Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O-:13])=[O:12])#[N:8].[K+].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([CH:24]=[N:25]O)=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[C:7]([C:9]1[C:10]([C:11]([O:13][N:25]=[CH:24][C:23]2[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:12])=[CH:14][CH:15]=[CH:16][N:17]=1)#[N:8]
Reactant: N#Cc1ncccc1C(=O)[O-]
Reactant: ON=Cc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ncccc1C(=O)ON=Cc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Oxalyl chloride (2.8 g, 0.022 mole) is added dropwise to a suspension of potassium 2-cyanonicotinate (4.1 g, 0.022 mole) in dichloromethane (40 ml). The mixture is then heated under reflux for one hour. A solution of 4-chlorobenzaldehyde oxime (3.1 g, 0.02 mole) and pyridine (1.6 g, 0.02 mole) in dichloromethane (20 ml) is then added to the mixture, at 20° C. The mixture is then stirred for 2 hours at 20° C. The solvent is evaporated off and the residue treated with water (50 ml). The solid formed is filtered off and is washed with water and then with ethyl ether. A white solid 4.4 g, 77%) corresponding to the structure 2 is thus obtained (M.p.: 160° C.).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[CH:4][CH:3]=1.[CH2:29]=[O:30]>CO>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][OH:30])[N:21]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3n[nH]c4nnccc34)c2F)c1
Reactant: C=O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3nn(CO)c4nnccc34)c2F)c1
Temperature: 67 °C
Reaction time: 35 h

Procedure:
step 1—A suspension of 3-[6-bromo-2-fluoro-3-(1H-pyrazolo[3,4-c]pyridazin-3-ylmethyl)-phenoxy]-5-chloro-benzonitrile (R-73, 1.32 g, 2.88 mmol), 37% aqueous formaldehyde (100 mL) and MeOH (100 mL) was stirred at 67° C. for 35 h. The volatile solvents were evaporated and the residue diluted with H2O and the resulting precipitate filtered, washed with H2O and air-dried to afford 1.27 g of 3-[6-bromo-2-fluoro-3-(1-hydroxymethyl-1H-pyrazolo[3,4-c]pyridazin-3-ylmethyl)-phenoxy]-5-chloro-benzonitrile (12).
Reaction SMILES: O[CH:2]([CH3:8])[C:3]#[C:4][C:5](=[O:7])[CH3:6].[C:9](O)(=[S:11])[CH3:10].O>C(Cl)Cl.S(=O)(=O)(O)O>[CH3:8][C:2]1[O:7][C:5]([CH3:6])=[CH:4][C:3]=1[C:9](=[S:11])[CH3:10]
Reactant: CC(=O)C#CC(C)O
Reactant: CC(O)=S
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=S)c1cc(C)oc1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5.61 g of 5-hydroxyhex-3-yn-2-one [prepared according to A. F. Thomas et al., Tet. Let. 27, 505, (1986)] in 50 ml of methylene chloride are added dropwise while stirring within 15 min. to a mixture of 11.42 g of thioacetic acid in 50 ml of methylene chloride and 100 ml of 2N sulphuric acid. After leaving to stand at room temperature for 2 hours the mixture is heated to 40° C. and stirred at 40° C. for a further 4 hrs. The reaction mixture is poured into 100 ml of H2O and extracted 2× with 100 ml of methylene chloride. The organic phases, dried over MgSO4, are concentrated and fractionally distilled in a high vacuum (65° C./0.2 mbar). There are obtained 5.7 g (67% of theory) of a yellow liquid.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[NH:14][N:15]=[C:16]([NH:17][CH3:18])[C:12]=2[C:11](=[O:19])[N:10]([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>>[CH2:1]([N:8]1[C:13]2=[N:14][N:15]([CH3:27])[C:16]([NH:17][CH3:18])=[C:12]2[C:11](=[O:19])[N:10]([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCCCn1c(=O)c2c(NC)n(C)nc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
A mixture of 7-benzyl-5-butyl-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.5 g, 4.58 mM), methyl iodide (0.48 ml, 6 mM) and potassium carbonate (0.82 g, 6 mM) was stirred at room temperature for 12 hours. The mixture was concentrated to dryness and the residue was extracted with chloroform and water. The organic layer was washed with water, dried (MgSO4) and concentrated to dryness to give a solid. Recrystallization from 80% ethanol gave colorless needles (0.88 g, 50%), m.p. 146°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:16]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH3:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc[nH]n2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc(F)cc2)n1
Yield: 29.5 %

Procedure:
Treat a solution of 3-(4-fluorophenyl)pyrazole (7.17 g, 44.2 mmol) in dry DMF (60 mL) with NaH (2.2 g, 92.8 mmol) at 0° C. for 15 min. Add iodomethane (3.3 mL, 53.04 mmol) and slowly warm to RT. Quench the reaction mixture with methanol (5 mL) and dilute with water (100 mL). Extract with EtOAc (3×70 mL), dry (MgSO4) and concentrate and purify (Biotage system eluting with dichloromethane:methanol 50:1) to give desired compound as a white solid (2.3 g, 29% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+].Cl>N1C=CC=CC=1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: Fc1ccccn1
Reactant: NCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(O)CCCCCCNc1ccccn1

Procedure:
To a stirring solution of 7-aminoheptanoic acid in pyridine (0.5 M) was added 2-fluoropyridine (2 eq) and 2N NaOH (1 eq), and the reaction was refluxed overnight. The mixture was adjusted to neutral pH with 6N HCl and concentrated in vacuo. The residue was suspended in 10:1:1 EtOH/NH4OH/H2O, filtered through a plug of silica, and concentrated in vacuo to afford a colorless solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].F[B-](F)(F)F.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+]#N)=[CH:12][CH:11]=1>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: N#[N+]c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(Cl)cc1
Yield: 75 %

Procedure:
Sodium cyanide (2.94 g; 0.06 mol) was added to water and stirred. Cuprous cyanide (2.7 g; 0.03 mol) was added to the mixture stirred until it became homogeneous. 4-chlorobenzenediazonium tetrafluoroborate (5.66 g; 0.025 mol) in water (10 ml) was added to one portion. The mixture was allowed to react at room temperature. The mixture was extracted by ethyl acetate and the extract analysed by means of gas chromatography which indicated that 4-chlorobenzonitrile had been formed in 75% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20]Cl)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:22])[CH2:20][N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1[C@H]2CCC[C@H]2N(C(=O)CCl)c2ccccc2N1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CN(Cc2ccccc2)Cc2ccccc2)c2ccccc2N1Cc1ccccc1
Yield: 28 %

Procedure:
A solution of (3aR*,10aS*)-9-benzyl-4-(chloroacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (1.0 g, 2.7 mmol) and dibenzylamine (5.36 g, 27.1 mmol) in 1,2-dichloroethane (30 mL) was refluxed for 17 hours, to which was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with dichloromethane. The extract solution was washed with water and dried, followed by distilling off the solvent. The residue was purified by silica-gel column chromatography (ethyl acetate-hexane 1:1) to give 0.40 g (yield 28%) as an oily product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.C[O:10][C:11](=[O:36])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:35])[CH2:21][O:22][CH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=1)=[O:25]>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([NH:19][C:20](=[O:35])[CH2:21][O:22][CH2:23][C:24](=[O:25])[NH:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:33]=2)=[C:12]([CH:17]=1)[C:11]([OH:36])=[O:10]
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)NCc1cccc(Br)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2ccsc2)c1

Procedure:
Using the same method as in Example 19-(ii), 3-thiopheneboronic acid was reacted with the 2-[((2-[(3-bromobenzyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid methyl ester to give 5-chloro-2-([(2-oxo-2-([3-(thiophene-3-yl)benzyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 77%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[C:11]1([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([C:17]([F:19])([F:20])[F:18])=[N:8]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A mixture of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 4.4 mmol) and 1N aqueous sodium hydroxide solution (17.3 mL) in methanol (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and acidified to pH˜1 with 1N aqueous hydrochloric acid. The slurry was extracted with methylene chloride and the combined organic layers were washed with saturated sodium chloride and dried over sodium sulfate. Filtration and concentration gave 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1 g, 89% yield) as an off-white solid, which was directly used in the next step without further purification. LCMS calcd for C11H7F3N2O2 (m/e) 256, obsd 255 (M−H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[C:5]([F:14])[CH:4]=1.[B:15](OC)([O:18]C)[O:16]C.Cl>C1COCC1.C(OCC)(=O)C>[F:14][C:5]1[CH:4]=[C:3]([B:15]([OH:18])[OH:16])[CH:8]=[CH:7][C:6]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OB(O)c1ccc(OC(F)(F)F)c(F)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
Well-dried magnesium (3.05 g) and THF (20.0 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 55° C. Then, 1-bromo-3-fluoro-4-trifluoromethoxybenzene (T-13; 25.0 g) dissolved in THF (100 ml) was slowly added dropwise thereto in the temperature range of 47° C. to 60° C., and stirred for additional 60 minutes. The obtained Grignard reagent was added dropwise to trimethyl borate (14.0 g) in a THF (100 ml) solution in the temperature range of −74° C. to −65° C., and stirred for additional 180 minutes while allowing temperature to come to 25° C. After the reaction mixture had been cooled to −30° C., 6N-hydrochloric acid (90 ml) was slowly added dropwise and stirred for additional 180 minutes while temperature was allowed to come to 25° C. Then, the reaction mixture was poured into a vessel containing ice-water (250 ml) and 3,000 ml, and mixed. Ethyl acetate (300 ml) was added to separate the mixture into organic and aqueous layers, and an extraction operation was carried out. The obtained organic layer was fractionated, washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, whereby 11.7 g of 3-fluoro-4-trifluoromethoxy phenylboronic acid (T-14) was obtained. The yield based on the compound (T-13) was 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[OH-].[K+].C([OH:37])C.Cl>O.C(Cl)Cl>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH2:30])=[O:37])=[CH:27][CH:28]=2)=[O:31])[C@@H:14]([CH3:32])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CCO
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C#N)cc2)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(N)=O)cc2)c2ccccc21

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-cyanobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (143 mg, 0.33 mmol) and potassium hydroxide (55 mg, 1.00 mmol)) were dissolved in water (150 mL), ethanol (3 mL) and heated to 70° C. for 4 h. The slurry was portioned between 1N HCl (until acidic) and methylene chloride. The organic layer was collected, concentrated and subjected to flash chromatography (EtOAc to 20% MeOH, EtOAc) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[NH:13][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH:11][C:10]2=[O:21])[CH:6]=[CH:7][CH:8]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[NH:13][CH:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:24](=[O:26])[CH3:25])[NH:11][C:10]2=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCNC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Product: CCCCN(C(C)=O)C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 66 %

Procedure:
A mixture of 3-(3-trifluoromethylphenyl)-6-n-butylaminotetrahydro-1,3,5-triazine-2,4-dione (4.0 g.) and acetic anhydride (40 ml.) was heated under reflux for 2 hours. The mixture was then distilled at atmospheric pressure over 2 hours, fresh acetic anhydride being added to maintain the original volume. The mixture was then distilled at atmospheric pressure so that the final volume was about 10 ml. Ether (60 ml.) and petroleum ether (b.p. 40°-60° C.) [hereinafter referred to as "40-60 petrol"] (20 ml.) was then added. The white solid which precipitated was washed with ether (2×30 ml.) and air dried to give 3-(3-trifluoromethylphenyl)-6-[(N-acetyl)-n-butylamino]-tetrahydro-1,3,5-triazine-2,4-dione (3.7 g., 66%), m.p. 146°-148° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:36].C(N(CC)CC)C.[F:44][C:45]1[CH:46]=[C:47]([S:52](Cl)(=[O:54])=[O:53])[CH:48]=[CH:49][C:50]=1[CH3:51]>C(#N)C>[F:44][C:45]1[CH:46]=[C:47]([S:52]([O:1][C:2]2[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]3[N:14]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:36])(=[O:54])=[O:53])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: COc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccc(C)c(F)c1)CNC2=O
Yield: 27.2 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.188 g, 0.382 mmol) was dissolved in acetonitrile (8.0 mL), and the solution was treated with triethylamine (0.160 mL, 1.15 mmol) and 3-fluoro-4-methylbenzenesulfonyl chloride (0.120 mg, 0.574 mmol) to obtain 4-(3-fluoro-4-methylbenzenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0690 g, yield 27%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@@H:10]1[CH:20]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(=[CH:41][C:42]([O:44][CH3:45])=[O:43])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@@H:10]1/[CH:20]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H](c2cccnc2)[C@@H]1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 9.75 g (0.0292 mol) of (2S,3S,4S)-4-(t-butyldimethylsilyloxy)2-(3-pyridyl)tetrahydrofuran-3-carboxaldehyde in 120 ml of methylene chloride is added 9.75 g (0.0292 mol) of methyl (triphenylphosphoranylidene)acetate, the mixture is stirred at room temperature overnight and evaporated. The residue is triturated with ether to precipitate out most of the triphenylphosphine oxide, filtered and washed with ether. The filtrates are evaporated and the residue is purified by flash chromatography from silica gel (5×9 cm2) using methylene chloride-ethyl acetate (1:1) as eluent to give 6.77 g of methyl (E)-(2S,3S,4S)-3-[4-(t-butyldimethylsilyloxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]-2-propenoate with elemental analysis: C, 62.67; H, 8.12; N, 3.86 (theory: C, 62.78, H, 8.04; N, 3.85) and optical rotation [α]D 25=+26.77 (8.9 mg/ml methanol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][C:14]#[CH:15])[C:9]1=[O:16].[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[C:9]1=[O:16]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CCCC[Sn](/C=C/C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C)(CCCC)CCCC
Yield: 86.7 %

Procedure:
To a solution of (3R,45)-1-(2-tetrahydropyranyloxy)-3-(2-propyne-1-yl)-4-methylazetidin-2-one (1.32 g, 5.83 mmol) in 20 mL of toluene is added tributyltin hydride (1.70 g, 5.83 mmol) and AIBN (30 mg). The resulting solution is heated at reflux for 4 h then concentrated ir vacuo. The reaction mixture is purified by silica gel chromatography (elution with 8:1 hexanes-EtOAc) to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-tributylstannyl-2-propene-1-yl)-4-methylazetidin-2-one as an oil (2.6 g, 87% yield).
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:13])[CH:11]=[CH2:12])=[C:4]([CH3:14])[CH:3]=1.CN(C)C=O.[NH:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:22][CH2:21]1>C(O)(C)C>[I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH2:11][CH2:12][N:20]2[CH2:21][CH2:22][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24][CH2:25]2)=[O:13])=[C:4]([CH3:14])[CH:3]=1
Reactant: C=CC(=O)Nc1cc(C)c(I)cc1C
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1I
Temperature: 50 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
To a solution of N-(4-iodo-2,5-dimethylphenyl)acrylamide (32.2 g, 107 mmol) in a 6:1 v/v mixture of N,N-dimethylformamide and isopropanol (700 mL) was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (36.3 g, 123 mmol). The resulting mixture was heated at 50° C. for 24 hours and then at 80° C. for 24 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in dichloromethane (1 L) and this solution was washed with 1N aqueous hydrochloric acid (500 mL), water (500 mL), brine (500 mL) and saturated aqueous sodium bicarbonate solution (500 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Ethanol (400 mL) was added and the resulting mixture was concentrated under vacuum to a volume of about 400 mL, at which time a precipitate had formed. The precipitate was filtered and dried to afford biphenyl-2-ylcarbamic acid 1-[2-(4-iodo-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (59.6 g, 84% purity, 79% yield). m/z: [M+H+] calcd for C29H32IN3O3 598.49; found 598.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CCOCC.C(Cl)Cl.P(Br)(Br)[Br:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][Br:29])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nn1ccc2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nn1ccc2cc(CBr)ccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 86.4 %

Procedure:
To an ice-cold solution of 5-hydroxymethylindole-1-carbamic acid tert-butyl ester (0.51 g, 2.1 mmol) in 4:1 Et2O/CH2Cl2 (4 mL) was added PBr3 (0.2 mL, 2.2 mmol), and the reaction mixture was stirred for 40 min. The reaction mixture was diluted with CH2Cl2, washed a saturated solution of NaHCO3 (3×10 mL), dried (Na2SO4), filtered, and the solvent was removed under reduced pressure to provide 5-bromomethyl-indole-1-carbamic acid tert-butyl ester as a yellow solid (0.59 g, 93%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9 Hz, 1H), 7.68-7.62 (m, 2H) 7.33 (d, J=9 Hz, 1H), 6.60 (s, 1H), 4.68 (s, 2H), 1.67 (s, 9H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]([CH3:17])=[CH2:16]>CC#N.C([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:13][O:14][C:15]([CH3:17])([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(C)(C)ON1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of 20 g (123 mmol) of N-hydroxyphthalimide in 360 ml of CH3CN, 26.42 ml (276 mmol) of 2-methoxypropene and 42.36 mg (0.246 mmol) of anhydrous p-toluenesulfonic acid are added in portions at r.t. After stirring for 1 h, the mixture is diluted with 25 ml of sat. NaHCO3 and concentrated under reduced pressure. The residue is extracted with EtOAc and the organic layer is washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to give 21.84 g of 2-(1-methoxy-1-methyl-ethoxy)isoindole-1,3-dione as a white solid; NMR (CDCl3): 1.57 (s, 6H), 3.61 (s, 3H), 7.75 (dd, 2H, J=5.56 Hz, J=3.0 Hz), 7.83 (dd, 2H, J=5.56 Hz, J=3.0 Hz).