=[CH:58][CH:59]=2)(=[O:65])=[O:64])[CH:5]1[CH2:15][O:16][CH:17]1[CH:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])=[CH:27][CH:28]=2)[CH2:21][CH2:20][N:19]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:18]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2N(CCO)c3ccccc3C2(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2N(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 0.457 g of tert-butyl 3-[1-(2-hydroxyethyl)-3,3-dimethyl-2,3-dihydro-1H-indol-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.274 ml of triethylamine and 0.008 g of 4-dimethylaminopyridine in 10 ml of dichloromethane is admixed with stirring at 0° C. with 0.301 g of p-toluenesulphonyl chloride and stirred at room temperature over 18 hours. The reaction mixture is admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.C(O)=O.CS(O)(=O)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CSc1ccccc1F)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O=CO
Solvent: O
Product: O=C(O)C(CSc1ccccc1F)c1ccc(F)cc1
Yield: 95.6 %

Procedure:
The crude ester from Step B (5.3 g, 16 mmole) was combined with 20 ml of 88% formic acid and 2.1 ml (33 mmole) of methane sulfonic acid. The emulsion was refluxed for five hours during which time it gradually became homogeneous. After cooling, water and methylene chloride were added and the aqueous phase was separated and extracted twice with methylene chloride. The organic phases were combined, dried (MgSO4) and concentrated. The crude residue was taken up in 4% ethyl acetate/hexane and filtered through a plug of silica gel to remove nonpolar impurities. The product acid was then rinsed from the silica gel with ethyl acetate and the solvent concentrated. The acid was a colorless solid (4.5 g, 95% yield). 1H NMR (CDCl3) δ: 10.05 (1H, br s), 7.20 (5H, m), 7.03 (3H, m), 3.81 (1H, dd, J=6, 8 Hz), 3.57 (1H, m), 3.23 (1H, dd, J= 6, 12 Hz).