Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][C@H:10]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:11]([O:13][CH3:14])=[O:12])=[O:7])=[CH:4][CH:3]=1.[C:27]([Si:31]([O:34][CH2:35][C:36]#[C:37][CH2:38]Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>>[Si:31]([O:34][CH2:35][C:36]#[C:37][CH2:38][O:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][C@H:10]([N:15]2[CH2:16][CH2:17][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:20]2)[C:11]([O:13][CH3:14])=[O:12])=[O:7])=[CH:4][CH:3]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:32])[CH3:33]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCCl
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCC#CCO[Si](C)(C)C(C)(C)C)cc1)N1CCN(S(C)(=O)=O)CC1
Yield: 89.8 %

Procedure:
In a manner similar to example 4-5, starting from 400 mg (1 mmol) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate (prepared as described in example 4-4) and from 270 mg (1.2 mmol) of tert-butyl(4-chloro-but-2-ynyloxy)-dimethylsilane; 510 mg (88%) of methyl (S)-3-{4-[4-(tert-butyldimethylsilanyloxy)but-2-ynyloxy]benzoyl-amino}-2-(4-methanesulphonylpiperazin-1-yl)propanoate are obtained in the form of a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]([NH2:22])=[O:21])=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]([NH2:22])=[O:21])=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Yield: 76 %

Procedure:
Using the procedure in Example 37 294 mg (1 mmol) of 4-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was treated with 40 mg (1 mmol) of 60% NaH/mineral oil and 0.10 mL (1 mmol) of methyl 2-bromoacetate to give, after silica chromatography (eluted with 50% EtOAc/hexane, then EtOAc, followed by 2% MeOH/EtOAc), 278 mg (76% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, mp, 206°-208° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:18]([O-:20])=[O:19])[CH:6]=[CH:7][C:8]=2[N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:7]=[CH:6][C:5]([N+:18]([O-:20])=[O:19])=[C:4]4[C:9]=3[CH2:10][N:2]([CH3:1])[C:3]4=[O:21])[CH2:12][CH2:13]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN1Cc2c(N3CCC(=O)CC3)ccc([N+](=O)[O-])c2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CN1Cc2c(N3CCC(N4CCN(C(=O)OC(C)(C)C)CC4)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a solution of 2-methyl-7-nitro-4-(4-oxo-piperidin-1-yl)-2,3-dihydro-isoindol-1-one (4.2 g, 14.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.24 g, 17.4 mmol) in 1,2-dichloroethane is added sodium triacetoxy borohydride (3.69 g, 17.4 mmol) at 0° C. under nitrogen atmosphere. After the mixture is stirred at room temperature for 5 hours, 1N sodium hydroxide aqueous solution is added at 0° C. The mixture is extracted with dichloromethane and the organic layer is washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (AcOEt; AcOEt: MeOH=9: 1) to give 4-[1-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (4.16 g, 62%). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.47 (s, 9H), 1.66-1.76 (m, 2H), 1.94-2.02 (m, 2H), 2.42-2.59 (m, 5H), 2.84-2.93 (m, 2H), 3.05 (s, 3H), 3.40-3.49 (m, 4H), 3.49-3.57 (m, 2H), 4.35 (s, 2H), 7.00 (d, 1H), 7.76 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:18]([O-])=O)=[CH:10][C:11]=1[C:12]2=[O:17].[ClH:21]>>[ClH:21].[NH2:18][C:9]1[CH:8]=[CH:7][C:6]2[O:5][C:4]3[C:13](=[CH:14][CH:15]=[CH:16][C:3]=3[O:2][CH3:1])[C:12](=[O:17])[C:11]=2[CH:10]=1
Reactant: COc1cccc2c(=O)c3cc([N+](=O)[O-])ccc3oc12
Agent: Cl
Product: COc1cccc2c(=O)c3cc(N)ccc3oc12

Procedure:
5-Methoxy-2-nitroxanthone (5.0 g.) is added in small portions during 30 minutes to a stirred mixture of stannous chloride dihydrate (30 g.) and concentrated hydrochloric acid (30 ml.) heated on a steam-bath. The mixture is stirred and heated on a steam-bath for a further 2 hours. The precipitate is filtered off, washed with water and stirred with 5 N sodium hydroxide solution (50 ml.) for 1 hour. The solid is filtered off, made into a slurry with methanol and treated with ethereal hydrochloric acid. The solid is crystallised from methanol-ether to give 2-amino-5-methoxyxanthone hydrochloride, m.p. 271°-273° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 102 mg of 4-ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.13 (t, 3H, J=8.0 Hz), 2.53 (q, 2H, J−15.3 Hz, 7.6 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=2.8 Hz), 7.34-7.42 (m, 4H), 7.48 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.56 (m, 3H), 7.76 (d, 1H, J=8.8 Hz), 9.75 (s, 1H). MS: m/z 400.8 (M++1).
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:28]=[CH:27][C:19]4[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=4[C:17]=3[CH2:29][CH2:30][CH3:31])=[C:9]([CH2:34][CH2:35][CH3:36])[C:8]=2OC)=[CH:4][S:3]1.[N+](C)([O-])=O.C1COCC1.[CH2:48](Br)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CCCCCC.C(OCC)(=O)C.C(OCC)C.O>[C:49]1([CH2:48][S:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:33]=[CH:32][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]4[CH:28]=[CH:27][C:19]5[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=5[C:17]=4[CH2:29][CH2:30][CH3:31])=[C:9]([CH2:34][CH2:35][CH3:36])[CH:8]=3)[N:6]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1c(OCCCOc2ccc(-c3csc(=S)[nH]3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Solvent: CCOC(C)=O
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CCCc1cc(-c2csc(SCc3ccccc3)n2)ccc1OCCCOc1ccc2c(c1CCC)OC(C(=O)O)CC2
Yield: 71.7 %

Procedure:
The compound of Example 26 (30 mg, 53.7 μmol) was added to 1.5 ml of nitromethane, 0.5 ml of THF, and 30 ml (0.25 mmol) benzyl bromide. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into ethyl ether/water, and the ether layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. Flash chromatography of the residue on silica gel using 10:1 to 7:1 hexane/ethyl acetate (1% acetic acid) gave the product (25 mg, 38.5 μmol, 72% yield). High resolution mass spectrum, m/e 648.2490 (calculated for C36H42NO6S2 (M+H), 648.2453).
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:27]2[CH:44]=[CH:43][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][C:4]1([CH3:17])[C:3](=[O:18])[C:2]([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:43][CH:44]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 53.6 %

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (100 mg, 0.32 mmol, 1 eq), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (115 mg, 0.32 mmol, 1 eq), and Cs2CO3 (521 mg, 1.6 mmol, 5 eq) in toluene (7 mL) and water (2.5 mL) was degassed. Then Pd(dppf)Cl2 (52 mg, 0.06 mmol, 0.2 eq) was added under an inert atmosphere and the solution was again degassed. The reaction mixture was then refluxed for 3 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2,2-dimethyl-5-(4-nitrophenyl)-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (80 mg, 54%) as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.42 (d, J=8.5 Hz, 1 H), 8.27 (d, J=8.5 Hz, 2 H), 8.00 (t, J=7.9 Hz, 2 H), 7.82-7.76 (m, 3 H), 7.68 (d, J=8.5 Hz, 1 H), 7.61 (t, J=7.2 Hz, 1 H), 7.18 (d, J=8.7 Hz, 2 H), 7.10 (d, J=8.7 Hz, 2 H), 5.38 (s, 2 H), 1.48 (s, 6 H). MS: [M+H]: m/z=467.1. HPLC: 89%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: Cl.[CH2:2]([N:9]([C:17]1[CH:18]=[C:19]([CH:44]=[CH:45][CH:46]=1)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:23]=1)=[O:21])C(OC(C)(C)C)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[CH2:2]([NH:9][C:17]1[CH:18]=[C:19]([CH:44]=[CH:45][CH:46]=1)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:23]=1)=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(C(=O)c2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCCn1cc(C(=O)c2cccc(NCc3ccccc3)c2)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
4N Hydrochloric acid in 1,4-dioxane (2 ml) was added to a solution of benzyl 4-[3-[3-[N-benzyl-N-(tert-butoxycarbonyl)amino]benzoyl]indol-1-yl]butyrate (0.31 g) in 1,4-dioxane (2 ml). The mixture was stirred at room temperature for 1 hour and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated to give benzyl 4-[3-(3-benzylaminobenzoyl)indol-1-yl]butyrate (258 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1.[CH3:22][C:23]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2cccc(Cl)c2)cc1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.05 g of 3-[4-(3-chlorophenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 5.78 g of ethyl 3-[4-(3-chlorophenoxy)benzoyl]acrylate in the form of an oil.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.[CH3:46][NH:47][CH:48]=[O:49]>[Cu]I.O1CCOCC1>[CH2:9]([NH:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([N:47]([CH3:46])[CH:48]=[O:49])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNC=O
Reactant: O=C(NCc1ccccc1)c1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: CN(C=O)c1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 97.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), 4-iodo-N-benzylbenzamide (350 mg, 1.04 mmol), K3PO4 (450 mg, 2.12 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 11 mol %), dodecane (235 μL), N-methylformamide (74 μL, 1.27 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; ethyl acetate-dichloromethane 2:1; 20 mL fractions). Fractions 7–18 provided 273 mg (98% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.90–7.86 (m, 2H), 7.40–7.29 (m, 5H), 7.25–7.20 (m, 2H), 6.62 (br s, 1H), 4.66 (d, J=5.7 Hz, 2H), 3.35 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.6, 162.3, 145.2, 138.4, 132.2, 129.2, 129.0, 128.3, 128.1, 121.5, 44.6, 32.0.
Reaction SMILES: Br[CH2:2][CH:3](OCC)OCC.Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+].[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][N:24]=1>O>[N:22]1[CH:2]=[CH:3][N:24]2[CH:25]=[CH:26][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:28][C:23]=12
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: COC(=O)c1ccn2ccnc2c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A mixture of 1.31 parts of 2-bromo-1,1-diethoxyethane, 10 parts of water and 1.5 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 1 hour. The mixture was poured onto 50 parts of water and the whole was neutralized with potassium carbonate. Then there were added successively 5 parts of sodium hydrogen carbonate and 3 parts of methyl 2-amino-4-pyridinecarboxylate. The reaction mixture was stirred and heated for 15 minutes at 55° C. in an oil-bath. After 30 minutes, gas-evolution had ceased and the mixture was cooled. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.9 parts (82.3%) of methyl imidazo-[1,2-a]pyridine-7-carboxylate; mp. 143.2° C. (intermediate 13).
Reaction SMILES: [C:1]([N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](Cl)=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)(=[O:3])[CH3:2].O.[NH2:36][NH2:37].CCOC(C)=O>CO>[F:33][C:31]([F:32])([F:34])[C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=1)[CH2:20][N:4]([CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:36][NH2:37])=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)[C:1](=[O:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)NN)c2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
A mixture of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl chloride (1.0 mmol, 0.52 g) and hydrazine hydrate (50.0 mmol, 1.56 mL) in MeOH (5 mL) was refluxed at 70° C. for 12 h with vigorous stirring. The solvent was removed in vacuo and the crude product was purified by crystallization using EtOAc. The product was obtained as white solid; Rf 0.2 (EtOAc); MS (ES+): 523 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[OH2:17].C[N+]1([O-])CCOCC1.S([O-])([O-])=O.[Na+].[Na+].[OH2:32]>O1CCCC1.O.O.[O-][Os]([O-])(=O)=O.[K+].[K+]>[CH2:10]([O:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH2:1][OH:32])([OH:17])[CH2:3][CH2:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C1CCC(COCc2ccccc2)CC1
Reactant: O
Agent: O=[Os](=O)([O-])[O-]
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Product: OCC1(O)CCC(COCc2ccccc2)CC1
Reaction time: 18 h

Procedure:
To a solution of EXAMPLE 399A (4.77 g) and 4-methylmorpholine 4-oxide hydrate (3.28 g), in a mixture of tetrahydrofuran (90 mL) and water (13.50 mL) was added potassium dioxidodioxoosmium dihydrate (0.325 g) and the resulting suspension was stirred rapidly 18 hours. Sodium sulfite (12.51 g) and water (90 mL) were added and stirring was continued for 1 hour. The reaction was diluted with water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel and eluted with a 50, 100% ethyl acetate in hexane step gradient to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:55]=[CH:54][CH:53]=[CH:52][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH:32]2[CH2:37][N:36](S(C3C=CC(C)=CC=3)(=O)=O)[C:35]3[CH:48]=[CH:49][CH:50]=[CH:51][C:34]=3[O:33]2)=[CH:13][CH:12]=1.[Mg]>CO.C(OCC)(=O)C>[O:33]1[C:34]2[CH:51]=[CH:50][CH:49]=[CH:48][C:35]=2[NH:36][CH2:37][CH:32]1[CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:52]=[CH:53][CH:54]=[CH:55][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CN(S(=O)(=O)c3ccc(C)cc3)c3ccccc3O2)cc1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CNc3ccccc3O2)cc1

Procedure:
A solution of 0.66 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[4-(toluene-4-sulphonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2(R,S)-ylmethoxy]piperidine-1-carboxylate in 10 ml of methanol is treated in an ultrasound bath in the presence of 0.5 g of magnesium turnings over 30 minutes. The reaction mixture is decantered off from the magnesium, diluted with ethyl acetate, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:2 EtOAc-heptane); Rt=5.62.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([C@@H:10]([CH2:17][CH2:18][CH3:19])[CH2:11][N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:25][CH3:26].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@@H:10]([CH2:17][CH2:18][CH3:19])[CH2:11][N:12]2[CH2:15][CH:14]([O:16][CH2:25][CH3:26])[CH2:13]2)[CH3:9])=[O:7])=[CH:20][CH:21]=1
Reactant: CCI
Reactant: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC[C@@H](CN1CC(OCC)C1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To (S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide (Example 8.2 A) (85 mg, 0.27 mmol) in dry THF (3 mL) was NaH (60% in mineral oil) (16.41 mg, 0.41 mmol) added carefully. The mixture was stirred at rt for 30 minutes then iodoethane (0.023 mL, 0.29 mmol) was added in one portion. The mixture was left standing at rt on. NaHCO3 and DCM were added and the two layers were separated using a phase separator. The organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound (36 mg, 39%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.71, 0.86, 0.93-1.08, 1.08-1.32, 1.33-1.49, 2.36, 2.49-2.53, 2.54-2.61, 2.66, 2.70, 2.72-2.80, 3.19-3.32, 3.48, 3.96, 7.32, 7.38, 7.47. HRMS (M+H)+: calculated 339.1839. found 339.1840.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH3:29])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12>>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]4[N:28]([CH3:29])[N:27]=[N:26][N:25]=4)[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)O)C1=CSCCO1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCO1

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (anti isomer, 1 g.) was allowed to react with 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) in a similar manner to that of Example 1 to give the captioned compound (1.8 g.), pale yellow powder, mp. 144° to 148° C. (dec.).
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][Cl:23])[O:17][C@H:16]([CH2:18][Cl:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@H:9]([OH:24])[C@@H:8]([OH:25])[C@H:7]1[Cl:26])=O.C[O-].[Na+]>CO>[CH2:5]([OH:4])[C@@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][Cl:23])[O:17][C@H:16]([CH2:18][Cl:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@@H:9]([OH:24])[C@@H:8]([OH:25])[C@H:7]1[Cl:26]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@]2(CCl)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@@H]1O[C@H](O[C@]2(CCl)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H](O)[C@H]1Cl
Reaction time: 2 h

Procedure:
A mixture of 20 g of dry sucralose-6-acetate obtained from Example 5 and 70 ml of methanol was heated to from 40° C. to 50° C. When the reacting mixture became a clear solution, a small quantity of a 30% sodium methylate solution was added. After the mixture was stirred for 2 hours, methanol was removed under reduced pressure. The resultant mixture was diluted to a 30% mixture by adding a certain quantity of water, which was decolored and then filtered. The filtrate thus obtained was concentrated to a 65% solution, which was cooled to form crystallized sucralose. The obtained crystal was filtered and dried to give sucralose with a yield of over 95% and purity of over 98.0%.