Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:9][CH:8]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>ClCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][NH:13][C:11](=[O:12])[CH2:10][CH:8]2[CH2:7][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:9]2)=[O:24])=[CH:18][CH:17]=1
Reactant: NNC(=O)CC1CN(C(=O)C2CC2)C1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(CC1CN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
In a round bottom flask, a solution of 2-[1-(cyclopropylcarbonyl)-3-azetidinyl]acetohydrazide (0.316 g, 1.602 mmol) in dichloromethane (10 mL) was treated with 4-bromophenylisocyanate (0.317 g, 1.602 mmol) and the reaction mixture was stirred at room temperature for 1 h (white precipitate formed). The white solid was filtered, rinsing with cold dichloromethane (4×), and dried under air suction to give the title compound (0.455 g, 87% pure, 62% yield). MS(ES)+ m/e 394.9, 396.6 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[C:15]([N:17]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:14]([C:15](=[O:16])[N:17]([CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH2:40])[CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:13]=1)[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)C2CCCC2)c1)c1ccncc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(N)=O)C2CCCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 43 h
Yield: 81.8 %

Procedure:
To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-cyclopentyl-amino)-butyric acid (0.049 g), TBTU (0.058 g) and HOBt (0.024 g) in DMF (1 ml) was added DIPEA (0.031 ml) followed a 0.5M solution of ammonia in 1,4-dioxane (0.36 ml) after 15 min. The reaction mixture was stirred at room temperature for 43 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.040 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccccc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Dayal, et al., Steroids, 1990, 55(5), 233-237), a reaction mixture of methyl 2-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]benzoate (23a) (1.97 g, 5.0 mmol) and commercial lithium hydroxide monohydrate (LiOH.H2O) (420 mg, 10.0 mmol) in a mixture of water (10 mL) and methanol (MeOH) (3 mL) is stirred at room temperature. The reaction is monitored by TLC and/or LC/MS to completion. The solvent is partially removed under reduced pressure using a rotary evaporator. Acidic aqueous work-up and purification by silica gel column chromatography furnish the title compound 2-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]benzoic acid (23b) which may be used directly in the next step without further isolation and purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:12][N:11]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCc1ccccc1)[C@H]1CCNC1
Reaction time: 0.5 h
Yield: 115.1 %

Procedure:
A solution of tert-butyl (S)-3-(N-benzyloxycarbonyl-N-methylamino)pyrrolidine-1-carboxylate (Intermediate 130, 1.81 g) in trifluoroacetic acid (8 mL) and DCM (8 mL) was left to stand at room temperature for 30 minutes. The resultant mixture was concentrated in vacuo and the residue was dissolved in DCM and brine, basified with 2M sodium hydroxide and filtered through a phase separator. The filtrate was concentrated in vacuo to give benzyl N-methyl-(S)-pyrrolidin-3-ylcarbamate (1.46 g) as a light coloured oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[C:44]([OH:46])[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][C:40]1[CH:41]=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[C:44]([OH:46])[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(F)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 70 °C
Yield: 51.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (110 mg, 0.19 mmol) was dissolved in 1.32 mL 1,2-dimethoxyethane and 0.33 mL water. (3-Fluoro-5-hydroxyphenyl)boronic acid (69 mg, 0.44 mmol), sodium carbonate (47 mg, 0.44 mmols) and bis(triphenylphosphine)palladium(II) dichloride (13 mg, 0.02 mmol) were added under argon atmosphere and the mixture was heated at 70° C. for 2 h. The reaction mixture was poured into a saturated ammonium chloride solution and extracted twice with water. The organics were washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 61 mg (53% yield) of the title compound. Purity 99%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](OC)([O:16]C)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[O:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(OC)C2CCC1CN(Cc1ccccc1)C2
Agent: Cl
Product: O=C1C2CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
3-Benzyl-8,8-dimethoxy-3-aza-bicyclo[3.2.1]octane (50.4 g, 0.19 mol) and 3N HCl (500 mL) were heated to reflux 4 h (or until judged complete by TLC). Upon cooling to room temperature, the aqueous solution containing product was washed with ether (2×200 mL) then back extracted from the ether layer with 1N HCl (100 mL). The combined aqueous layers were made alkaline with NaOH (˜50 g) in water (500 mL). The product was extracted with EtOAc (3×300 mL), washed with saturated aqueous NaCl solution (1×200 mL), dried over Na2SO4, filtered through a pad of silica (5×4 in), rinsed with 100% EtOAc, and concentrated to a brown liquid (42.0 g, 100%). (TLC 30% EtOAc/hexanes Rf 0.55); 1H NMR (400 MHz, CDCl3) δ 7.37–7.24 (5H), 3.59 (s, 2H), 2.98 (ddd, J=9.5, 4.2, 2.1 Hz, 2H), 2.54 (d, J=10.8 Hz, 2H), 2.16 (brs, 2H), 2.06 (dd, J=12.4, 4.8 Hz, 2H), 1.85 (m, 2H); APCI MS m/z 216.3 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:3](=[O:35])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1.C(O)(=O)C.O>[F:1][C:2]([C@:3]1([OH:35])[O:11][C@@H:10]2[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C@H:6]2[CH2:5][CH2:4]1)([F:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(F)(F)[C@@]1(O)CC[C@H]2[C@@H](CC(=O)[C@@H]2CCCCCCC(=O)OCc2ccccc2)O1
Temperature: 40 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of benzyl 7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy) cyclopentyl]heptanoate (1) (39.84 g, 70.54 mmol) in tetrahydrofuran (40 ml), acetic acid (260 ml) and water (140 ml) were added. The mixture was stirred at about 40° C. for 4 hours. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Fuji Silysia BW-300 1600 g, ethyl acetate:hexane=1:3). Fractions containing impurities were purified again by silica gel column chromatography (Fuji Silysia FL-60D 1600 g, ethyl acetate:hexane=1:4). Fractions still containing impurities were collected and further purified repeatedly with silica gel column chromatography (Fuji Silysia FL-60D 1000 g, IPA:hexane=8:100), (Fuji Silysia FL-60D 1600 g, IPA:hexane=7.5:100→3:40), (Fuji Silysia FL-60D 1600 g, IPA:hexane=3:40). Fractions containing substantially no impurities were collected and evaporated to give benzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanate (2) (25.68 g, 53.44 mmol, yield: 75.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.C(O)C.O.NN>C1COCC1.[Ni]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cc(CN2CCOCC2)cc(C(F)(F)F)c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(CN2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a solution of 4-(3-nitro-5-trifluoromethylbenzyl)morpholine (168 mg; 0.57 mmol) in THF:ethanol mixture (1:1) (30 mL) was added a catalytical amount of Raney-Nickel and hydrazine hydrate (4.0 mmol) and the mixture was stirred for 2 hours at ambient temperature, then filtered through a Celite/silical gel pad. The filtrate was evaporated to provide the title compound (152 mg, 98%), which was used in further reactions without purification.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([OH:23])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[C:28]([O:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[C:16]2[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)([CH3:30])[CH3:29])[CH3:25]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2[nH]c(Cc3ccccc3)c(-c3ccncc3)c2c1
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(Cc3ccccc3)c(-c3ccncc3)c2c1

Procedure:
The above compound was prepared from 2-benzyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18](=[O:34])[N:19]([CH3:33])[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:9]=1)(C)(C)C>CCCCCCC.CCOC(C)=O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1)[C:18]([N:19]([CH3:33])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])=[O:34]
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 85, intermediate a, from {3-[methyl-(4-o-tolyl-pyridin-3-yl)-carbamoyl]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless solid (94%). MS (ESI): m/z=386.147 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1>[CH3:31][O:30][CH2:29][CH:4]([CH2:3][O:2][CH3:1])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:41])[NH2:17])=[CH:11]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
To a solution of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (1.0 g) in tetrahydrofuran (15 mL) was added Lawesson's reagent (1.0 g) and the mixture was stirred at 50° C. for 45 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 70/30, volume ratio) to give the title compound (0.94 g, 90%) as a yellow amorphous solid. MS 466 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]C)=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH:13]=[O:14])[CH:4]=1.C(O)C[OH:17]>>[C:13]([OH:14])(=[O:17])[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: OCCO
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COc1cc(C(=O)O)cc(OC)c1O
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
106 g (0.5 mole) of TMBA, 66 g (1.6 mole) of soda in pellets in 200 g of ethylene glycol, are heated under nitrogen. Solution is complete towards 160° C. Distillation commences and stops at the end of 30 minutes, at around 195° C. This temperature is held for 30 minutes. After cooling under nitrogen, it is diluted with 1 l of water and acidified to pH 3 with 170 ml of 10 N sulphuric acid, with heating to bring it to reflux. It is then cooled and left to crystallize for 1 hour. By filtration, 163.3 g of moist, crude product are isolated and this recrystallized in 900 ml of water. After washing and drying, 76.4 g of recrystallized syringic acid are obtained, namely a yield of 77.2% with respect to the TMBA. The acid obtained has a melting point of 210° C. Analysis by liquid-liquid chromatography indicates that it contains less than 1% of residual TMBA and that it is free of 3-hydroxy 4,5-dimethoxybenzoic acid and of dihydroxymonomethoxybenzoic acid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3].[NH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].C(O)C>O>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc(NCCC(=O)O)c([N+](=O)[O-])c1
Temperature: 55 °C

Procedure:
4-azido-1-fluoro-2-nitro-benzene (90 mg) is mixed with an aqueous solution (0.5 ml) containing 3-aminopropionic acid (53 mg) and Na2CO3 (106 mg). Following addition of 2 ml of ethanol and 0.5 ml of water, the solution is heated for 24 h at 55° C. After removal of the unreacted materials by several ether extractions, the product (3-(N-(4-azido-2-nitrophenyl)-amino)propionic acid) is obtained by ether extraction of the acidified (pH 2.0) aqueous phase.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:3]1[N:2]([CH3:1])[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(Cl)n(C)c12
Yield: 81 %

Procedure:
A solution of 2.00 g (9.70 mmol) of methyl 1-methyl-2-oxo-1,3-dihydro-2H-benzimidazole-7-carboxylate in 20 mL of phosphorous oxychloride was heated at 100° C. for 6 h. The reaction was concentrated in vacuo and the thus obtained residue was quenched with water and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The thus obtained residue was purified via flash chromatography eluting with a solution of 20% ethyl acetate/hexanes to give 1.77 g (81%) of the title compound as white solids.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[SH:16])([CH3:3])[CH3:2].[CH3:17][CH2:18][O-:19].[Na+].C(OC(OCC)CBr)C.Cl>CC(C)=O.O.C(O)C>[CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[S:16][CH2:17][CH:18]=[O:19])([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(C(C)C)c(S)c(C(C)C)c1
Reactant: CC[O-]
Agent: CCOC(CBr)OCC
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(SCC=O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Na (0.35 g, 15 mmol) was added in small pieces under Ar to dry ethanol (7 mL). A solution of 2,4,6-triisopropylthiophenol (3.55 g, 15 mmol) was added to the solution of NaOEt and the resulting mixture stirred for 5 min at RT. Bromoacetaldehyde diethylacetal (2.5 mL, 16.5 mmol, Aldrich) was added dropwise to the solution of Na thiolate and the resulting mixture refluxed for 2 h. After that, it was poured into H2O (100 mL), extracted with CH2Cl2 (3×50 mL), the extracts dried (MgSO4), filtered and evaporated (aspirator). The NMR showed the presence of the product and ca. 15% of bromoacetaldehyde diethylacetal impurity. The crude reaction mixture was refluxed with 2% aq. HCl (20 mL) and acetone (30 mL) for 2 h 10 min. The reaction mixture was extracted with CH2Cl2 (3×50 mL), the extracts were dried (MgSO4), filtered and evaporated. Distillation of the product gave a clear liquid, bp 108–114C/0.5 mm, 3.58 g (85.6%). 1H NMR (CD2Cl2) 9.57 (t, 1H; J=3.4 Hz); 7.00 (s, 2H); 3.86 (septet, 2H; J=7.1 Hz); 3.33 (d, 2H; J=3.4 Hz); 2.87 (septet, 1H; J=7.0 Hz); 1.23 (d, 6H; J=7.0 Hz); 1.22 (d, 12H; J=7.1 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:23][CH:22]([NH2:24])[CH2:21]2)[CH2:16]1.C(N(CC)CC)C>O1CCCC1>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:24][CH:22]1[CH2:23][N:20]([CH:17]2[CH2:18][CH2:19][O:15][CH2:16]2)[CH2:21]1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CN(C2CCOC2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NC2CN(C3CCOC3)C2)c([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
4-Fluoro-3-nitrobenzenesulfonamide (0.084 g), 1-(tetrahydrofuran-3-yl)azetidin-3-amine (0.090 g) and triethylamine (0.266 ml) in tetrahydrofuran (3 mL) was heated to 60° C. After stirring for 4 hours, the reaction was cooled, the tetrahydrofuran was removed and the residue was partitioned between dichloromethane (200 mL) and water (20 mL). The organic layer was separated, washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:27][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CCCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCNCc1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To a solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (334 mg, 1.27 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and hexylamine (Aldrich, 98 μL, 1.53 mmol) in DCE (15.00 mL) was added acetic acid (110 mL) and sodium triacetoxyborohydride (405 mg, 1.91 mmol) and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was then diluted with DCM and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silicagel (DCM, DCM/MeOH/NH4OH 98:2:1 then 95:5:1) to give 144 mg (32%) of the title compound. HPLC, Rt: 4.59 min (purity: 98.7%). 1H NMR (CD3Cl3) δ: 0.87 (t, J=6.9 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.28-1.64 (m, 13H), 2.6 (t, J=7.3 Hz, 4H), 3.78 (s, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H).
Reaction SMILES: [C:1](OC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl[Sn](Cl)(Cl)Cl.[Si](Cl)(Cl)(Cl)Cl>ClC1C=CC=CC=1.COC(=[W-2](=C=O)(=C=O)(=C=O)(=C=O)=C=O)C1C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: COC(c1ccccc1)=[W-2](=C=O)(=C=O)(=C=O)(=C=O)=C=O
Agent: Cl[Si](Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: CCCCCCCCC=CCCCCCCCC
Yield: 16 %

Procedure:
Several other runs were carried out to demonstrate the use of embodiment A for the disproportionation of unsaturated esters. In run 201, 21 mmoles of methyl oleate, 0.22 mmoles of (methoxyphenylcarbene)pentacarbonyltungsten(0), 2.2 mmoles of SnCl4, and 2.2 mmoles of SiCl4 in about 18 ml of chlorobenzene were stirred at 55° C. for 72 hours. The reaction product mixture contained a 16% yield of 9-octadecene and about a 10% yield of dimethyl 9-octadecen-1,18-dioate. The yield of 9-octadecene is increased over the yield of run 168 which did not use SiCl4.