Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:22]=[C:21]([C:23](=[O:38])[NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)(=[O:27])=[O:26])[CH:20]=[CH:19][C:18]=1[C:39]1[C:40]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[N:41][N:42]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:43]=1[CH2:44][CH2:45][CH2:46][CH3:47])=[O:16])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:22]=[C:21]([C:23](=[O:38])[NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)(=[O:27])=[O:26])[CH:20]=[CH:19][C:18]=1[C:39]1[C:40]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[N:41][N:42]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:43]=1[CH2:44][CH2:45][CH2:46][CH3:47])=[O:16]
Reactant: CCCCc1c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C(=O)OCC)nn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN)c(C(=O)OCC)nn1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To the solution of ethyl 4-(2-((S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (60 mg, 0.075 mmol, Example 261) in THF (2.0 mL) was added triphenylphosphine (59 mg, 0.226 mmol) followed by 0.2 ml of 1N NaOH. The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was quenched with sat. aq. sodium bicarbonate solution and then extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-15% methanol/DCM). The residue was lyophilized from acetonitrile/water to give the title compound (29 mg, 50%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.60 (s, 1H), 8.32 (s, 1H), 8.19-7.91 (m, 5H), 7.58-7.34 (m, 8H), 7.21-7.00 (m, 3.5H), 6.79-6.78 (m, 0.5H), 5.21-5.20 (m, 0.5H), 4.74-4.70 (m, 0.5H), 4.43-4.10 (m, 3H), 3.75-3.74 (m, 0.5H), 3.62-3.60 (m, 0.5H), 3.01-3.00 (m, 2H), 2.75-2.48 (m, 4H), 1.13-0.92 (m, 4H), 0.99 (t, J=8 Hz, 3H), 0.57-0.54 (m, 3H); MS(ESI+) m/z 770.5 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[C:12]([CH:14]([OH:17])[C:15]#[N:16])[CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH-].[Na+]>O>[NH2:16][CH2:15][CH:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:13]=1)[OH:17]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC(O)c1cccc(Oc2ccccc2)c1

Procedure:
10 g of 3-phenoxybenzaldehyde cyanohydrin were added dropwise to a mixture of 5.1 g of lithium aluminum hydride and 500 ml of tetrahydrofuran, whilst ice-cooling, and the resulting mixture was heated under reflux for 4 hours. At the end of this time, 5 ml of water, 6 ml of a 15% w/v aqueous solution of sodium hydroxide and 18 ml of water were added in that order to the reaction mixture, whilst ice-cooling. Insoluble materials were filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 3:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give the title compound having an Rf=0.32 (thin layer chromatography over silica gel, using a 5:5:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][CH2:7][CH:8]([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:9]([CH:8]1[O:16][C:29](=[O:31])[N:6]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=2)[CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(CNc1ccc(Br)cc1)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(Cc2ccccc2)CN1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 121.6 %

Procedure:
A solution containing 1-(4-bromoanilino)-3-phenyl-2-propanol (1.90 g, 0.00621 mol), N,N-diisopropylethylamine (2.48 g, 0.0193 mol) and N,N-dimethylaminopyridine (0.152 g, 0.00124 mol) in anhydrous dichloromethane (64 mL) was cooled to 0° C. and the solution of triphosgene (0.92 g, 0.0031 mol) in anhydrous dichloromethane (16 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature while stirring under an atmosphere of nitrogen for 18 hours. The organic phase was washed with saturated solution of sodium bicarbonate in water (70 mL), brine (60 mL) and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 5-benzyl-3-(4-bromophenyl)-1,3-oxazolan-2-one (1.25 g, 0.00377 mol) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:20][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Br)ccc1Sc1ccccc1
Product: Cc1ccc2c(Nc3cc(Br)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 121c (437 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (129 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 6.43 (d, J=6.99 Hz, 1 H) 7.20 (d, J=8.46 Hz, 1 H) 7.34 (s, 5 H) 7.69 (dd, J=8.82, 2.21 Hz, 1 H) 7.81 (m, 2 H) 8.47 (d, J=6.99 Hz, 1 H) 8.95 (d, J=8.46 Hz, 1 H); MS (ESI+) m/z 422 (M+H−TFA)+.
Reaction SMILES: N[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.N([O-])=O.[Na+].O[PH2]=O>O.C1COCC1>[Br:13][C:8]1[CH:7]=[C:3]([CH:2]=[C:10]([O:11][CH3:12])[CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1cc(Br)cc(C(=O)O)c1N
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)cc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution of 2-amino-5-bromo-3-(methyloxy)benzoic acid (16.40 g, 66.65 mmol) in H2O (80 mL), was added conc. HCl (30 mL) and THF (5 mL) at 0° C. The reaction mixture was stirred for 30 min, and then NaNO2 (14.00 g, 202.91 mmol) was cautiously added to the solution. This solution was stirred for 2 h, and then H3PO2 (22.00 g, 333.35 mmol) was cautiously added to the solution. The solution was kept stirring overnight at the room temperature (monitored by TLC), then filtered and rinsed with water (50 mL×2). The resulting solid was dried to afford 3-bromo-5-(methyloxy)benzoic acid (9.60 g, 62%). 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J=1.6 Hz, 1H), 7.31 (q, J=16.8 Hz, 1H), 7.21 (t, J=16.8 Hz, 1H), 3.84 (s, 1H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C:3]([O:5]C)=O.[NH2:15][CH2:16][CH2:17][SH:18].C(=O)([O-])[O-].[K+].[K+].COC(=O)CSC(C1C=CC=C(OC)C=1)CN>O.C(O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH:2]2[S:18][CH2:17][CH2:16][NH:15][C:3]2=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(Br)c1cccc(OC)c1
Reactant: NCCS
Agent: COC(=O)CSC(CN)c1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cccc(C2SCCNC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
In a 500 mL round-bottomed flask, methyl 2-bromo-2-(3-methoxyphenyl)acetate (5.2 g, 20.1 mmol), 2-aminoethanethiol (1.55 g, 20.1 mmol) and potassium carbonate (5.55 g, 40.1 mmol) were combined with ethanol (150 ml) to give a light yellow suspension. The resultant mixture was stirred at 85° C. (bath temp.) for 2.5 h. No starting material remained. The intermediate, [2-amino-1-(3-methoxy-phenyl)-ethylsulfanyl]-acetic acid methyl ester, was the major product with 25% of the cyclized product. The mixture was further heated at reflux for an additional 4.5 h. Complete by LCMS. Reaction mixture was allowed to cool to room temperature and sit overnight. The reaction mixture was poured into 500 mL H2O and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting pale yellow solid was triturated with cold ether and dried under vacuum to afford 2-(3-methoxyphenyl)thiomorpholin-3-one (3.7 g, 83%) as a yellow solid. (M+H)+=224 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.88 (td, J=5.81, 2.78 Hz, 2H) 3.67 (td, J=5.81, 3.54 Hz, 2H) 3.82 (s, 3H) 4.63 (s, 1H) 6.42 (br. s., 1H) 6.85 (ddd, J=8.34, 2.53, 0.76 Hz, 1H) 7.00 (t, J=2.15 Hz, 1H) 7.01-7.05 (m, 1H) 7.29 (t, J=7.93, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[C:13]([O-])(=[O:15])[CH3:14].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:13]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([Cl:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: Clc1cccc2c1CNCC2
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cccc(Cl)c2C1

Procedure:
A mixture of 20.4 g. (0.1 mole) 8-chloro-1,2,3,4-tetrahydroisoquinoline, hydrochloride, 9.85 g. (0.12 mole) sodium acetate 40 ml. acetic anhydride and 100 ml. acetic acid was heated for 3 hours on a steambath with stirring. After the solvent was removed under reduced pressure, the residue was dissolved in water which was then made basic with concentrated ammonium hydroxide. The crude product was extracted into methylene chloride and the organic solution was washed with water, 10% hydrochloric acid, water and 5% aqueous sodium bicarbonate. The organic solution was then dried over anhydrous magnesium sulfate and then concentrated to dryness under vacuum to afford 2-acetyl-8-chloro-1,2,3,4-tetrahydroisoquinoline as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[CH3:19][C:16]1[O:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: Cc1cnc(C2=CCN(Cc3ccccc3)CC2)o1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cnc(C2CCNCC2)o1
Yield: 91.8 %

Procedure:
25 g 1-benzyl-4-(5-methyl-oxazol-2-yl)-1,2,3,6-tetrahydro-pyridine and 6 g palladium charcoal in 200 mL tetrahydrofuran and 200 mL ethanol were stirred at RT for 12 h under hydrogen atmosphere (30 psi). The mixture was filtered and the filtrate concentrated to yield 15 g of the desired product. Rf: 0.05 (petrolether/ethyl acetate=1/1), (M+H)+: 167
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)C.[S:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=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>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:27][CH:28]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To the solution of Ethyl 3-bromo-5-(4-chlorophenyl)thiophene-2-carboxylate (compound 33a, 1.45 g, 4.19 mmol) in a mixture of toluene: ethanol (10:40 ml) was added (4-sulfamoylphenyl)boronic acid (0.84 g, 4.19 mmol) and potassium carbonate (1.16 g, 8.39 mmol) at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100° C. for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite, the celite cake was washed with Ethanol (2×25 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.35 g, 76.27%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:16])[CH:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][C:9]([OH:11])=[O:10]>O.O1CCOCC1>[CH2:12]([CH:7]([CH2:8][C:9]([OH:11])=[O:10])[C:6]([OH:16])=[O:5])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)C(CC(=O)O)CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CC(CC(=O)O)C(=O)O
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A solution of lithium hydroxide monohydrate (26 mg, 0.61 mmol) in water (250 μl) was added to a stirred solution of (2R) 2-isobutylsuccinic acid 1-methyl ester (100 mg, 0.53 mmol) in 1,4-dioxane (500 μl). The mixture was stirred for 2 hours then lithium hydroxide monohydrate (26 mg, 0.61 mmol) was added and stirring continued for 24 hours. The majority of solvents were removed by distillation in vacuo then the residue was dissolved in water (5 ml) and acidified using hydrochloric acid (1M) to pH=1. The product was extracted into dichloromethane (5×5 ml), dried (Na2SO4) and the solvent removed in vacuo to obtain (2R) 2-isobutylsuccinic acid (49 mg, 53%) as a solid. HPLC-MS (single UV peak with Rt=6.223 mins, 197.1 [M+Na]+).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[S:5][CH2:4][C:3]1([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14].[CH2:23]([Si](C)(C)C)[CH:24]=[CH2:25]>ClCCCl.[I-].[Zn+2].[I-]>[CH2:25]([CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[S:5][CH2:4][C:3]1([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14])[CH:24]=[CH2:23]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2O)cc1
Reactant: C=CC[Si](C)(C)C
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: C=CCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a solution of 4-hydroxy-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (11.4 g, 36.3 mmol) in 1,2-dichloroethane (360 ml) was added zinc iodide (13.9 g, 43.5 mmol) and allyltrimethylsilane (11.5 ml, 72.5 mmol) which was stirred for 1 day at room temperature. The reaction solution was added saturated aqueous NHCl solution, extracted with CHCl3, and washed with brine. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica-gel with 1% AcOEt in hexane to give 9.19g (74%) of (3RS,4RS)-4-allyl-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8](C=O)[CH:7]=[CH:6][C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:21]([O:26][CH3:27])([O:24][CH3:25])OC.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:21]([O:24][CH3:25])[O:26][CH3:27])[CH:7]=[CH:6][C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(C=O)ccc1OCc1ccccc1
Reactant: COC(OC)OC
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(OC)OC)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
39.1 g of 2-benzyloxy-5-formylbenzoic acid methyl ester was dissolved in 300 ml of methanol. 60 ml of trimethyl orthoformate and 2 g of p-tosylic acid were added thereto, and the solution was heated under refluxed for 4 hours. After the solution was cooled down to room temperature, 5 ml of triethylamine was added thereto, and the solution was evaporated. The residue was dissolved in ethyl acetate, and the solution was successively washed with water and saturated sodium bicarbonate water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 39.08 g of 2-(benzyloxy)-5-(dimethoxymethyl)benzoic acid methyl ester.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1([C:15]2([O:19][CH2:18]2)[CH2:16]Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[OH:19][CH2:18][C:15]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:16]1
Reactant: ClCC1(c2ccccc2)CO1
Reactant: Oc1ccccc1O
Product: OCC1(c2ccccc2)COc2ccccc2O1

Procedure:
Catechol and 2-phenyl epichlorohydrin were reacted to give the intermediate 2-hydroxymethyl-2-phenyl-1,4-benzodioxan (method (a) of Example 2) which was converted to the imidazoline compound by method (b) of Example 2. The free base was recrystallised from light petroleum (60°-80°); m.p. 114.5°-116°.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]([CH3:38])([CH3:37])[CH2:15][O:16][C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18].O[CH:40]([CH2:62][CH2:63][CH3:64])[CH:41]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>C1COCC1>[CH3:38][C:14]([CH3:37])([CH3:13])[CH2:15][O:16][C:17]([NH:19][C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C@H:40]([CH2:62][CH2:63][CH3:64])[CH:41]([C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:53])[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1)=[O:18]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)c([N+](=O)[O-])c1)NC(=O)OCC(C)(C)C
Reactant: CCCC(O)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCC[C@@H](Oc1ccc(C[C@H](NC(=O)OCC(C)(C)C)C(=O)OCC)cc1[N+](=O)[O-])C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
5.43 g of polymer-bound DEAD (diethyl azodicarboxylate) in 30 ml of THF are added to a solution of 4 g of 12 and 5.35 g of dibenzyl 2-hydroxypentanedicarboxylate (X) in anhydrous THF. The mixture is shaken for 16 hours. The polymer is separated off, and the solvent is removed. The residue is taken up in ethyl acetate, and conventional work-up gives 13, which is not purified further for the further reaction.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([C:15]4[S:16][C:17]([C:26]([F:29])([F:28])[F:27])=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=4)[O:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([C:15]4[S:16][C:17]([C:26]([F:27])([F:28])[F:29])=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=4)[O:12][N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: FC(F)(F)c1sc(-c2nc(-c3ccc4c(c3)CCN4)no2)cc1-c1ccccc1
Temperature: 19 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a stirred solution of 3-(1H-indol-5-yl)-5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazole (40 mg, 0.097 mmol) in acetic acid at 12-14° C. was added slowly sodium cyanoborohydride (19 mg, 0.29 mmol). At the end of the addition the reaction was allowed to warm to 18-20° C. and was stirred for 2 h. After completion the reaction mixture was neutralized with 50% sodium hydroxide and extracted with ethyl acetate (50 ml×2). The organic layers were combined and dried over Na2SO4 and removed under reduced pressure. The crude indoline compound was purified by column chromatography using CH2Cl2/MeOH (9:1) to offer the product in 84.3% yield (33.8 mg, 0.082 mmol). MS (EI) m/z: 414 (M+)
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH2:19]([NH2:22])[C:20]#[CH:21]>CO>[C:1]([NH:3][C:4]([NH:22][CH2:19][C:20]#[CH:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: C#CCN
Reactant: CSC(=NCCSCc1ncccc1Cl)NC#N
Solvent: CO
Product: C#CCNC(=NCCSCc1ncccc1Cl)NC#N
Yield: 67.3 %

Procedure:
A mixture of the product of Step A (3.0 g; 10.0 mmoles) and propargylamine (5.16 g; 93.7 mmoles) in methanol (20 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 16 hours. The reaction mixture was evaporated under reduced pressure and the crude product was recrystallized from isopropyl alcohol with activated carbon treatment to give 2.07 g of the title compound; mp 115°-116°.
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]([F:33])([F:32])[F:31])CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([C:28]#[C:29][C:30]([F:33])([F:32])[F:31])[C:3]([NH2:22])=[N:4][C:5]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](C#CC(F)(F)F)(CCCC)CCCC
Reactant: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N)c(C#CC(F)(F)F)nc2-c2ccc(C)cc2)cc1
Temperature: 140 °C

Procedure:
A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (Ex 1, step 3) (200 mg, 0.565 mmol) in dioxane (4 ml) bubbled with nitrogen was treated with tributyl(3,3,3-trifluoroprop-1-ynyl)stannane (238 mg, 0.621 mmol) and PdCl2(dppf)-CH2Cl2-Adduct (46.1 mg, 0.056 mmol). The resulting mixture was heated at 140° C. for 1 hour using microwave radiation. After cooling to RT, the mixture was concentrated under reduced pressure. The crude residue was dissolved in DCM and loaded onto a 25 g Silica column. Purification by chromatography on silica eluting with 0-5% EtOAc in iso-hexane afford the title compound;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@@H:2]12.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([N:4]1[CH2:5][CH2:6][O:1][C@@H:2]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][C@@H:3]12)(=[O:25])[CH3:24]
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCO[C@@H]2c3ccccc3OCC[C@H]21
Reaction time: 8 h

Procedure:
To a stirred solution of 2.41 g of trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine, prepared in accordance with Example 2, and 3.5 ml of triethylamine dissolved in 50 ml of methylene chloride is added dropwise a solution of 0.85 ml of acetyl chloride dissolved in 25 ml of methylene chloride. The mixture is stirred overnight, washed with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. The volatiles are removed by evaporation leaving an oil which yields the compound trans-4-acetyl-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine having a mp. of 97°-98° C.