Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([CH2:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3].[H-].[Na+].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:26]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH2:17]([O:16][C:14]([C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:22][C:23]1[CH:24]=[C:25]([CH3:26])[CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:19])=[O:6])=[O:15])[CH3:18]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cc(C)cc(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 13.8 g (50.2 mMol) of diethyl [(1,1-dimethylethoxycarbonyl)methyl]-malonoate in 400 ml of anhydrous tetrahydrofuran, 2.3 g (52.7 mMol) of sodium hydride was added whilst being externally cooled with iced water. After stirring for 30 minutes, and maintaining a reaction temperature of 0 to +5° C., the solution of 10.0 g (50.2 mMol) of 3,5-dimethylbenzylbromide in 80 ml tetrahydrofuran was added dropwise and the mixture allowed to warm to room temperature within 14 hours. The reaction mixture was freed from the solvent in vacuo, 200 ml of 10% citric acid was added to the residue and the resulting mixture was thoroughly extracted with ethyl acetate. After the usual working up, the combined extracts yielded 19.7 g (100% of theory) of a colourless oil of Rf=0.67 (eluant: dichloromethane), which was used in the following steps without further purification.
Reaction SMILES: C[Si](I)(C)C.C[O:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15].O>C(#N)C>[OH:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 83.6 %

Procedure:
Trimethylsilyl iodide (11.1 mL, 76.3 mmol) was added to a solution of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (7.00 g, 15.3 mmol) in dry acetonitrile (100 mL) under argon for 21 h. Water (40 mL) was added to quench the reaction and the acetonitrile was removed in vacuo. The residue was diluted with ethyl acetate-(200 mL) and 1M aqueous hydrochloric acid. The organic layer was separated and further washed with 10% w/v aqueous sodium thiosulfate pentahydrate to remove residual iodine. The organic layer Was separated, dried (MgSO4), filtered and evaporated and purified by column chromatography, eluting with 3% to 5% methanol in DCM, to give the title compound as a white foam (5.70 g, 84%). Recrystallisation from hot ethanol (125 mg/mL) afforded the title compound as colourless needles (87% recovery). Mpt 126-132° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)C=CC=CC=1.O>O1CCOCC1>[C:18]1([N:13]2[C:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(-c3ccccc3)c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
2,3-Diphenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of the above compound (0.28 g) in 5 mL of 1,4-dioxane was added 0.29 g of K3PO4, 104.3 mg of phenylboronic acid and 43.0 mg of PdCl2dppf. The mixture was heated at 80° C. for 3 h. More phenylboronic acid (0.10 g) and PdCl2dppf (26 mg) were added and the temperature was increased to 100° C. After an additional 12 h, the mixture was poured into water (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were filtered through diatomaceous earth and the filtrate was concentrated in vacuo. Chromatography on SiO2 (0 to 20% EtOAc/hexanes) afforded 158.8 mg of the desired compound. MS (ESI): exact mass calculated for C24H27N3O2, 389.21; found, m/z 390.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][S:16][CH3:17])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][OH:19]>O1CCOCC1.C(OCC)(=O)C>[OH:19][NH:18][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:15][S:16][CH3:17]
Reactant: COC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Reactant: NO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NO
Yield: 33 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxycarbonylamino)-4-(methylthio)butanoate (1 g, 3.8 mmol) in dioxane (10 mL) and hydroxylamine (50% in water, 10 mL) was stirred at room temperature for 2 days. The solution was diluted with ethyl acetate (200 mL). The organic layer was washed with 1N HCl, brine, and dried over sodium sulfate, filtered and concentrated to give a residue, which was purified on silica gel column (hexane:ethyl acetate, 1:1 to pure acetate) to give (S)-tert-butyl 1-(hydroxyamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate as a white solid (0.33 g, 33%). MS calcd for (C10H20N2O4S+H)+: 265.1; MS found: (M+H)+=266.2, 166.2 (-Boc).
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([OH:15])(=O)[C:6]1[NH:13][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]=1>O>[O:12]=[C:11]1[NH:13][C:6]([C:5]([Br:3])=[O:15])=[CH:7][C:8](=[O:9])[NH:10]1
Reactant: O=S(Br)Br
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Solvent: O
Product: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 45 °C

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 10.07 mL (130 mmol) of thionyl bromide, and a water condenser, is placed 15.61 g (100 mmol) of orotic acid. Addition of the thionyl bromide is completed with heating to about 45° C. over the course of about 80 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl bromide (orotoyl bromide). This acyl bromide, 6.57 g (30 mmol), is put into a dry separatory funnel and combined with 25 mL of dry DCM for use in the next step of the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:13](N(OC)C)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH:26]([Mg]Br)=[CH2:27].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:13](=[O:14])[CH:26]=[CH2:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of 2-[3-chloro-4-(methylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (8.64 g) in tetrahydrofuran (90 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 88.8 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hr, and added to 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (7.15 g, yield 90%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:36]([CH2:38][NH2:39])[OH:37]>CN(C=O)C.C(OCC)(=O)C>[OH:37][CH2:36][CH2:38][NH:39][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of quinaldic acid (5.0 g, 28.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 g, 28.87 mmol), and 1-hydroxybenzotriazole (5.1 g, 37.49 mmol) in DMF (60 mL) at 0° C. was added ethanolamine (1.74 mL, 28.87 mmol) and 4-methylmorpholihne (4.76 mL, 43.31 mmol). The reaction was stirred at 0° C. for an additional 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate, washed 3 times with H2O, once with NaHCO3 (sat), once with brine, dried over MgSO4, and concentrated in vacuo to provide 1.5 g (24% yield) of a pale yellow solid. Electrospray Mass Spec: m/z 216.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][C:2]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(=O)c1cccc(O)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c, which was used without purification. MS m/z (M+H+) 290.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1cccc(Cl)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCC(=O)c1cccc(Cl)c1OC
Temperature: 25 °C
Yield: 98 %

Procedure:
3′-Chloro-2′-hydroxypropiophenone (10 g, 54.3 mmol) and potassium carbonate (17.5 g) in 70 ml of acetone are admixed with 7 ml of dimethyl sulphate. The reaction mixture is boiled at reflux for three hours. After it has cooled to room temperature, the batch is subjected to suction filtration through Celite and the filter cake is washed with diethyl ether. After the solvent has been removed on a rotary evaporator, the yellow oil which remains is diluted with 200 ml of diethyl ether and the organic phase is washed with 0.2 M aqueous sodium hydroxide solution (100 ml) and brine (100 ml). The organic phase is dried over sodium sulphate and the solvent is removed on a rotary evaporator. This leaves the desired title compound as a colourless oil (98% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])(=[O:24])=[O:23].C(N(CC)CC)C>C(#N)C>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([NH:28][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:29]=[CH:30][CH:31]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn(-c3ccc(Cl)cc3)c2C(F)(F)F)c1
Temperature: 60 °C

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.250 g, 0.808 mmol) was added to a solution of 3-methylsulfonylaniline hydrochloride (0.184 g, 0.889 mmol) and triethylamine (0.563 mL, 4.04 mmol) in acetonitrile (20 mL). The reaction mixture heated at 60° C. for 12 h, concentrated and crude product purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methane sulfonyl-phenyl)-amide. 1H-NMR (CD3OD, 300 MHz) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.97 (d, 1H, J=8.5 Hz), 7.73 (d, 1H, J=8.0 Hz), 7.59–7.66 (m, 3H), 7.51 (d, 2H, J=8.8 Hz), 3.15 (s, 3H); LCMS m/z=443.9 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:54]1([S:60]([NH:63][C@@H:64]([CH2:68][NH2:69])[C:65]([OH:67])=[O:66])(=[O:62])=[O:61])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:69][CH2:68][C@H:64]([NH:63][S:60]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)(=[O:62])=[O:61])[C:65]([OH:67])=[O:66])=[O:17])=[CH:18][CH:19]=2)=[CH:5][CH:6]=1
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Reactant: O=C(O)c1ccc(OCCCc2ccncc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc(OCCCc2ccncc2)cc1
Reaction time: 3 h
Yield: 106.1 %

Procedure:
A solution of 19-5 (200 mg, 0.78 mmol), NEt3 (0.22 mL, 1.5 mmol), and DMF (4 mL) at ambient temperature was treated with BOP (345 mg, 0.78 mmol). After 3.0 h, NEt3 (0.22 mL, 1.5 mmol) and 19-2 (190 mg, 0.78 mmol) were added. After 20 h, the reaction mixture was concentrated and subjected to flash chromatography (silica, 10/1/1 CH2Cl2 /CH3OH/AcOH) to give impure 19-6 (400 mg). Prep HPLC purification (Delta Pak C-18Å column, 0 to 100% CH3CN/H2O containing 0.1% trifluoroacetic acid) gave pure 19-6 as a whim solid after lyophilization. Rf 0.74 (silica, 10/1/1 CH2Cl2 /CH3OH/AcOH).
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][S:17]([O-:20])(=[O:19])=[O:18].[C:21]1([I+]C2C=CC=CC=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1.ClC1C=CC=CC=1>[CH3:15][O:16][S:17]([O-:20])(=[O:19])=[O:18].[C:21]1([S+:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: [Cu+2]
Agent: COS(=O)(=O)[O-]
Agent: O=C([O-])c1ccccc1
Solvent: Clc1ccccc1
Product: c1ccc([S+]2c3ccccc3Oc3ccccc32)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 20 g of phenoxathiin, 43.1 g of diphenyliodonium methylsulfate, 0.9 g of copper(II) benzoate, and 210 g of chlorobenzene was heated and stirred at 120° C. for 3 hours. The reaction solution was cooled to room temperature and combined with 20 g of diisopropyl ether for crystallization. The solid was dried under reduced pressure, obtaining the target compound, 10-phenyl-10-phenoxathiinium methylsulfate. Amount 24.7 g, yield 63%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][C:3]=1[Br:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate(60 mg, 0.228 mmol) in Acetonitrile (4 mL) in ice bath was added NBS (36.5 mg, 0.205 mmol) and stirred. LCMS after 30 min showed ˜1:1 mixture of starting material and desired product. To this added 12 mg (0.3 equiv.) of NBS and stirred 30 min. LCMS shows complete reaction. To the reaction mixture was added aqueous saturated NaHCO3 stirred 10 min and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered off, and evaporated. The crude product was used for next step without purification (65 mg, 83%). LCMS (m/z): 342.1/344.1 (MH+), 0.624 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:17])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)c1cc(C(=O)OC)ccc1C1CC1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-cyclopropyl-3-propanoylbenzoic acid (compound 10.6, 500 mg, 2.29 mmol) in N,N-dimethylformamide (20 mL) and potassium carbonate (633 mg, 4.55 mmol). The mixture was cooled to 0-5° C. then iodomethane (157 μL, 2.52 mmol) was added drop-wise. The resulting mixture was stirred for 1 h at 5-10° C., then quenched with water/ice (80 mL). The aqueous phase was extracted with ethyl acetate (2×150 mL) and the combined organic layers were washed with brine (20 mL), sodium carbonate (sat., 20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Obtained 400 mg (75%) of the title compound as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:13][C@@H:14]3[CH2:16][O:15]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:17]1[C:29]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][C:18]=1[N:30]1[CH2:37][C@H:36]2[NH:38][CH2:39][C@@H:31]1[CH2:32][CH:33]=[CH:34][CH2:35]2.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:13][C@@H:14]([OH:15])[CH2:16][N:38]3[CH2:39][CH:31]4[N:30]([C:18]5[CH:19]=[CH:20][C:21]6[C:22]7[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=7)[CH2:28][C:29]=6[CH:17]=5)[CH2:37][CH:36]3[CH2:35][CH:34]=[CH:33][CH2:32]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2c(c1)Cc1ccccc1-2
Reactant: Clc1ccc2c(OC[C@@H]3CO3)ccnc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O[C@H](COc1ccnc2cc(Cl)ccc12)CN1CC2CC=CCC1CN2c1ccc2c(c1)Cc1ccccc1-2
Temperature: 95 °C

Procedure:
(S)-7-Chloro-4-oxiranylmethoxy-quinoline (20 mg, 0.084 mmol) and Z-(1S,6S)-7-(9H-fluoren-2-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene (22 mg, 0.073 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via reverse phase chromatography (gradient 20% to 90% CH3CN/water for 12 min) to yield the title compound as a residue.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH2:4][OH:5].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]>>[CH2:14]([CH:15]1[S:1][CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH2:4][O:5]1)[CH2:13][CH2:12][CH2:11][C:10]#[CH:9]
Reactant: C#CCCCCC=O
Reactant: CC(C)C(CO)CS
Product: C#CCCCCC1OCC(C(C)C)CS1

Procedure:
Using the method described in Example 4(ii), and starting from 2-mercaptomethyl-3-methylbutan-1-ol and hept-6-ynal, 2-(hex-5-ynyl)-5-isopropyl-1,3-oxathiane was obtained as a mixture of isomers. Column chromatography on silica, eluting with hexane/ether gradients, gave a mixture of trans-and cis-isomers (50:50) followed by an enriched mixture of the trans-compound (95:5).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[N+](=[CH2:12])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.C(OCC)C>[CH3:12][O:7][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:4][C:5]#[N:6]
Reactant: N#CCC(=O)C(F)(F)F
Reactant: C=[N+]=[N-]
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=CC#N)C(F)(F)F
Yield: 35.1 %

Procedure:
Diethylether (300 ml) was added to trifluoroacetoacetonitrile (13.7 g, 0.100 mole) and to this was added an ethereal solution of diazomethane, which was prepared from N-nitrosomethylurea (25.77 g, 0.250 mole), a 50% solution of potassium hydroxide (112.22 g, 1.00 mole) and diethylether (180 ml), with ice cooling. The solution was allowed to stand over night while cooling with ice. Next day, until the pH being 3-4 (by an universal test paper) acetic acid in limited amounts was added to the reaction mixture to decompose an excess of diazomethane and the solution was concentrated to about 200 ml at atmospheric pressure by using a distillation apparatus equipped with a fractionating column. The concentrate was washed with a 8% solution of sodium bicarbonate and water and dried with anhydrous sodium sulfate. Diethyl ether was distilled off by using a distillation apparatus equipped with a fractionating column at atmospheric pressure and the residue was distilled under reduced pressure to give the title compound (5.31 g, 35.1%) as a colorless liquid, b.p. 58.0° C./68 mmHg-64.0° C./70.0 mmHg. The structure of the product was confirmed by IR and NMR.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[N:5]=1)([CH3:3])=[CH2:2].[Cl:12]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Cl:12][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[N:5]=1)=[CH2:3]
Reactant: C=C(C)c1cccc(SC)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(SC)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
A mixture of 14.5 g of 2-isopropenyl-6-methylthiopyridine, 12.9 g of N-chlorosuccinimide and 30 ml of benzene was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 4.3 g of the objective compound.