Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1ccccc1
Solvent: CO
Product: COc1cc(C=Nc2ccccc2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (50 ml) and aniline (560 mg, 6.01 mmol, 0.35 ml, neat liquid) was added to the solution by syringe. The resultant reaction mixture was stirred overnight at room temperature under nitrogen then taken to dryness in-vacuo. The yellow crystals thus obtained were triturated with hot ether, allowed to cool, filtered and the collected solid was washed with ether to yield the title product: 1H NMR (300 MHZ, CDCl3) δ , 8.33 (S, 1H), 7.42-7.39 (m, 2H), 7.21-7.18 (m, 5H), 5.84 (S, 1H), 3.98 (S, 6H)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[OH:35]/[N:34]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(=O)O)cc1

Procedure:
In analogy to example 151, step 3, {4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoylamino}-acetic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=446.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:10]1>CO.C(O)(=O)C.[Zn]>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[C:11]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: N#Cc1ccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)cc1
Yield: 53.5 %

Procedure:
To a solution of Example 8B (40 mg, 0.083 mmol) in a mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (54 mg, 0.83 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (20 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.34-7.54 (m, 2H), 6.25-6.98 (m, 9H), 5.82-5.96 (m, 2H), 5.73-5.83 (m, 1H), 3.30-3.47 (m, 1H), 1.28-1.80 (m, 4H). MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([S:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]#[C:11][Si](C)(C)C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[C:9]([S:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]#[CH:11])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#CC(=Nc1ccc(Cl)cc1)SCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#CC(=Nc1ccc(Cl)cc1)SCC1CCCCC1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
Cyclohexylmethyl N-(4-chlorophenyl)-3-(trimethylsilyl)thiopropynimidate (0.34 g) was dissolved to methanol (5 mL), a small amount of potassium carbonate was added thereto under ice-cooling and stirred for 30 minutes. The reaction solution was poured into aqueous solution of sodium chloride, and extracted with ethyl acetate. The organic layer was washed with water, dried. The solvent was distilled off to obtain cyclohexylmethyl N-(4-chlorophenyl)thiopropynimidate (0.27 g).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([OH:3])=O.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.ClC1C=CC=CC=1Cl.Cl>C(OCC)(=O)C>[CH3:16][C:15]1([CH3:19])[N:14]2[C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[CH:4]=[C:1]2[O:3][CH2:18]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: CC1(C)COc2cc3ccccc3c(=O)n21

Procedure:
A mixture of 1 g. of 2-carboxymethylbenzoic acid, 0.5 g. of 2-amino-2-methylpropanol, and 5 ml. of o-dichlorobenzene was heated to 150°-160° C. for 4 hours. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was dissolved in 30 ml. of ethyl acetate. Then, the solution was successively wased with diluted hydrochloric acid, a diluted sodium carbonate solution, and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. By recrystallizing the residue obtained from cyclohexane, 700 mg. of 3,3-dimethyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-b]isoquinoline was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[C:9]([F:22])[CH:8]=1)=[O:5])[CH3:2].F[C:24]1C=C(C=CC=1B1OC(C)(C)C(C)(C)O1)N.C1(N=C=O)CC1>>[CH:1]1([NH:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([B:13]3[O:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[O:17]3)=[C:9]([F:22])[CH:8]=2)=[O:5])[CH2:24][CH2:2]1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Agent: O=C=NC1CC1
Product: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Prepared as 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) using 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and cyclopropyl isocyanate as starting materials. The crude reaction mixture was then partitioned between DCM and water. The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo to yield a light orange solid (3.2 g, 10 mmol, 100%).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:28]([CH:35]1[C:41]2[CH:42]=[C:43]([C:46]([O:48][CH3:49])=[O:47])[CH:44]=[CH:45][C:40]=2[O:39][CH2:38][C:37](=O)[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O1CCCC1.ClCCl.O>[CH2:28]([CH:35]1[C:41]2[CH:42]=[C:43]([C:46]([O:48][CH3:49])=[O:47])[CH:44]=[CH:45][C:40]=2[O:39][CH2:38][C:37](=[CH:8][Cl:7])[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(Cc1ccccc1)CC(=O)CO2
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(Cc1ccccc1)CC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
1.1 equivalents of n-butyllithium are added to a suspension of 40 mg (0.12 mmol) of chloromethyltriphenylphosphonium chloride in 3 ml of tetrahydrofuran cooled to 0° C. After stirring for one hour, the ylide is added at 0° C. via a hollow tube to 30 mg (0.1 mmol) of methyl 5-benzyl-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 9. After stirring at ambient temperature for 30 minutes, water, 1N hydrochloric acid and dichloromethane are added. The phases are separated by settling and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are then dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 5/95) to provide 18 mg (53%) of methyl 5-benzyl-3-(chloromethylene)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of a mixture of two isomers in a Z/E ratio (60/40); exact mass (CI): calculated 343.11009; found 343.11027.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:23][C:24](=[O:28])[CH:25](Br)[CH3:26])[CH3:22]>CC(C)=O>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([N:9]1[C:8]2[CH:14]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(C(C)=O)cc21
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a mixture of 6-acetyl-4H-benzo[1,4]oxazin-3-one (Alfa, 5 g, 26.18 mmol) and K2CO3 (5.4 g, 39.2 mmol) in acetone (50 mL) was added 2-bromo-propionic acid ethyl ester (14.14 g, 78.54 mmol) and the mixture was heated to reflux for 3 h. The reaction mixture was cooled to ambient temperature and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-acetyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a white solid (6.14 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 7.62 (dd, J=2 Hz, J=8.4 Hz, 1H), 7.52 (d, J=2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.29 (t, J=6.8 Hz, 1H), 4.68 (d, J=15.6 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 2.56 (s, 3H), 1.65 (d, J=6.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N:9]([C:11]1[C:12]([NH2:26])=[N:13][C:14]([NH2:25])=[N:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>O>[NH2:25][C:14]1[N:13]=[C:12]([NH2:26])[C:11]([NH2:9])=[C:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:15]=1
Reactant: Nc1nc(N)c(N=O)c(OCc2ccccc2)n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(N)c(N)c(OCc2ccccc2)n1

Procedure:
Sodium dithionite is added in portions to a suspension of 17 g 5-nitroso-2,4-diamino-6-benzyloxy-primidine (8) in 300 mL H2O at 50° C. until the red nitroso compound is fully reduced. The free base is separated out by adding aqueous ammonia. The crude product is cooled, suctioned off and crystallized from water, to which activated charcoal and a trace of sodium dithionite is added yielding 9.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:36])(=[O:35])[N:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:37]([OH:39])=O)=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl.[CH3:43][N:44]([CH2:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:36])(=[O:35])[N:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:37]([NH:56][C:55]4[CH:57]=[CH:58][C:52]([CH2:51][N:44]([CH3:43])[CH:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)=[CH:53][CH:54]=4)=[O:39])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
In DMF (25 ml) were suspended 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3 g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.19 g) and 1-hydroxybenzotriazole (0.07 g). Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g), triethylamine (0.37 ml) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 47) (0.12 g) as colorless crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH2:7]([C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C@@H:10]([CH3:16])[C:11]([N:13]([CH3:15])[CH3:14])=O)[CH3:8].[ClH:24].CO>O1CCCC1>[ClH:24].[CH3:15][N:13]([CH3:14])[CH2:11][C@H:10]([CH3:16])[C@H:9]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH2:7][CH3:8]
Reactant: CC[C@@H](c1cccc(O)c1)[C@@H](C)C(=O)N(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Reaction time: 2 h
Yield: 90 %

Procedure:
Lithium aluminum tetrahydride (730 mg, 20 mmol) was suspended in tetrahydrofuran (10 ml), and it was cooled in an ice-water bath, then the solution of product of Example 26 (2 g, 8.5 mmol) in tetrahydrofuran (10 ml) was added dropwise, the reaction was carried out for 2 hours and then quenched by adding 10% NaOH aqueous solution. The reaction solution was then extracted with ethyl acetate for three times, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to 2 mL, then the concentrated hydrochloric acid (710 μl, 8.5 mmol) was added dropwise therein, and the resulted solution was concentrated and recrystallized with isopropanol-ethyl acetate to obtain the target 1.97 g, yield: 90%. [α]D=+24.3° (c=1.10, CH3OH). 1HNMR (300 MHz, CD3OD): δ 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.7-2.8 (6H, br s), 2.2-2.3 (1H, m), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.2 (3H, d, J=6.7), 0.8 (3H, t, J=7.4, 14.4). ESI-MS: 222.4 (M+H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:15]([OH:18])[CH:16]=[CH2:17]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:15]([O:18][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:8][CH:9]=1)[CH:16]=[CH2:17]
Reactant: C=CCO
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: C=CCOCc1ccc(C(C)(C)C)cc1

Procedure:
88 g (1.1 mol) of 50% sodium hydroxide solution are treated with 4.6 g (0.016 mol) of tetrabutylammonium chloride. At a temperature of 35° C. there is added dropwise within about 20 minutes while stirring well a mixture of 182.5 g (1.0 mol) of p-tert-butylbenzyl chloride and 61.5 g (1.06 mol) of allyl alcohol. The temperature is held at <70° C., which is accomplished if necessary by slight cooling. The mixture is stirred well at 70° C. for a further 12 hours. After cooling, the reaction mixture is washed twice with dilute hydrochloric acid. 204 g of practically pure p-tert-butylbenzyl allyl ether are obtained. The substance can be used without distillation for the next step.
Reaction SMILES: [CH2:1]([C@@:8]1([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][NH:18][C:19](=[O:26])[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][OH:24])[O:11][C@:9]1([N:27]=[C:28]=[O:29])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([C@@:8]1([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:14]([O:15][C:23](=[O:24])[CH3:22])[C@H:13]([O:16][C:19](=[O:26])[CH3:20])[C@@H:12]([CH2:17][NH:18][C:19](=[O:26])[CH2:20][CH2:21][C@H:22]([O:25][C:9](=[O:10])[CH3:8])[CH2:23][O:24][C:12](=[O:11])[CH3:13])[O:11][C@:9]1([N:27]=[C:28]=[O:29])[OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=N[C@]1(O)O[C@H](CNC(=O)CC[C@H](O)CO)[C@@H](O)[C@H](O)[C@@]1(Cc1ccccc1)OCc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OC[C@H](CCC(=O)NC[C@H]1O[C@@](O)(N=C=O)[C@](Cc2ccccc2)(OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)OC(C)=O

Procedure:
(S)-4,5-Dihydroxy-pentanoic acid (benzyl 2-benzyloxy-carbonylamino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide was acetylated as described in Ex. 14.B. and gave (S)-4,5-diacetoxy-pentanoic acid (benzyl 3,4-di-O-acetyl-2-benzyloxy-carbonylamino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide, [α]+89.5° (c 0.2; dioxan), MS: m/z 687.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:11][O-:12].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:12][CH3:11])[CH:7]=1
Reactant: C[O-]
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cnc(C#N)c(Cl)c1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
To a solution of 3,5-dichloropicolinonitrile (1.0 eq.) in dimethyl formamide (DMF) (0.5 M) was added sodium methoxide (1.5 eq.) and heated to 75° C. After stirring for 14 hours, the reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous NaHCO3 three times, water twice, dried over anhydrous MgSO4, and concentrated en vacuo. The crude residue was purified by a COMBIFLASH® system (ISCO) using 15% ethyl acetate in hexane to give a mixture of two methoxy regioisomers, one of which was the desired product. The mixture was carried onto the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].[CH3:23][N:24](C=O)C>C(#N)C>[CH3:7][C:5]1[NH:4][C:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:2]([CH3:1])[C:6]=1[C:23]#[N:24]
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)[nH]1
Solvent: CC#N
Product: Cc1[nH]c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A mixture of 3,5-dimethyl-2-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole (576.0 mg, 1.809 mmol) and N-chlorosulfonylisocyanide (197 μl, 2.261 mmol) in acetonitrile (9.0 ml) was stirred at 25° C. for 1 hour. DMF (140 μl, 1.809 mmol) was then added and the resulting mixture was stirred for an additional 16 hours. It was quenched with water (100 ml) and extracted with dichloromethane (100 ml×2). The organic layers were combined, filtered, and evaporated to give an oil. The oil was purified by column chromatography (0 to 70% ethyl acetate in hexanes) to give 2,4-dimethyl-5-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole-3-carbonitrile (513.6 mg, 1.495 mmol, 83% yield) as brown oil. 1H NMR (CDCl3/400 MHz) δ (ppm) 9.10 (bs, 1H), 7.82-7.77 (m, 1H), 7.46-7.40 (m, 1H), 7.30-7.23 (m, 2H), 4.10 (s, 2H), 3.33-3.27 (m, 4H), 2.20 (s, 3H), 2.18 (s, 3H), 1.92-1.88 (m, 4H). MS m/z: 344.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:13])[CH3:12].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18].Cl>C(#N)C.C(OCC)C>[CH3:15][O:16][C:17]([NH:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:12])[CH3:13])=[S:21])=[O:18]
Reactant: CN(C)CC(=O)Nc1ccccc1N
Reactant: COC(=O)N=C=S
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)NC(=S)Nc1ccccc1NC(=O)CN(C)C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
A suspension of N-(2-aminophenyl)-2-dimethylaminoacetamide (4.8 g) in dry acetonitrile (20 ml) was stirred vigorously during the dropwise addition of methoxycarbonyl isothiocyanate (3.5 g), the temperature being maintained between 15° C. and 20° C. by external cooling, and afterwards for a further 5 minutes. The mixture was then diluted with diethyl ether (500 ml) and treated with an excess of a saturated solution of hydrogen chloride in diethyl ether. The precipitate was filtered off, dissolved in the minimum quantity of water, and treated with an excess of a 2N aqueous solution of sodium hydroxide. The precipitate was filtered off and recrystallised twice from benzene to give 1-methoxycarbonyl-3-(2-dimethylaminoacetamidophenyl)thiourea (3.5 g), m.p. 130°-131° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(COC)=O)[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[C:20]([O:26][C:27]([F:30])([F:29])[F:28])[CH:19]=1.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:22]/[C:21]1[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][C:20]=1[O:26][C:27]([F:29])([F:28])[F:30])[CH3:2]
Reactant: CCOC(=O)CP(=O)(COC)OCC
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.5 %

Procedure:
To a solution of (ethoxy-methoxymethyl-phosphinoyl)-acetic acid ethyl ester (3.45 g, 15.4 mmol) in THF (230 mL) was added 60% sodium hydride in oil (370 mg, 15.4 mmol). The mixture was stirred at ambient temperature for 50 min and cooled at 4° C. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (3 g, 11.2 mmol) in THF (100 mL). The mixture was stirred at ambient temperature for 15 hr. The solution was poured into H2O, and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 5% EtOAc in hexane) to give (E)-3-(4-Bromo-2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (2.98 g, 79%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:35])[C@H:30]([C@@H:32]([CH3:34])[OH:33])[NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:35])[CH:30]([NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH:32]([OH:33])[CH3:34])[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.