Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu][C:14]#[N:15].N.O>CN1CCCC1>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:2]=1[C:14]#[N:15]
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: N#C[Cu]
Agent: CN1CCCC1
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(N)c(C#N)c1
Temperature: 180 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloro-4-methylsulfonyl aniline (1.0 g, 4.9 mmol) in N-methylpyrrolidine (10 mL) was added copper (I) cyanide (4.35 g, 48.6 mmol) under nitrogen. The reaction mixture was stirred at 180° C. for 72 hours, cooled to room temperature, poured to a 1:1 mixture of ammonia and water (200 mL), stirred for 1 hour, and then filtered off. The residue was washed with CH2Cl2 (50 mL) and filtrate was extracted with CH2Cl2 (3×20 mL). The combined organic layers were backwashed with water (50 mL), dried over sodium sulfate, and concentrated to provide crude material, which was purified by flash column chromatography (silica gel; 230-400 mesh; ethyl acetate/hexanes=1:5) to obtain 2-amino-5-methanesulfonyl-benzonitrile as a white solid. Yield: 0.1 g (13%). A suspension of potassium hydroxide (2.05 g, 36.7 mmol) in ethylene glycol (9 mL) was heated to 80° C. KOH was dissolved completely at this stage. 2-Amino-5-methanesulfonyl-benzonitrile (0.900 g, 4.59 mmol) was added to the reaction mixture and the bath temperature was increased to 185° C. and stirred for 16 hours. The resultant reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with CH2Cl2 (3×30 mL). The aqueous layer was acidified with 2 N HCl to pH 4-5, extracted with EtOAc (3×30 mL), and the combined organic layers were backwashed with water (30 mL), then brine (30 mL), dried over sodium sulfate, and evaporated, to obtain 2-amino-5-methanesulfonyl-benzoic acid. Yield: 0.750 g (75%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (50 mg, 0.11 mmol) in DMF (1 mL) and triethylamine (1 mL), (trimethylsilyl)acetylene (0.045 mL, 0.33 mmol) was added at room temperature followed by copper(I) iodide (4.2 mg, 0.022 mmol) and bis(triphenylphosphine)dichloropalladium(II) (7.7 mg, 0.011 mmol). The resulting mixture was stirred under nitrogen at room temperature for 1 h, and then was quenched with water, extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamide (44 mg, 94%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.51 (d, J=7.0 Hz, 1H), 8.20 (dd, J=8.0, 1.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 2H), 7.72 (dd, J=8.0, 1.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.49 (t, J=8.0 Hz, 1H), 4.32-4.29 (m, 1H), 3.52 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.12-2.76 (m, 5H), 2.18-2.02 (m, 2H), 1.80-1.62 (m, 3H), 0.29 (s, 9H); MS (ESI+) m/z 444 (M+H); HPLC>99% (AUC), tR=14.91 min.
Reaction SMILES: [H-].[K+].[CH3:3]CCCCC.[OH:9][CH2:10][CH:11]1[C:20]23[CH2:21][CH2:22][CH:13]([CH:14]4[O:29][C:28]5[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:27]=5[C:15]42[CH2:16][CH2:17][N:18]([CH2:24][CH2:25][CH3:26])[C:19]3=[O:23])[CH2:12]1.CI>O1CCCC1>[CH3:35][O:34][C:30]1[C:28]2[O:29][CH:14]3[CH:13]4[CH2:22][CH2:21][C:20]5([CH:11]([CH2:10][O:9][CH3:3])[CH2:12]4)[C:15]3([CH2:16][CH2:17][N:18]([CH2:24][CH2:25][CH3:26])[C:19]5=[O:23])[C:27]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CCCN1CCC23c4cccc(OC)c4OC2C2CCC3(C1=O)C(CO)C2
Reactant: CCCCCC
Agent: [H-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCN1CCC23c4cccc(OC)c4OC2C2CCC3(C1=O)C(COC)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 9 g of 35% potassium hydride in oil, prewashed with hexane, and 40 mL of tetrahydrofuran was added 4.05 g of 5-hydroxymethyl-9-methoxy-3-n-propyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one. The mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 30 minutes. Methyl iodide (8 mL) was added to the cooled mixture which was then heated under reflux for one hour. Excess hydride was destroyed by addition of 10 mL of methanol, and the solvent was removed. The product was taken up in methylene chloride/water, and the aqueous layer was extracted with methylene chloride. Removal of the solvent gave 4.45 g of 9-methoxy-5-methoxymethyl-3-n-propyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one. NMR spectrum (δ in CDCl3); 6.8 (m, 2H); 6.5 (m, 1H); 4.5 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H) and 1.0 (t, 3H), among others.
Reaction SMILES: C[N:2]1[CH2:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH2:4][CH2:3]1.Br.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O.C1(C)C=CC=CC=1>[ClH:19].[NH:2]1[CH2:3][CH2:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:7]1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=CCCNC1
Product: Cl
Temperature: 57.5 °C

Procedure:
Arecoline hydrobromide (25 g, 106 mmol) was neutralized with sodium carbonate (12.8 g, 120 mmol, 1.1 eq) in water (200 mL) for 30 min. The neutralized product was dissolved in toluene (50 mL) and added dropwise to a solution of triphosgene (16.3 g, 54.9 mmol, 0.52 eq) in toluene (100 mL) at 0° C. The resulting mixture was heated at 55-60° C. overnight. The reaction mixture was then concentrated in vacuo and the residue was dissolved in water (300 mL) and heated at 80° C. for 3 h. The water was evaporated and chased with toluene 3 times. The crude methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride, obtained as a thick brown oil, was used as is in the next reaction.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[C:7]([Si](C)(C)C)=[CH:6][O:5][CH:4]=1.[I:14]I>C1COCC1.CCOCC.FC(F)(F)C([O-])=O.[Ag+].[Ag]>[I:14][C:7]1[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])=[CH:4][O:5][CH:6]=1
Reactant: II
Reactant: C[Si](C)(C)c1cocc1[Si](C)(C)C
Agent: [Ag+]
Agent: [Ag]
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)c1cocc1I
Temperature: -78 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stir-bar was placed the 3,4-bis(trimethylsilyl)furan (2.00 g, 9.41 mmol) as a solution in THF (138 mL). Silver trifluoroacetate (4.16 g, 18.8 mmol) was added and the mixture was stirred for 5 min at room temperature until the silver salt dissolved. The resulting colorless solution was cooled to −78° C. and I2 was then added as a solution in THF (50 mL) over 10 min. The mixture was stirred at −78° C. for 3 h after which time it was warmed to room temperature diluted with Et2O (200 mL) and then filtered through a cake of celite. The resulting brown solution was then washed with 50% aqueous Na2S2O3 (2×80 mL) followed by saturated aqueous NaHCO3 (50 mL), and then brine (50 mL). The organic layer was then dried over Na2SO4. Evaporation of the solvent in vacuo gave a yellow oil that was eluted through a plug of silica gel (hexanes, ca. 400 mL eluent) to give a colorless solution. Evaporation of the solvent gave (4-iodofuran-3-yl)trimethylsilane as a pale pink oil (2.20 g, 87%). 1H NMR: δ 7.49 (d, 1H, J=1.5 Hz), 7.22 (d, 1H, J=1.5 Hz), 0.30 (s, 9H). Ref.: Song, Z. Z., Wong, H. N. C. Liebigs Ann. Chem. 1994, 29-34.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][CH2:35][CH3:36])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][CH2:35][CH3:36])[NH2:32])=[O:16])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 80.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (154 mg, 0.53 mmol, 1.0 eq), L-norleucine N-benzylamide (234 mg, 1.07 mmol, 2.0 eq) and dichloromethane (1.0 mL), was treated with triethylamine (446 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (680 uL, 1.07 mL, 2.0 eq), to provide 210 mg (80%) of L-norleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-Prolyl] benzylamide as a white foam.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=3)[C:12]2=[O:22])[CH:10]=1.O.[NH2:25][NH2:26]>C(O)C>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:22])[N:11]([C:9]1[CH:10]=[C:5]([CH2:4][C:3]([NH:25][NH2:26])=[O:2])[CH:6]=[N:7][CH:8]=1)[CH2:20][CH2:19]2
Reactant: NN
Reactant: COC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 90 °C

Procedure:
[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-acetic acid methyl ester (100 mg, 0.30 mmol) and hydrazine monohydrate (0.75 mL) were dissolved in ethanol (8.0 mL) and the reaction mixture was heated at 90° C. for 3 h before it was cooled and concentrated in vacuo to give a crude product (100 mg, quant.) as light yellow oil. MS: 331.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([CH3:28])[CH2:26][NH2:27].CC1N(C(N(C)C)=O)C1>N1C=CC=CC=1>[CH3:24][CH:25]([CH3:28])[CH2:26][NH:27][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Agent: CC1CN1C(=O)N(C)C
Solvent: c1ccncc1
Product: CC(C)CNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 100 °C

Procedure:
A mixture of 0.16 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10, 11-dihydro-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine, 40 mg of pyridine and 2 ml of 2-methylpropylamine is stirred and heated at 100° C. in a sealed vessel for 1 hour. To the mixture is added 0.2 ml of N,N-dimethylpropyleneurea and the mixture is heated at 110° C. for 7 hours. The volatiles are removed under vacuum and 10 ml of 0.5N NaOH is added to the residue. The mixture is filtered and the solid washed with water and then hexane. The solid is dissolved in ethyl acetate and the solution washed with 0.5N NaOH, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is triturated with diisopropylether-hexane to give 0.18 g of white solid; mass spectrum (CI) 361 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].Cl[CH2:19][C:20]#[N:21]>CN(C=O)C>[C:20]([CH2:19][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:21]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1CC#N
Reaction time: 8 h

Procedure:
A solution of 2-2 (11.2 g, 44.4 mmol) in DMF (400 mL) was treated with NaH (3.2 g of 60% dispersion in oil, 66.6 mmol) for 0.5 hour and then chloroacetonitrile (Aldrich, 5.6 mL, 88.8 mmol) was added and the reaction was stirred overnight. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The water layer was extracted with EtOAc, the organic layers were combined, washed with water, brine, dried with MgSO4, filtered and evaporated to give 2-3 as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26].CC(C)=O>CCCCCC>[CH:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:27])[CH3:26]
Reactant: O=S1(=O)c2ccccc2Oc2cc(O)ccc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O
Reaction time: 8 h

Procedure:
A mixture of 1.00 gm (0.0043 mole) of 3-hydroxyphenoxathiin 10,10-dioxide (Example 7) 1.48 gm (0.0107 mole) of anhydrous granular potassium carbonate, 5.5 mL of 2-iodopropane (Aldrich Chemical Co.), and 60 mL of acetone were stirred overnight. The acetone was removed under water pump vacuum and the residue mixed with methylene chloride and filtered. The filtrate was washed with 2×200 mL of water and dried over magnesium sulfate. The solvent was removed under water pump vacuum to give an oil. Some hexane was added to the oil and the mixture heated on a steam bath. This gave a white solid which was recrystallized from ethyl acetate/hexane to yield 0.75 gm of 3-isopropoxyphenoxathiin 10,10-dioxide, m.p. 94-95°.
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[CH2:20]([O:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21]
Reactant: CCI
Reactant: COC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC1=C(c2ccccc2)C(CCC(=O)OC)OC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69 %

Procedure:
A mixture of methyl 3-(4-hydroxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionate (262 mg), ethyl iodide (234 mg) and potassium carbonate (207 mg) in dimethylformamide (3 ml) was stirred for 3.5 hours at ambient temperature. The mixture was poured into a mixture of dichloromethane (10 ml) and water (10 ml). The separated organic layer was washed with water three times, dried and evaporated to dryness. The oily residue was purified by column chromatography on silica gel (8 g, elution by benzene) to yield methyl 3-(4- ethoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (0.20 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH3:18])[C:9]([N:11]1[O:16][CH:15]2[CH2:17][CH:12]1[CH:13]=[CH:14]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:24]CC1.[OH2:28]>[Os](=O)(=O)(=O)=O>[OH:28][CH:14]1[CH:13]([OH:24])[CH:12]2[CH2:17][CH:15]1[O:16][N:11]2[C:9](=[O:10])[C@H:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:18]
Reactant: O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1OC2C=CC1C2
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1OC2CC1C(O)C2O
Yield: 98 %

Procedure:
A solution of tert-butyl-(R)-1-(3-oxa-2-aza-bicyclo[2.2.1]hept-5-en-2-yl)-1-oxopropan-2-ylcarbamate (27.3 g, 101.75 mmol, 1.00 equiv.) in teterahydrofuran:water (5:1) (600 mL), osmium tetroxide (230 mg, 0.90 mmol, 0.01 equiv.), and N-methylmorpholine-N-oxide (25.26 g, 215.62 mmol, 2.10 equiv.) was stirred at about 20° C. for about 50 minutes. After adding sodium thiolsulfate (22 g), the resulting solution was extracted with ethyl acetate (3×200 mL) and the organic layers combined. The organic phase was washed with a saturated sodium bicarbonate solution (1×250 mL) and then concentrated in vacuo to give the desired product as a yellow liquid (30.1 g; yield=98%). 1H NMR (300 MHz, CDCl3) δ: 5.29 (b, 1H), 4.36-4.74 (m, 3H), 3.76-4.09 (m, 4H), 2.67 (m, 1H), 1.90 (m, 1H), 1.43 (s, 9H), 1.30 (d, J=6.9 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][C:20]#[CH:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][C:20]#[CH:21]
Reactant: O=[N+]([O-])O
Reactant: C#CCC1=C(C)[C@H](O)CC1=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: C#CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Into a mixed solution of 8 g of fuming nitric acid and 24 g of acetic anhydride, kept at a temperature of -5° to 10° C., was added dropwise 6 g of (R)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-1-one ([α]D23 ; -19.5° (C=1.36, in chloroform), (R)-isomer/(S)-isomer=96.7/3.3). Then, the mixture was stirred for 30 minutes at the same temperature. Thereafter, the reaction mixture was poured into 200 ml of ice water, and then subjected to a toluene extraction. The toluene layer was separated and washed with an aqueous 5% sodium hydrogencarbonate solution and then with water. The extract was dried over anhydrous magnesium sulfate and, then, concentrated to give 7.56 g of crude (R)-3-methyl-4-nitroxy-2-(2-propynyl)-2-cyclopenten-1-one.
Reaction SMILES: [P:1]([O:11][C:12](C)(C)C)([O:6]C(C)(C)C)([O:3]C[Cl:5])=[O:2].[I-].[Na+].[CH3:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[C:25]1[CH:26]=[C:27]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)[N:28]=[CH:29][C:30]=1[N:31]([C:33]([C:35]([C:38]1[CH:39]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)([CH3:37])[CH3:36])=[O:34])[CH3:32].[ClH:59].O1CCOCC1>CC(C)=O>[ClH:5].[Cl-:59].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:43]=[C:38]([C:35]([CH3:36])([CH3:37])[C:33]([N:31]([C:30]2[C:25]([C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:18])=[CH:26][C:27]([N:52]3[CH2:53][CH2:54][N+:55]([CH3:58])([CH2:12][O:11][P:1]([OH:6])([OH:3])=[O:2])[CH2:56][CH2:57]3)=[N:28][CH:29]=2)[CH3:32])=[O:34])[CH:39]=[C:40]([C:48]([F:49])([F:51])[F:50])[CH:41]=1
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: Cc1ccccc1-c1cc(N2CC[N+](C)(COP(=O)(O)O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: [Cl-]
Temperature: 50 °C

Procedure:
To the solution of chloromethyl di-tert-butyl phosphate in Acetone (22.1 g from a 10% solution, 85.58 mmole), 15.5 g (103.24 mmole) of sodium iodide and 33.0 g (57.00 mmole) of netupitant were added and the solution heated at 50° C. for at 6-16 h. The precipitated salts were filtered off, the acetone distilled under reduced pressure and the crude product dissolved in 43.0 g of methanol and 43.0 g 1,4-dioxane. 12.6 g of HCl 4M in dioxane (113.85 mmole) were added, and then methanol is distilled off at 40° C. under reduced pressure. The solution is cooled at 5° C. and stirred at 5° C. for at least 2 h at 5° C. The product was isolated by filtration, purified by additional slurry in acetone (238 g), and filtered and washed with acetone (47 g) and pentane (2×72 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:11].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[C:1]1([S:7][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of thiophenol (5.5 g) and 2-bromo-1-(4-(methanesulfonyl)phenyl)ethanone (14.8 g) in acetone (250 mL) was added K2CO3 (13.8 g). The mixture was stirred at r.t. for 1 hr then H2O added and the solution was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was triturated in EtOAc/Et2O, filtered and air dried, giving 13.4 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][C:3]=1[Br:17].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[C:30](OCC)(=O)C.C1CCCCC1>C(Cl)Cl>[Br:17][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][S:26]([CH3:25])(=[O:28])=[O:27])=[C:12]([CH3:30])[CH:11]=2)=[CH2:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C=C(c1ccc(O)cc1)c1ccc(F)c(Br)c1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(c1ccc(OS(C)(=O)=O)c(C)c1)c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-[1-(4-Fluoro-3-bromo-phenyl)-vinyl]-phenol was produced from {4-[1-(3-bromo-4-fluoro-phenyl)-vinyl]-phenoxy}-tert-butyl-dimethyl-silane according to Building Block X & AA. To a solution of 4-[1-(4-fluoro-3-bromo-phenyl)-vinyl]-phenol (1.5 g, 4.88 mmol, 1.0 eq) in DCM (15 mL), triethylamine (2.0 mL, 14.65 mmol, 3.0 eq) was added and the reaction mixture cooled to 0° C. Then methanesulfonyl chloride (0.416 mL, 5.37 mmol, 1.1 eq) was added dropwise and the mixture was allowed to warm to room temperature and stirred 16 h. The reaction was examined by TLC (ethyl acetate/cyclohexane 20%) which showed complete conversion to the desired product. After night time water was added and organic and water phase were separated. Organic solution was dried over magnesium sulfate filtered and evaporated. The crude was purified by flash chromatography eluting with cyclohexane, then ethyl acetate/cyclohexane 20%. 1.4 g of clean product was obtained as colorless liquid (yield: 75%)
Reaction SMILES: [H-].[Na+].CS(C)=O.[ClH:7].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[Cl:7][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[NH2:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Reactant: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
Sodium hydride (60 wt %, 0.72 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 20 min. 4-Amino-3-chlorophenol hydrochloride (1.61 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (0.80 g, yield 60%).