Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Cl.C(=O)(O)[O-].[Na+].[CH2:14]([O:21][C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.O1CCOCC1.C(OCC)(=O)C>[CH2:14]([O:21][C:22]1[N:27]2[CH:3]=[CH:4][N:28]=[C:26]2[CH:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cc(-c2ccccc2)cc(OCc2ccccc2)n1
Reactant: COC(CBr)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(COc2cc(-c3ccccc3)cc3nccn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bromoacetaldehyde dimethyl acetal (0.16 mL, 1.38 mmol) in water (2 mL) was added hydrochloric acid (0.046 mL, 0.276 mmol). After stirring at room temperature for 2 hours, the reaction was heated to 80° C. for 40 mins to give a clear solution. The reaction was cooled down to room temperature, and sodium bicarbonate (147 mg, 1.75 mmol) was added, followed by a solution of 6-(benzyloxy)-4-phenylpyridin-2-amine (254 mg, 0.919 mmol) in 1,4-dioxane (2 mL). The reaction was stirred overnight at ambient temperature, then diluted with ethyl acetate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 5-(benzyloxy)-7-phenylimidazo[1,2-a]pyridine. LRMS (ESI) calculated for C20H17N2O [M+H]+, 301.1; found 301.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][Si](C(C)(C)C)(C)C)=[CH2:12])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][OH:14])=[CH2:12])=[CH:22][CH:23]=1
Reactant: C=C(CCOCc1ccc(OC)cc1)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C(CO)CCOCc1ccc(OC)cc1

Procedure:
Combine 4-(p-methoxybenzyloxy)-2-(t-butyldimethylsilyloxymethyl)but-1-ene (1.5 g, 4.75 mmol) and a solution of tetrabutylammonium fluoride (4.75 mL, 1M, 4.75 mmol). After 2.5 hours chromatograph on silica gel eluting with 1/2 ethyl acetate/hexane to give the title compound; Rf =0.24, silica gel, 1/2 ethyl acetate/hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[O:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: CC1(C)CCC(Oc2ncnc3c(N)cccc23)CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC(Oc2ncnc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-((4,4-dimethylcyclohexyl)oxy)quinazolin-8-amine (Intermediate-10, 100 mg, 0.369 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 211 mg, 0.738 mmol), oxalyl chloride (139 mg, 1.11 mmol), DMF (1 drop) and DIPEA (143 mg, 1.11 mmol) in CH2Cl2 (5 mL) to afford 8 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.81-8.62 (m, 2H), 8.16 (br t, 1H), 7.95-7.92 (d, J=8.4 Hz, 1H), 7.74-7.69 (t, J=8.4 Hz, 1H), 7.41-7.30 (m, 2H), 5.37 (m, 1H), 4.31-4.30 (d, J=5.4 Hz, 2H), 1.94 (m, 2H), 1.82-1.78 (m, 2H), 1.52 (m, 2H), 1.34 (m, 2H), 1.14 (s, 9H), 1.00 (s, 3H), 0.67 (s, 3H); MS (m/z): 541.14 (M+H)+.
Reaction SMILES: [CH3:1][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:35])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[CH:3]=1.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[CH3:1][N:2]1[CH:7]=[CH:6][CH2:5][C:4]([C:8](=[O:35])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]([CH2:31][CH2:32][Cl:33])[CH2:28][CH2:29][Cl:30])=[CH:25][CH:26]=3)[CH2:12][CH2:11]2)=[CH:3]1
Reactant: C[n+]1cccc(C(=O)NC2CCC(OC(=O)CCCc3ccc(N(CCCl)CCCl)cc3)CC2)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1C=CCC(C(=O)NC2CCC(OC(=O)CCCc3ccc(N(CCCl)CCCl)cc3)CC2)=C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The quaternary salt prepared in Example 81 (0.34 g, 05 mol) was dissolved in 0.5 mL of acetonitrile and taken up in 20 mL of degassed water (bubbling N2) cooled to 0° C. To the stirring solution, sodium bicarbonate (0.27 g, 0.003 mol) was added, followed first by 0.37 g (0.002 mol) of sodium dithionite and then by 20 mL of ethyl acetate. After 90 minutes, the organic phase was removed and the aqueous phase was extracted 3 to 4 times with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and evaporated in vacuo. The residual solid was washed several times with anhydrous ether and dried. The residue thus obtained was applied to a neutral alumina column and eluted with chloroform under pressure. Evaporation of chloroform left 0.18 g (65%) of a hygroscopic yellow solid of the formula ##STR116## The identity of the product was confirmed by UV analysis.
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](Cl)=[O:25]>ClCCCl>[F:20][C:21]1[CH:22]=[C:23]([C:24]([N:8]2[CH2:9][CH2:10][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:18][C:19]=3[CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: ClCCCl
Product: O=C(c1ccc(F)c(F)c1)N1CCc2c([nH]c3ccccc23)C1c1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
The title compound was prepared by the addition of 1-phenyl-2,3,4,9-tetrahydro-1H-beta-carboline (95 mg, 383 μmol), DCE (5 mL), 3,4-difluorobenzoyl chloride (88 mg, 498 μmol), and TEA (1.0 mL) to a 25 mL flask. The solution was allowed to stir at 55° C. for 16 hours. The reaction solution was concentrated, and the crude sample was chromatographed (SiO2, 100% hexane to 25% EtOAc) to yield 53 mg of title compound; 1H NMR (CDCl3) δ 8.02 (1H, br s), 7.53 (1H, d), 7.30-7.33 (6H, m), 7.15-7.23 (5H, m), 7.07 (1H, br s), 3.75 (1H, m), 3.41 (1H, m), 2.93 (1H, m), 2.84 (1H, dd); MS (ESI): 389 (MH+).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15]>C(O)CC(C)C>[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: CC(=O)N1CCNCC1
Solvent: CC(C)CCO
Product: CC(=O)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and N-acetylpiperazine (98 mg; 0.76 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 8 h) and worked up. The crude product obtained in this way is purified by column chromatography; yield: 12 mg (8%), crystals;
Reaction SMILES: [Si]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)(C(C)(C)C)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:58]([O:60][C:61]1[CH:69]=[CH:68][C:64]([CH2:65][CH2:66][NH2:67])=[CH:63][C:62]=1[O:70][CH3:71])[CH3:59].F.F.F.C(N(CC)CC)C>CN(C)C(=O)C>[CH2:58]([O:60][C:61]1[CH:69]=[CH:68][C:64]([CH2:65][CH2:66][NH:67][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=3)([CH3:24])[CH3:23])[CH:15]=2)=[CH:63][C:62]=1[O:70][CH3:71])[CH3:59]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: CCOc1ccc(CCN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOc1ccc(CCNC(=O)c2cccc(CC(C)(C)NC[C@H](O)c3ccc(O)c(CO)c3)c2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
Solutions of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methylphenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90 mg, 0.19 mmol) in N,N-dimethylacetamide (1 mL) and 0-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) in N,N-dimethylacetamide (0.5 mL) were added to a solution of 4-ethoxy-3-methoxyphenethylamine (37 mg, 0.19 mmol) in N,N-dimethylacetamide (0.5 mL). The resulting mixture was stirred for 72 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (700 μL), triethylamine trihydrofluoride (30 μL, 0.19 mmol) was added and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water/0.05% diethylamine:acetonitrile, 5:95 to 95:5, to afford the title compound in 30% yield (30.9 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH:34]2[CH3:40].C([O-])(O)=O.[Na+]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH:34]4[CH3:40])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CC1c2cccc(N)c2C(=O)N1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4C)n2)cc1)OCC
Yield: 66.5 %

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (179.0 mg, 0.4224 mmol) and 7-amino-2,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 157A, 83.7 mg, 0.475 mmol). The reaction mixture was poured into a separatory funnel containing saturated NaHCO3 and was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified using a Teledyne/ISCO Combiflash system, eluting first with 40-100% EtOAc:Heptane and then 0-15% MeOH:CH2Cl2. The product was purified again by MDP (under basic conditions; ammonium bicarbonate buffer (pH 9)) to afford the title product as an off-white solid (158.3 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.61 (br s, 1H), 9.93 (s, 1H), 8.71 (br s, 1H), 8.48 (s, 1H), 7.38-7.80 (m, 3H), 7.15-7.33 (m, 3H), 4.59 (q, J=6.6 Hz, 1H), 3.90-4.02 (m, 4H), 3.22 (d, J=21.5 Hz, 2H), 3.01 (s, 3H), 1.43 (d, J=6.6 Hz, 3H), 1.18 (t, J=6.9 Hz, 6H). MS (ES+): m/z 564.17 (100) [MH+]. HPLC: tR=1.56 min (TOF, polar—3 min).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:26]1[CH:30]([OH:31])[CH2:29][NH:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:28]1[CH2:27][CH2:26][CH:30]([OH:31])[CH2:29]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: OC1CCNC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCC(O)C1

Procedure:
5-(3-Hydroxy-pyrrolidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and DL-3-pyrrolidinol. Mass spectrum (ES) MH+=407.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:15])(=O)=O.O>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([Cl:15])[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCC(=O)CC(=O)OC
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.0 g 3-Oxo-heptanoic acid methyl ester were dissolved in 80 ml dry dichloromethane and 2.82 ml sulfurylchloride were added. The reaction mixture was stirred at room temperature for 30 minutes. 20 ml of water were added and the reaction mixture extracted five times with portions of 30 ml of dichloromethane. The combined organic extracts were washed with water and saturated NaHCO3 solution and brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester as raw material. This material was used without further purification. 6.0 g 2-Chloro-3-oxo-heptanoic acid methyl ester were dissolved in 50 ml ethanol and 6.4 g 4-(Trifluoromethyl)thiobenzamide were added. The reaction mixture was heated under reflux overnight. The solvent was removed under reduced pressure and the residue purified by chromatography with the eluent n-heptane:ethyl acetate=100:1=>60:1. This gives 7.4 g 4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-carboxylic acid methyl ester as yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C@@H:10]1([NH:21][C:22]([NH2:24])=[S:23])[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12]>C(O)C>[BrH:1].[C@@H:10]1([NH:21][C:22]2[S:23][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:24]=2)[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]1[OH:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CCO
Product: Br
Product: CCOC(=O)c1csc(N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n1

Procedure:
Ethyl bromopyruvate (8.99 g., 0.047 mole) was added to a suspension of N-β-D-glucopyranosylthiourea (10 g., 0.042 mole) in 120 ml. of hot ethanol, and the reaction was completed by heating 30 minutes. During the heating, the mixture became a clear solution. The reaction solution was evaporated to dryness in vacuo. The residue was crystallized from ethanol and acetone, filtered, and dried at room temperature in vacuo, yielding 16.03 g. (91.9%); white powder; m.p. 162°-163°(dec.).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C=CC(O)=CC=1)[OH:10].ClOC(C)(C)C.ClCl.Cl.C(Cl)C=C>>[CH2:1]1[O:10][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: CC(C)(C)OCl
Agent: Cl
Agent: ClCl
Solvent: C=CCCl
Product: c1ccc(C2CO2)cc1
Reaction time: 3 h

Procedure:
The reaction given in the above example was repeated with styrene in the presence of 0.1 g. of hydroquinone stabilizer. The styrene charged was 49.3 cc (44.8 g., 430 mmole). The t-butyl hypochlorite charged was 48.0 cc (45.0 g., 408 meq. active chlorine), and the total reaction time was three hours. A trace of hydrochloric acid was found in the aqueous product layer. The product pattern in the organic layer was similar to that observed in the allyl chloride reaction. Saponification, as in Example 5, of the organic layer produced styrene oxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>C(O)(C)C.CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]3[N:3]=2)[CH:23]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: COc1ccc(F)cc1[C@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 160 °C
Reaction time: 24 h
Yield: 32.1 %

Procedure:
In a sealed tube, ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 500 mg, 2.22 mmol), (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride salt (513 mg, 2.22 mmol), and diisopropylethylamine (0.774 mL, 4.43 mmol) were combined in isopropanol (2 mL) and heated at 160° C. for 3 days. 2N NaOH (6 mL) and MeOH (5 mL) were added and the reaction mixture stirred at ambient temperature for 24 hours, followed by heating to 40° C. for 3 hours. The reaction was partially concentrated, treated with saturated aqueous NH4Cl (10 mL) and the mixture extracted with EtOAc. The combined organic extracts were filtered, concentrated and the residue purified by reverse phase chromatography eluting with 0-60% acetonitrile/water to yield the title compound as a pink solid (254 mg, 32.2% yield). MS (apci) m/z=357.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:7][CH3:8])=[N:4][S:5][CH:6]=1.[F:9][S:10]([O:13][CH3:14])(=[O:12])=[O:11]>>[F:9][S:10]([O-:13])(=[O:12])=[O:11].[Br:1][C:2]1[C:3]([O:7][CH3:8])=[N+:4]([CH3:14])[S:5][CH:6]=1
Reactant: COS(=O)(=O)F
Reactant: COc1nscc1Br
Product: COc1c(Br)cs[n+]1C
Product: O=S(=O)([O-])F
Yield: 81 %

Procedure:
4-Bromo-3-methoxyisothiazole (8.0 g, 0.041 mol) and 10 ml of methyl fluorosulfonate were heated at 90° for 45 min. After cooling, the solid was washed with ether to yield 10.3 g (81%) of 4-bromo-3-methoxy-2-methylisothiazolium fluorosulfonate, mp 180°-182° C.
Reaction SMILES: O=[C:2](C1SC=CC=1)[CH2:3]C#N.[C:11]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH3:12].CC1SC=C(C(=O)CC#N)C=1>>[C:11]([O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])([O:19][CH2:20][CH3:21])[CH2:12][CH2:2][CH3:3]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC(=O)c1cccs1
Agent: Cc1cc(C(=O)CC#N)cs1
Product: CCCC(OCC)(OCC)OCC

Procedure:
The general procedure of Example 11 is repeated but replacing the β-oxo-2-thiophenepropionitrile and triethyl orthoacetate employed in that example with equivalent amounts of 5-methyl-β-oxo-3-thiophenepropionitrile and triethyl orthobutyrate whereby there is obtained the title compound in equally good yield.
Reaction SMILES: ClC1C([CH:8]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:23]3)[N:9]2[C:17](=O)C3C(=CC=CC=3)C2=O)=NC=CN=1.NN.[CH2:38]([Cl:40])Cl>CCO>[Cl:40][C:38]1[C:17]([NH:9][CH2:8][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][C:24]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:23]3)=[N:23][CH:22]=[CH:27][N:26]=1
Reactant: ClCCl
Reactant: O=C1c2ccccc2C(=O)N1C(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: NN
Solvent: CCO
Product: Clc1nccnc1NCc1ccc2ncc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A flask containing crude (3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methanol (153 mg, ˜0.44 mmol) was flashed with Ar and charged with phthalimide (71 mg, 0.48 mmol) and triphenylphosphine (130 mg, 0.48 mmol) and anh. THF (10 mL). DIAD (0.1 mL, 0.48 mmol) was added slowly dropwise at rt and then the reaction was stirred at rt for 16 h. The reaction was concentrated under reduced pressure and purified by flash chromatography (silica gel, 5% EtOAc in DCM to 10%) affording 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione compound as a creamy solid. To stirred solution of the crude 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione (147 mg, 0.31 mmol) in anh. EtOH (12 mL) and anh. DCM (2 mL) under Ar was added anh. hydrazine (0.03 mL, 0.9 mmol). The reaction mixture was stirred at rt for 22 h. The 1:1 mixture of the product and a partially cleaved phthalimide was concentrated under reduced pressure at rt and dried under high vacuum overnight. The light yellow, solid residue was dissolved in anh. i-PrOH (6 mL) and anh. CHCl3 (3 mL) and heated under Ar at 50° C. for 16 h. Later the reaction was cooled to rt, evaporated to dryness and triturated with DCM. The DCM aliquots were filtered through a pad of Celite affording the title compound as a light yellow solid; 1H NMR (400 MHz, CD3OD/CDCl3) δ 9.37 (s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.23 (d, J=6.8 Hz, 2H), 8.12 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.88 (dd, J=0.8 Hz, 8.8 Hz, 1H), 7.62-7.52 (m, 3H), 5.81 (s, 1H). MS (ES+): m/z 348.0 (40) [MH+]; HPLC: tR=2.08 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH:1]1[O:7][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: C1=COCCC1
Reactant: OCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a mixture of pentane-1,5-diol(5.2 g, 0.05 mol) and p-toluenesulfonic acid (0.1g, 0.53 mmol) in CH2Cl2 (120 mL) was added slowly dihydro-2H-pyran (4.6 g, 0.055 mol) in CH2Cl2 (30 mL) at 0° C. After stirring for 2 h at 0° C. and for another 1 h at room temperature, saturated NaHCO3 (50 mL ) was added to the reaction mixture. The CH2Cl2 layer was washed with saturated NaHCO3 (50 mL), water (50 mL), and dried (MgSO4). The residue was purified by column chromatography on silica gel with EtOAc:hexane (1:1, v/v) and subsequent Kugelrohr distillation to give the title product (4, 5.1 g, 54%); bp 80°-85° C./0.1 torr; IR(neat): 3450 (broad) and 1135 cm-1 ; 1H NMR: 1.3-1.9 (m, 12H), 2.4 (b s, 1H ), 3.3-3.9 ( m, 6H ), and 4.58 ppm (m, 1H ).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].O1CCCC1.Cl>N1C=CC=CC=1>[Cl:22][C:5]1[CH:4]=[C:3]([F:23])[C:2]([NH:1][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][C:6]=1[O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)COc1ccccc1Oc1cc(N)c(F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccccc1Oc1cc(NC(=O)OCC)c(F)cc1Cl
Temperature: 25 °C

Procedure:
Into a mixture of ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23], ethyl chloroformate and tetrahydrofuran is added dropwise pyridine, and the mixture is stirred at room temperature. Dilute hydrochloric acid is added to the reaction solution, and this is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain ethyl [2-(2-chloro-4-fluoro-5-ethoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A8-23].