Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:13]=[C:14](/[CH:16]=[CH:17]/[CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].C1(C)C=CC=CC=1.C1(S(NN)(=O)=O)C=CC=CC=1>CCOCC>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC/C=C/c1cc(/C=C/COC)cc(C(=O)OC)c1
Agent: NNS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCCCc1cc(CCCOC)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3,5-bis[(1E)-3-methoxyprop-1-en-1-yl]benzoate (1 eq.) from the previous step in refluxing toluene was added benzenesulfonohydrazide (5 eq) in five portions over 2 h. The reaction was stirring as reflux for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with 1 N aqueous HCl, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [Na+:1].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[K+]>O>[Na+:1].[NH:12]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)([O-])CCCCCBr
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCCCCNc1ccccc1
Yield: 79.9 %

Procedure:
The mixture is washed with ether and the aqueous layer is concentrated to give white solids. The solids are dissolved in ethanol with heating, and cooled slowly to room temperature to precipitate sodium bromide. The precipitates are filtered off and the filtrate is put in a refrigerator overnight to obtain 5-bromo-1-pentanesulfonic acid sodium salt (12.9 g, 68%) as white crystals. A solution of 5-bromo-1-pentanesulfonic acid sodium salt (12.9 g, 0.05 mol) and aniline (20 g, 0.22 mol) in water (150 mL) is heated under reflux with potassium bicarbonate (6.3 g, 0.075 mol) for 8 hr. After the reaction is completed, the reaction mixture is washed with ether and the aqueous layer is concentrated to give white solids. The solid is recrystallized in methanol to obtain 5-anilino-1-pentanesulfonic acid sodium salt (10.6 g, 80%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2cc(-c3ccccc3Cl)sc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc2cc(-c3ccccc3Cl)sc2c(Cl)c1Cl
Yield: 72.4 %

Procedure:
A mixture of 26.8 g of 6,7-dichloro-2-(2'-chlorophenyl)-5-methoxybenzo[b]thiophene and 260 g of pyridine hydrochloride is heated at 190°-200° for 4.5 hrs. To the cooled mixture is added 800 ml of water and the aqueous mixture is extracted with three 400-ml portions of ethyl ether. The organic layers are collected, washed with 400 ml of 2N hydrochloric acid and with 200 ml of water. The organic layer is dried over anhydrous magnesium sulfate, decolorized (charcoal) overnight and the solvent is removed. Recrystallization from acetone-hexane gives 18.6 g of 6,7-dichloro-2-(2'-chlorophenyl)-5-hydroxybenzo[b]thiophene, mp 174°-175°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O.CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1)[CH3:10]
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
A mixture of 1.5 g (4.4 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide and 1.9 ml (22.1 mmol) morpholine was heated in the microwave at 120° C. for 30 min. Subsequently the RM was diluted with water and EtOAc and the layers were separated. The organic layer was washed with a 1M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Crystallisation (hexane/EtOAc 3:1) of the residue yielded 1.3 g (3.3 mmol, 75%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 2). [M+H]+ 390.2.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])([CH3:7])([CH3:6])[CH3:5].C(OC(=O)[C@H](CC(C)C)N)(C)(C)C.N[C@:31]([C:37]1[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=1)([CH3:36])[C:32](OC)=[O:33]>CN(C=O)C>[Br:43][C:40]1[CH:39]=[CH:38][C:37]([C@@:31]2([CH3:36])[C:32](=[O:33])[N:11]([C@@H:10]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:16])[C:2](=[O:3])[NH:1]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@@](C)(N)c1ccc(Br)cc1
Reactant: [N-]=C=O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N[C@@](C)(c2ccc(Br)cc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
4.8 g of L-leucine tert-butyl ester isocyanate (prepared from L-leucine tert-butyl ester analogously to J. S. Nowick et al., J. Org. Chem. 1996, 61, 3929) were added to a solution of 5.8 g (22.5 mmol) of 169.1 in 50 ml of DMF. After stirring at room temperature for 4 h, the solvent was removed and the residue was chromatographed on silica gel using heptane/tert-butyl methyl ether=6/4. The fractions containing the intermediate were combined, the solvent was removed in vacuo, the residue was dissolved again in 90 ml of absolute DMF and the solution was treated at 0° C. with 775 mg of a 55-65% strength sodium hydride dispersion in oil. After stirring at room temperature for 3 h, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/tert-butyl methyl ether=1/1. After concentration of the product fractions, 7.8 g (79%) of 169.2 were obtained as a colorless solid.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[O:27]1[CH2:28][CH2:29][N:24]([C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]3=[CH:5][N:4]=2)[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2nc(N3CCOCC3)ncc2c(=O)[nH]1

Procedure:
A stirred solution of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and morpholine (1.25 g) in pyridine (20 ml) was heated under reflux for 45 hours. The reaction mixture was evaporated under reduced pressure to yield a crude product which was washed with water and twice recrystallized from methanol to yield the title compound, 0.25 g., m.p. 175.5-177° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[C:5]([N+:32]([O-])=O)[CH:4]=1)#[N:2].[CH2:35](OC=C(C#N)C#N)C.CC(C)=O>C(O)C.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=3)[CH:35]=[N:32][C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)CC1
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)CC1
Yield: 10 %

Procedure:
5-(4-Cyano-2-nitrophenyl)amino-3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-1H-indole was used. Reduction was by aqueous FeSO4 in ethanol, the cyclization reaction used ethoxymethylene malononitrile, and the cyclization reaction was heated for 56 hours. Chromatography using 5% acetone in methylene chloride afforded the title compound (10%) as a brown foam: Rf =0.5 in 5% acetone in methylene chloride; HRMS calculated for C26H25N5O2 439.2011, found 439.1999.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[CH3:18])=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: Cc1cc(Cl)ccc1N=C=S
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2 g, 0.008 mol), (2-methyl-4-chlorophenyl isothiocyanate (1.76 g, 0.0096 mol) and toluene (10 ml) was heated under reflux for 5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 2.72g (77%), m.p. 176°-177 ° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CC1C=CC=CC=1.ClC(OC)=O.[C:31]1([CH2:37][O:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:39][O:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:15])[C@@H:10]([CH3:12])[OH:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NOCc1ccccc1
Agent: CN(C)Cc1ccccc1
Agent: COC(=O)Cl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
N-(t-Butyloxycarbonyl)-L-threonine (82.2 g) was dissolved in 1 liter of ethyl acetate and 40.5 g of dimethyl (phenylmethyl)amine was added. After stirring for 10 minutes the mixture was cooled to -10° C. and 31.05 g of methyl chloroformate were added dropwise. The mixture was stirred for 30 minutes at -10° C., after which a solution of 40.65 g of (phenylmethoxy)amine in 300 ml of ethyl acetate was added at -10° C. The temperature was then permitted to rise to 5° C. during a 90 minute period. The reaction mixture was evaporated in vacuo and redissolved in 1 liter of ethyl acetate the insoluble material was filtered off and the filtrate washed, with cooling, with water, dilute hydrochloric acid, (pH of aqueous phase not less than 2.5), sodium bicarbonate solution and brine. After drying (MgSO4) the solvent was removed in vacuo to yield an oil, which crystallized on treatment with petroleum ether, yielding 79.4 g of the title compound, melting point 87° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][Li].C.Cl>CCOCC.CCOC(C)=O.C1COCC1>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: [Li]C
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (10.0 g, 48.5 mmol) and THF (100 mL) was cooled to <5° C. (internal temperature) and methyllithium (95 mL of a 1.6M solution in Et2O, 152 mmol) was added, keeping the internal temperature≦20° C. (slow addition, methane generation). Following methyllithium addition, the solution was warmed to ambient temperature and stirred for 1 h. The solution was then re-cooled to 10° C. and treated carefully with EtOAc (100 mL) and 2N HCl (100 mL). The reaction mixture was further diluted with EtOAc (100 mL) then washed with water (100 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone (10.3 g) which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:16][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)NCCc1ccccc1

Procedure:
5 ml of triethylamine were added to a solution of 3.64 g of phenethylamine dissolved in 35 ml of methylene chloride, and the mixture was stirred, whilst ice-cooling. 2.63 ml of chloroacetyl chloride were then added dropwise to the mixture over a period of 5 minutes, after which it was stirred for 30 minutes whilst ice-cooling. The reaction mixture was then concentrated by evaporation under reduced pressure, after which ethyl acetate was added to the residue. The ethyl acetate solution was washed, in turn, with water, with a 5% w/v aqueous solution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was distilled off. The residue was recrystallized from a mixture of ethyl acetate and hexane, to give 4.96 g of the title compound as pale yellow-brown needles melting at 62°-65° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:55])[N:20]([CH2:39][CH:40]([O:47][Si](C(C)(C)C)(C)C)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:55])[N:20]([CH2:39][CH:40]([OH:47])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:37][C:4](=[O:7])[O:5][N:3]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(CC(O[Si](C)(C)C(C)(C)C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(O)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.29 g), sodium hydrogen carbonate (2.07 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.73 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.7 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was extracted with 1 M hydrochloric acid and ethyl acetate, and the ethyl acetate layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.37 g, 56%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)=[O:6].[N+:20]([C:23]1[CH:53]=[CH:52][C:26]([CH2:27][O:28][C:29]([N:31]=[C:32]([NH:38][C:39](=[O:51])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)N2C=CC=N2)=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCCC1>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29]([N:31]=[C:32]([NH:38][C:39]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:51])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[O:6])=[O:30])=[CH:52][CH:53]=1)([O-:22])=[O:21]
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCN)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CCCNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 109 %

Procedure:
To a solution of tert-butyl (3S)-3-(4-aminobutanoylamino)-1-pyrrolidinecarboxylate (1.36 g) in anhydrous tetrahydrofuran (30 ml), 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (1.60 g) was added under ice cooling. The resulting (mixture was then treated in a similar manner to that described in Referential Example 16-(1), whereby the title compound (2.50 g) was obtained as an amorphous substance.
Reaction SMILES: Cl.[CH2:2]([CH2:4][NH2:5])[OH:3].[Na].[CH2:7]([Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(C)C>C1(C)C=CC=CC=1>[ClH:14].[C:8]1([CH2:7][O:3][CH2:2][CH2:4][NH2:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: NCCO
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanolamine hydrochloride (20 g, 0.21 mol) in toluene (100 mL) was treated with sodium metal (pellets washed with hexane) (10.14 g, 0.44 mL). The reaction was refluxed until the sodium metal was no longer present. The mixture was cooled and benzyl chloride (24.17 mL, 0.21 mmol) was added, the reaction was stirred at room temperature overnight. The reaction mixture was filtered and the solid washed with toluene. The filtrate was cooled to 0° C. and HCl gas was bubbled in for 10 minutes. A white precipitate was obtained and filtered. The solid was recrystallized using 70 mL of isopropyl alcohol (10.4 g, 0.056 mol); MS-CI 188 (m+1).
Reaction SMILES: [ClH:1].Cl.C1(C[N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)C=CC=CC=1.[H][H].C(O)C>CO.O.[Pd]>[ClH:1].[NH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: C1CC(N2CCOCC2)CCN1
Temperature: 60 °C

Procedure:
30.00 kg (90.01 mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine-dihydrochloride (M) were dissolved in 67.5 L methanol and 20.0 L water. Then the mixture was hydrogenated at a pressure of 4 bar and an internal temperature of 50° C. in the presence of 1.80 kg palladium on charcoal until no further uptake of hydrogen could be detected. After the reaction had ended the catalyst was filtered off and washed with a mixture of 18.0 L methanol and 2.0 L water. The hydrogenation solution obtained was then transferred into a reactor and heated to 60° C. At 60° C. 540.0 L ethanol were metered in. The resulting suspension was cooled to 5° C. The product was centrifuged off and dried.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][CH:14]=O.C(NC(C)C)(C)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N+:13]#[C-:14]
Reactant: O=CNCc1cccc(C(F)(F)F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: [C-]#[N+]Cc1cccc(C(F)(F)F)c1Cl
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}formamide (0.67 g, 2.82 mmol) in anhydrous dichloromethane (20 ml) was cooled under argon in an ice-water bath before the addition of diisopropylamine (1.78 ml, 12.7 mmol) followed by phosphorus oxychloride (0.393 ml, 4.23 mmol). The reaction was stirred at between 2-5° C. for 2 hrs. The mixture was then reduced in vacuo and the residue treated with saturated aqueous sodium hydrogen carbonate (20 ml) and extracted with dichloromethane (20 ml). The organic layer was passed through a hydrophobic frit and the reduced in vacuo to give a yellow solid. Further drying in vacuo gave [2-chloro-3-(trifluoromethyl)phenyl]methyl isocyanide as an orange gum (0.66 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH3:19])[CH:4]=[C:5]2[C:11]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:9][CH2:8][C:7](=[O:18])[NH:6]2.[Br:20]Br.C([O-])(O)=O.[Na+]>CO>[Br:20][C:4]1[N:3]([CH3:19])[C:2]([CH3:1])=[C:11]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][CH2:8][C:7](=[O:18])[NH:6][C:5]=12
Reactant: BrBr
Reactant: Cc1c2c(cn1C)NC(=O)CN=C2c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c2c(c(Br)n1C)NC(=O)CN=C2c1ccccc1
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
3,7-dihydro-6,7-dimethyl-5-phenylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one (5.0 g, 0.020 mole) is dissolved in methanol (150 ml) and the obtained solution is cooled to -60° C. and stirred during the addition of a solution of bromine (3.4 g, 0.021 mole) in methanol (10 ml). After 20 minutes at -60° C., the reaction mixture is poured into an aqueous solution of NaHCO3 (1.5% w/v, 750 ml). The precipitate which forms is recovered by filtration and crystallized from methanol yielding 4.2 g of the compound of the title. M.p. 200°-2° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=O)[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:17]CC1C=CC=CC=1)[C:9]=2[N+:25]([O-])=O)=[O:5])[CH3:2].Cl>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([NH2:25])[C:10]([NH2:17])=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc(N)c(N)c2O1
Reaction time: 12 h
Yield: 96.5 %

Procedure:
A mixture of ethyl-7-benzylamino-8-nitro-4-oxo-4H-chromene-2-carboxylate (1.1 g, 3 mmol), Pd/C (0.10 g, 10%), and HCl (12 N 2 mL) in ethanol (90 mL) was hydrogenated for 12 hours. The catalyst was filtered through diatomaceous earth and solvent was removed under vacuum. The residue was dissolved in EtOAc (100 mL) and then washed with saturated NaHCO3 and concentrated to give 684 mg (97%) of product as a thick oil. The product was used without any further purification. 1H NMR (400 MHz), CDCl3) δ1.26 (t, J=7.1 Hz, 3H) 2.19 (m, 2H), 2.70 (m, 1H), 3.18) bs, 4H), 4.22 (q, J=7.1 Hz, 2H), 4.66 (m, 1H), 6.30 (d, J=8 Hz, 1H), 6.40 (d, J=8 Hz,1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:11]1)=[O:9].[CH3:22][O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][CH:32]=1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH2:25][CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:17][N:16]=2)[CH2:11]1)=[O:9]
Reactant: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(Nc1cnccn1)N1CC(Oc2ccc(Br)cn2)C1
Product: COCCOc1cccc(-c2ccc(OC3CN(C(=O)Nc4cnccn4)C3)nc2)c1
Yield: 58.3 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrazin-2-ylamide (100 mg, 0.285 mmol) was reacted with 2-[3-(2-Methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example 5 step 5, 118 mg, 0.855 mmol) to afford title compound (70 mg, 58%) as a colourless powder.