Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
4-Morpholin-4-ylmethyl-benzene-1,2-diamine (1 mol. eq.) and 4-nitro-1H-pyrazole-3-carboxylic acid (1 mol. eq.) were dissolved in dimethylformamide (DMF) (10 vol.). O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.2 mol. eq.) was added and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated in vacuo until no further solvent was seen to distil. The residue was then dissolved in glacial acetic acid (10 vol.) and heated at 65° C. for ˜12 hours. The mixture was concentrated in vacuo and then dissolved in water (6 vol.) at 75° C. The black solution was cooled to 0-5° C. over 2 hours during which time a solid was formed. The solid was removed by filtration and the aqueous filtrate was diluted with ethyl acetate (4 vol.) and tetrahydrofuran (2 vol.). Solid NaHCO3 was added slowly to the stirred mixture until no further effervescence was observed and a pH of 6.8 was reached. The mixture was then stirred until a precipitation was observed. After standing the mixture at 0-5° C. for 2 hours, the solid was collected by filtration and washed with water (2 vol.) and ethyl acetate (2 vol.) and dried to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole as a brown solid (40%). (LC/MS (basic method): Rt 1.93, [M−H+]− 327).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH3:10].C([Li])CCC.[CH:16](=[O:25])[C:17]1[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[Br:8][C:4]1[C:3]([O:9][CH3:10])=[C:2]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[OH:25])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1C=O
Reactant: COc1c(Br)cccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)c1cccc(Br)c1OC
Temperature: -63 °C

Procedure:
2,6-Dibromoanisole (138.0 g, 0.51 mol) was dissolved in 750 ml of tetrahydrofuran and the solution cooled to -63° C. Butyl lithium (319 ml of 1.6 M, 0.51 mol) was added slowly with stirring and the mixture stirred at -60° C. for 4.5 hours and then 69.4 g (0.51 mol) of o-anisaldehyde in 250 ml of tetrahydrofuran was added slowly with stirring and the mixture allowed to stir cold for 1 hour. The mixture was allowed to warm to ambient temperature and was then poured into a mixture of ice and saturated aqueous ammonium chloride. The resulting mixture was extracted with ether and the ether extract dried over magnesium sulfate and then concentrated by evaporation under reduced pressure to obtain the title compound. This was purified by preparative liquid chromatography eluting with a 5:95 mixture of ethyl acetate and hexane to obtain 44.6 g (24 percent of theory) of material having a proton nmr spectrum consistent with the assigned structure.
Reaction SMILES: O([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.C1COCC1.[Na].[CH3:31][SH:32]>C(OCC)(=O)C>[CH3:31][S:32][CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Reactant: CS
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC=CC(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
Phenyl 3-phenoxy-N-phenylacrylimidate (0.30 g) was dissolved to THF (5 ml), sodium salt of methyl mercaptan (0.075 g) was added thereto and stirred for four hours at room temperature. Ethyl acetate (50 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated of sodium chloride solution, dried over magnesium sulfate (anhydrous), concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-methylthio-N-phenylacrylimidate (0.20 g) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Si](C)(C)C)=[CH:18][C:17]=1[F:26].[I:28]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:28])=[CH:18][C:17]=1[F:26]
Reactant: ClI
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (2.4 g, 6.1 mmol) in dichloromethane (15 mL) at 0° C. was added ICl (2.0 g, 12.2 mmol). The mixture was stirred at 0° C. for 0.5 hour, then quenched with water, washed with a saturated solution of sodium sulphite followed by brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound as a brown solid (2.7 g, 98%). LCMS (method B): RT=3.81 min, [M+H]+=448.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH:7]=[C:8]([CH3:18])[CH2:9]P(OCC)(OCC)=O)[CH3:4].[Br:20][C:21]1[CH2:25][CH2:24][CH2:23][C:22]=1[CH:26]=O>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:18])/[CH:9]=[CH:26]/[C:22]1[CH2:23][CH2:24][CH2:25][C:21]=1[Br:20])[CH3:4]
Reactant: O=CC1=C(Br)CCC1
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(C)/C=C/C1=C(Br)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2.03 g of NaH (50% in mineral oil) was suspended in 120 ml of DMF. 12.9 g of 4-(diethoxy-phosphinyl)-3-methyl-but-2-enoic acid ethyl ester was added at 0°. The mixture was stirred for 15 min at 0° and for 30 min at RT. After recooling to 0°, 5.72 g of 2-bromo-cyclopent-1-enecarbaldehyde, dissolved in 11 ml of DMF, was added drop by drop and allowed to react for 10 min. at 0° and for 2 h at RT. The mixture was then poured onto crushed ice, extracted with EtOEt, washed with sat. NaCi-solution, dried over Na2SO4, and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/AcOEt=97/3) and crystallization from hexane/trace amounts of AcOEt yielded finally 3.408 g of pure (2E,4E)-5-(2-bromo-cyclopent-1-enyl)-3-methyl-penta-2,4-dienoic acid ethyl ester as yellowish crystals of mp. 85°-86°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH:16](C)[CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+].FC(F)(F)C1C=CC=CC=1CN1CCNCC1>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:36][N:31]3[CH2:32][CH2:33][N:28]([CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:29][CH2:30]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(C(C)CC=O)on2)cc1OC
Agent: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCCN3CCN(Cc4ccccc4)CC3)on2)cc1OC
Yield: 70.7 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]butanal (32 mg, 0.116 mmol) and 1-benzylpiperazine (20, 0.116 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (73.8 mg, 0.348 mmol), cold acetic acid (8.0, 0.139 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.5 hr and followed the same processes as in Example 1 to obtain 35.7 mg (70.7%) of the target compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:5].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>CN(C)C=O.C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[C:21]([O:1][CH2:2][CH2:3][N:4]([CH3:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CN(CCO)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of 2-[N-(2-hydroxyethyl)-N-methylamino]pyridine (3.87 g) in dry N,N-dimethylformamide (39 ml) was added sodium hydride (60% in oil, 1.12 g), and the reaction mixture was stirred at room temperature for 30 min. 2-Chloro-4-fluorobenzaldehyde (4.43 g) was added to the reaction mixture and the mixture was stirred for 3 days. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give the objective compound (3.30 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:27][CH3:28])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:29]=[CH:30]N(C)C)#[N:2].[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH2:27][CH3:28])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[N:2][CH:30]=[N:29]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1nccs1
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(Nc4nccs4)c3cc2OC)c1
Yield: 72 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol) with 2-aminothiazole (12.8 mg, 0.13 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 72% yield (40 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C=O)C.CCCCCC>[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: ClCc1ccnc2ccccc12
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccnc3ccccc23)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (430 mg, 60%, 10.75 mmol) was placed in a flask with hexane and stirred under nitrogen. After 10 minutes the hexane was discarded and 10 ml dry DMF was added. After cooling to 0° C., 4-hydroxy-benzoic acid methyl ester Q-2 (1.67 g, 11 mmol) was added and the mixture stirred for 15 minutes. 4-Chloromethyl-quinoline Q-1 (1.8 g, 10.1 mmol) was dissolved in 3 mL of DMF and added dropwise to the reaction mixture. The temperature was raised to 130° C. and the mixture stirred for a half hour. After cooling to room temperature the reaction mixture was poured into 50 mL 1N sodium hydroxide solution and extracted three times with 20 mL dichloromethane. The combined organic layers were washed twice with water, dried over sodium sulfate and concentrated in vacuo. The crude product (2.5 g) was recrystallized from ethyl ether to give 4-(quinolin-4-ylmethoxy)-benzoic acid methyl ester (1.6 g, 5.45 mM) as a white solid.
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][C:6]([CH2:8][NH2:9])=O.Cl.[CH3:11][CH:12]([O:14][NH2:15])[CH3:13].[CH3:16]O>>[ClH:2].[CH3:11][CH:12]([O:14][N:15]=[C:6]1[CH2:8][NH:9][CH:16]=[N:4][CH2:5]1)[CH3:13]
Reactant: NCC(=O)CN
Reactant: CC(C)ON
Reactant: CO
Agent: Cl
Solvent: O
Product: CC(C)ON=C1CN=CNC1
Yield: 47 %

Procedure:
1,3-Diaminoacetone dihydrochloride monohydrate (2.0 g, 11.2 mmol) was dissolved in refluxing methanol and O-(1-methylethyl)hydroxylamine hydrochloride (2.5 g, 22.4 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 24 hours the solvent was removed in Vacuo. Crystallization from methanol/ethyl acetate afforded 1.00 g (47%) light-brown material. Mp. 170.0° C.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].I[CH2:9][Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:19]([Sn:10]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC1CC1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 1.15 g of cyclopropyl carbinol in 30 mL of dry THF was added 312 mg of 98% sodium hydride. After stirring 1 h, 2.8 g of iodomethyl tributyltin (prepared as described by Seitz et al, 1983 Synthetic Commun. 13, 129) was added and the reaction mixture was stirred at room temperature for 24 h, and then poured onto water and extracted with hexanes. The extracts were washed with brine, dried and evaporated to a crude product that was purified by flash chromatography (hexanes then 30% ethyl acetate/hexanes eluents) to afford 1.03 g of tributyl (cyclopropylmethoxymethyl)tin as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2C(=O)C3=CC=CC=C3C2=O)[CH2:7][S:6][CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][N:3]1[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CNN>>[NH2:9][CH:8]1[CH2:7][S:6][CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][N:3]([CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CNN
Product: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O

Procedure:
0.4 g of diastereomer B of t-butyl α-[5-oxo-2-phenyl-6-phthalimidoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] was subjected to dephthaloylization with methylhydrazine in the same manner as described in Example 1(g), to give 0.22 g of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:29])[N:9]3[CH2:13][CH:12]([CH2:14][N:15]4[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]4)[C:11]=1[C:10]=23.C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:12]2[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:29])[N:9]([C:10]=43)[CH2:13]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A solution of 1,1-dimethylethyl {1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (13.35 g, containing about 12.5% dichloromethane) in dichloromethane (125 ml) was ice-cooled, treated with TFA (100 ml), stirred at room temperature for 1 hour and evaporated. The residue was shaken with aqueous sodium bicarbonate (excess) and 15% methanol/dichloromethane, separated and the aqueous extracted about 50 times with 15% methanol/dichloromethane. The combined organic phases were dried and evaporated and the residue chromatographed using dichloromethane/methanol/0.88 ammonia 9:1:0.1 to give the product (8.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[CH:10]([N:17]([CH2:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:40])[CH:10]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[N:17]([CH2:29][CH2:30][CH2:31][OH:32])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N(CCCO[Si](C)(C)C(C)(C)C)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(CCCO)C(C(=O)OCc2ccccc2)C2CCCCC2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of [[3-(tert-butyldimethylsilanyloxy)propyl](4-methoxybenzenesulfonyl) amino]cyclohexylacetic acid benzyl ester (13.67 grams, 23.2 mmol) in methylene chloride (60 mL) at room temperature was added boron trifluoride etherate (21 mL, 171 mmol). After 20 minutes, the reaction was quenched by addition of saturated ammonium chloride solution and subsequent addition of ethyl acetate and water. The organic phase was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent under vacuum gave an oil from which cyclohexyl[(3-hydroxypropyl)(4-methoxy-benzenesulfonyl)amino]acetic acid benzyl ester, a clear oil (11.25 grams, 100%), was isolated by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane and then 40% ethyl acetate in hexane.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1.[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14].Cl>>[CH:5]1([CH:12]([OH:11])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: C1=CCCCC1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: OC(C1C=CCCC1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Anhydrous aluminum chloride (8.4 g; 0.063 mole) was added portionwise over a period of 2 hours to a stirred mixture of cyclohexene (108 g; 1.32 moles) and chloral (97 g; 0.653 mole), the temperature of which was maintained at 0° C. The reaction was allowed to proceed for a further 1 hour at 0° C. and then poured into a mixture of ice and concentrated hydrochloric acid. The reaction mixture was extracted three times with ether and the combined extracts washed with water (2×200 ml). The dried (MgSO4) extract was evaporated and the residue distilled to give crude product (116 g; 85% purity as judged by G.L.C.), b.p. 90°-94° C./0.1 mm. The crude product was redistilled through a Widmer column to give 1-(2-cyclohexen-1-yl)-2,2,2-trichloroethanol (98 g; 65% yield based on chloral; 93% purity as judged by G.L.C.) b.p. 67°-68° C./0.03 mm. A sample was redistilled for analysis.
Reaction SMILES: I.CS[C:4](=[NH:18])[CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:19]([NH:27][NH2:28])(=O)[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>CC(O)C>[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[NH:18][C:4]([CH2:5][CH2:6][N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])=[N:28][N:27]=2)=[CH:21][CH:22]=1
Reactant: CSC(=N)CCN1C(=O)c2ccccc2C1=O
Reactant: NNC(=O)c1ccncc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CCc1nnc(-c2ccncc2)[nH]1
Temperature: 85 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a suspension of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiopropionimidic acid methyl ester hydroiodide (880 mg, 2.34 mmol) in 2-propanol (16 mL) were added isonicotinohydrazide (337 mg, 2.46 mmol) and sodium carbonate (248 mg, 2.34 mmol). The reaction mixture was stirred at 85° C. for 1 h. Acetic acid (32 mL) was added and the reaction mixture was stirred at 130° C. for 3 h. After cooling down to ambient temperature, all volatiles were evaporated. The residue was dissolved in acetic acid (30 mL) and the reaction mixture was stirred at 130° C. for 16 h. The reaction mixture was cooled down to RT and concentrated in vacuo. The residue was poured into saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was washed water (40 mL) and brine (40 mL), dried over MgSO4 and concentrated in vacuo. The residue was suspended in dichloromethane, filtered, washed with dichloromethane and dried in vacuo to give the product as brown solid (480 mg (purity 80%), 0.96 mmol, 41%). The filtrate was evaporated and pure product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light brown solid (180 mg, 562 μmol, 24.0%). MS: M=321.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[H-].[Na+].[C:9]([O:12][C@@H:13]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:14]1[OH:15])(=[O:11])[CH3:10]>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3](=[NH:4])[O:15][C@H:14]1[S:16][CH2:17][C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:13]1[O:12][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)SC[C@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Reaction time: 4 h
Yield: 53 %

Procedure:
1.5 ml (15.10-3 mol) of trichloroacetonitrile and 70 mg of NaH (2.3.10-3 mol of NaH in 80% dispersion) are added to a solution of 1 g (3.42.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranose in 10 ml of methylene chloride. After 4 h at room temperature, the reaction medium is filtered on silica in methylene chloride and then purified by chromatography on silica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent. 790 mg (yield: 53%) of the expected product are obtained after crystallization from an ethyl acetate/hexane mixture.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[O:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[O:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3[nH]2)o1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3n2Cc2ccc(F)cc2)o1
Reaction time: 0.5 h

Procedure:
To a solution of the compound obtained in Example 11′ (3) (20,mg) in N,N-dimethylformamide (2 ml), 60% sodium hydride (4.4 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 30 minutes, followed by addition of 4-fluorobenzyl bromide (2.6 mg), and the reaction mixture was stirred for further 30 minutes. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with toluene. The organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate 1:1) to obtain 18 mg of the desired product as a yellow powder.