Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[C:18]=2[CH2:27][CH2:28][CH3:29])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5](=[O:30])[C:4]([OH:31])=[O:3])=[CH:7][CH:8]=2)=[C:18]([CH2:27][CH2:28][CH3:29])[C:19]=1[OH:26])(=[O:25])[CH3:24]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A solution of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.7 g) in methanol (50 mL) was treated with sodium carbonate (0.38 g) in water (2.5 mL), and the reaction was stirred at room temperature for 2 hours. After the solvents were removed in vacuo, dichloromethane (40 mL) and water (40 mL) were added and the mixture was acidified with 3N hydrochloric acid. The dried (Na2SO4) organic layer was evaporated, and the residue was crystallized from dichloromethane-hexane to yield in two crops, 0.435 g of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid, mp 129°-130° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][CH2:4][Mg]Cl.[CH3:8][C@H:9]1[CH2:11][O:10]1.[NH4+].[Cl-]>C1COCC1.[Cu]I>[CH3:1][C:2]([CH3:7])=[CH:3][CH2:4][CH2:8][C@@H:9]([OH:10])[CH3:11]
Reactant: CC(C)=CC[Mg]Cl
Reactant: C[C@H]1CO1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Methylbut-2-enylmagnesium chloride, 0.50 M in THF (100 mL, 50 mmol) was cooled to 0° C., CuI (952 mg, 5.0 mmol), then (S)-2-methyl-oxirane (1.752 mL, 25.0 mmol) in anhydrous THF (12 mL) was slowly added to the stirred reaction mixture via syringe pump at a rate of 16 mL/h over 45 min to give a dark suspension which was stirred at 0° C. under an Argon atm for 1 h, then allowed to slowly warm to RT over several h. After stirring at RT for 18 h the reaction mixture was poured into sat aqueous NH4Cl (75 mL), the mixture was extracted with Et2O (3×100 mL), the organic extracts were combined, washed with water (100 mL), brine (100 mL), dried with MgSO4, and solvent was evaporated in vacuo (30 mm Hg) at 25° C. to give an oil which was purified by SiO2 flash chromatography to give the title compound as an oil in 2 fractions (2.2 g, 69%). H1 NMR (CDCl3): • 5.14 (m, 1H), 3.82 (m, 1H), 3.08 (m, 1H), 1.69 (s, 3H), 1.62 (s, 2H), 1.48 (m, 2H), 1.19 (d, 3H, J=6 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]([C:5]1[S:6][C:7]([CH2:10][N:11]2[CH2:15][C:14](=[O:16])[N:13](CC3C=CC(OC)=CC=3OC)[S:12]2(=[O:29])=[O:28])=[CH:8][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]([C:5]1[S:6][C:7]([CH2:10][N:11]2[CH2:15][C:14](=[O:16])[NH:13][S:12]2(=[O:28])=[O:29])=[CH:8][CH:9]=1)=[O:4]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)N(C)CCc4ccccc4)s3)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1ccccc1)C(=O)c1ccc(CN2CC(=O)NS2(=O)=O)s1

Procedure:
A solution of the title E compound, 5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylic acid methyl-phenethyl-amide (70 mg, 0.13 mmol) in CH2Cl2 (2 mL) is stirred with TFA (2 mL) at RT for 4 h. The volatiles are evaporated and the residue is stirred in equal volumes of MeCN/water (4 mL). The mixture is filtered through a 0.2μ Acrodisc and the solvents are evaporated to dryness. The residue is trituated from Et2O to afford 5-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2-carboxylic acid methyl-phenethylamide as an off white solid: [M−1]−=392.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:8]([C:10]([O:12]CC)=O)[CH3:9].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][CH2:6][N:7]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:8]([CH3:9])[C:10]1=[O:12])=[O:22]
Reactant: CCOC(=O)C(C)N(CCCC(=O)OC)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(Cc2ccccc2)C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[benzyl-(1-ethoxycarbonyl-ethyl)-amino]-butyric acid methyl ester (1.5 g, 4.9 mmol), potassium tert-butoxide (906 mg, 8.9 mmol) and toluene (100 mL) is stirred at rt for 3 h. The mixture is then partitioned between DCM and saturated aqueous NH4Cl. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated. The crude residue is used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:16])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[N:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([O:27][CH2:2][C:3]2[O:4][C:5](=[O:16])[N:6]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[N:7]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccccc1Cn1nc(CCl)oc1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cc1ccccc1Cn1nc(COC(=O)C(c2ccc(Cl)cc2)C(C)C)oc1=O
Temperature: 110 °C
Yield: 48.4 %

Procedure:
A solution of 2-chloromethyl-4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-one (13.3 g) in xylene (35 cc) is added in the course of 20 minutes to a solution of 2-(4-chlorophenyl)-3-methyl-butyric acid (19 g) and triethylamine (11.7 cc) in xylene (175 cc) heated to 110° C. The reaction mixture is heated at the reflux temperature for 4 hours and, after cooling, is washed successively with water (100 cc), a 3.5% strength aqueous hydrochloric acid solution (100 cc), a 4% strength aqueous sodium carbonate solution (100 cc) and water (100 cc). After drying, decolorizing over animal charcoal and concentrating under reduced pressure, the residue obtained is purified by chromatography on a silica column and gives [4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-on-2-yl]-methyl 2-(4-chlorophenyl)-3-methylbutyrate (11.2 g) in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=1[C:25]#[N:26].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([CH3:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:39][CH2:38][O:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:24]=1[C:25]#[N:26]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1O
Reactant: CS(=O)(=O)OCCOc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (50 mg, 0.12 mmol) dissolved in DMF (500 μL), methanesulfonic acid 2-(pyridin-2-yloxy)-ethyl ester (30 mg, 0.14 mmol) and K2CO3 (50 mg, 0.36 mmol) were added. The mixture was stirred at rt overnight then heated at 40° C. for 1 h. After filtration and dilution with MeOH the mixture was purified by prep HPLC yielding 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-benzamide 51-1. MS: 553.2 (M+H)+, tR=5.2 min (method 3).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][CH:9]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][CH2:41][CH2:42][CH2:43][CH:44]=O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:44][CH2:43][CH2:42][CH2:41][O:40][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][O:34]2)=[CH:32][CH:33]=1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(C=CCCCOC2CCCCO2)cc1
Yield: 47.7 %

Procedure:
In an argon atmosphere, butyllithium (10%; 37 ml) was added dropwise to a suspension of (4-chlorobenzyl)triphenylphosphonium chloride (24 g) in tetrahydrofuran (70 ml) with ice-cooling and stirring. After stirring at the same temperature for 30 minutes, a solution of 4-tetrahydropyranyloxy-1-butanal (9 g) in tetrahydrofuran (30 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was distilled off under reduced pressure and water was added to the residue, followed by extraction with petroleum ether. After washing with water and drying over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, elution being carried out with chloroform to give 1-(4-chlorophenyl)-5-(2-tetrahydropyranyloxy)-1-pentene (7 g) as a light-yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.N1C=CC=CC=1.[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:8][CH:9]=1)[CH3:17])[CH3:25]
Reactant: CC(C(=O)Cl)c1ccc(C2=CCCCC2)cc1
Reactant: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc(C2=CCCCC2)cc1
Reaction time: 3 h

Procedure:
7 g of α-[para-(1-cyclohexenyl)-phenyl]-propionic acid chloride are added dropwise to a solution, cooled to 10°C, of 10 ml of pyridine in 25 ml of ethanol. The mixture is allowed to stand at room temperature for 3 hours, then evaporated under reduced pressure, and the residue is dissolved in ether and the ethereal solution washed with water, 2N-hydrochloric acid, saturated sodium bicarbonate solution and again with water. The ethereal extracts are dried over sodium sulfate and evaporated, then distilled in a high vacuum to yield α-[para-(1-cyclohexenyl)-phenyl]-propionic acid ethyl ester of the formula ##SPC10##
Reaction SMILES: [CH:1]([C:3]1[C:4]2([CH3:14])[C:9]([CH2:10][CH2:11][CH:12]=1)=[CH:8][C:7](=[O:13])[CH2:6][CH2:5]2)=[CH2:2].C[O-].[Na+].[CH:18](OC)=[O:19].Cl>O1CCCC1>[CH:1]([C:3]1[C:4]2([CH3:14])[C:9]([CH2:10][CH2:11][CH:12]=1)=[CH:8][C:7](=[O:13])[C:6](=[CH:18][OH:19])[CH2:5]2)=[CH2:2]
Reactant: COC=O
Reactant: C=CC1=CCCC2=CC(=O)CCC12C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1=CCCC2=CC(=O)C(=CO)CC12C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A solution of 50.0 g (0.265 mol) of 5-ethenyl-4,4a,7,8-tetrahydro-4a-methyl-2(3H)-naphthalenone in 350 mL of tetrahydrofuran was cooled to -5° C. in an ice-methanol bath and stirred under nitrogen while 57.2 g (1.06 mol) of sodium methoxide was added. The resulting mixture was stirred for 30 min at -5° C. and then a solution of 114 mL (1.85 mol) of methyl formate in 100 mL of tetrahydrofuran was added slowly. The mixture was stirred overnight at room temperature and then poured onto a mixture of ice-water (1500 mL) and 6 N hydrochloric acid (265 mL). The product was extracted with ether and the combined extracts were washed with water. The dried extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford an oil. This oil was triturated with hexane (4×250 mL) and the combined triturates were dried over magnesium sulfate and concentrated in vacuo to afford 55.37 g of a red oil, consisting essentially of the above-entitled compound as established by proton NMR (PMR) spectral data.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.S(Cl)([Cl:21])=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:21])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=c1[nH]c(-n2cccn2)nc(-n2cccn2)c1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Yield: 61.2 %

Procedure:
To a solution of 1 g (3.26 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4(3H)-one (intermediate 8) in 10 ml of DMF and 40 ml of DCM was added dropwise a solution of 0.71 ml (9.8 mmol) of thionyl chloride in 10 ml DCM. The reaction mixture was refluxed for two hours, at which time no starting material was observed by TLC. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated to give 0.65 g (61.5%) of the 4-chloro-pyrimidine derivative.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38].CCCCCCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([Cl:38])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
A solution of 374 g (1.48 mol) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.6 l CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.241 (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction raised during 2 h to 35° C. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4 l of n-heptane, the reaction was evaporated to 2.9 l, cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 l of CH2Cl2. The solvents were evaporated and filtered through silica gel with hexane/tert.-butyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:9]1)C1C=CC=CC=1.[H][H]>Cl.[OH-].[OH-].[Pd+2].CO>[C:25]1([NH:24][C:22]([NH:21][C@@H:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]2[NH:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a PARR shaker was added 1-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylurea (1.4 g, 3.44 mmol), Pd(OH)2 (0.484 g, 3.44 mmol), MeOH (20 mL) and 3 drops of 1N HCl. The reaction vessel charged with hydrogen and the pressure was maintained at 30 psi with shaking overnight. After this time, the reaction was filtered through CELITE® and the filtrate was concentrated to give the product, 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (1.05 g, 3.32 mmol, 96% yield), as an off white solid. It was used in the next step without further purification. Anal. Calcd. for C18H28N4O m/z 316, found: 317.3 (M+H)+; 1H NMR (500 MHz, methanol-d3) δ ppm 7.35 (d, J=7.70 Hz, 2H), 7.24 (t, J=7.42 Hz, 2H), 6.97 (t, J=7.42 Hz, 1H), 3.49-3.37 (m, 1H), 3.16-3.03 (m, 1H), 2.94-2.83 (m, 1H), 2.70 (td, J=9.35, 4.95 Hz, 1H), 2.57-2.47 (m, 1H), 2.47-2.39 (m, 1H), 2.39-2.25 (m, 1H), 2.10-1.90 (m, 3H), 1.79-1.68 (m, 3H), 1.58-1.43 (m, 1H), 1.39-1.16 (m, 5H).
Reaction SMILES: [C:1]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>C(O)C>[OH:19][N:18]=[C:1]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(C(=O)C(C)C)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=NO)C(C)C)cc1
Temperature: 36 °C

Procedure:
A mixture of ethyl 4-isobutyrylbenzoate (0.56 g, 2.54 mmol), hydroxylamine hydrochloride (1.06 g, 15.2 mmol), and sodium acetate (1.25 g, 15.2 mmol) in ethanol (36 mL) was heated to 36° C. for 2 h. The reaction was then concentrated and the residue was dissolved in EtOAc (200 mL). The organic phase was washed with water (2×20 mL), brine, dried (MgSO4), and concentrated to give crude ethyl 4-(1-(hydroxyimino)-2-methylpropyl)benzoate as a slight-yellow solid. LC-MS: (FA) ES+ 236.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][C@@H:11]3[N:12]4[CH2:1][CH2:2][S:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[C:9]([C:13]4=5)[C@@H:10]3[CH2:17]2)=[C:24]([N+:30]([O-:32])=[O:31])[CH:25]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1OCCCCl
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Product: O=[N+]([O-])c1cc(F)ccc1OCCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCSC3

Procedure:
The title compound of EXAMPLE 6 was prepared from (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole and and 1-(3-chloropropoxy)-4-fluoro-2-nitrobenzene following the procedure described in EXAMPLE 4. 1H NMR(CDCl3, 300 MHz): δ 7.6 (m, 1H), 7.25 (m, 1H), 7.04 (m, 1H), 6.96 (d, 1H, J=6.6 Hz), 6.92 (d, 1H, J=6.6 Hz), 6.75 (m, 1H), 4.25 (m, 2H),3.82 (m, 2H), 3.59-3.00 (m, 8H), 2.80 (m, 2H), 2.48 (m, 2H), 2.22 (m, 2H), 1.20 (m, 2H) ppm. LRMS (ES)+: 444 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[S:10]([O-:13])([O-:12])=[O:11].[Na+:14].[Na+]>CC(C)=O.O>[I:1][C:2]1[CH:3]=[C:4]([CH2:5][S:10]([O-:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+:14]
Reactant: BrCc1cccc(I)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])Cc1cccc(I)c1
Yield: 118.8 %

Procedure:
A solution of 3-iodobenzyl bromide (3 g) and sodium sulphite (1.26 g) in acetone (15 ml) and water (30 ml) was heated at 70° for 3 h. The solvent was removed under reduced pressure and the residue was triturated in ether to give the title compound (3.8 g). LCMS RT=3.66 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=2)[N:7]=1)=O)C.[NH3:18]>CO>[OH:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=2)[N:7]=[C:6]([C:4]([NH2:18])=[O:3])[N:15]=1
Reactant: N
Reactant: CCOC(=O)c1nc(O)c2cc(O)ccc2n1
Solvent: CO
Product: NC(=O)c1nc(O)c2cc(O)ccc2n1
Reaction time: 3 h

Procedure:
4,6-Dihydroxy-quinazoline-2-carboxylic acid ethyl ester (11 mmol) is dissolved in methanol (50 ml) containing ammonia (4N). The mixture is stirred for 3 hours and the solid material formed is filtered off. A pale powder with mp. 305° C. (decomposition) is obtained.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.[C:45]([O:49][C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54]([C:57]#[CH:58])=[CH:53][CH:52]=1)([CH3:48])([CH3:47])[CH3:46]>C(#N)C.[Cu]I>[C:50]([C:51]1[CH:56]=[CH:55][C:54]([C:57]#[C:58][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:53][CH:52]=1)([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:59]
Reactant: CCOC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccc(C#Cc3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Reaction time: 8 h

Procedure:
100 ml of triethylamine, 6.3 g of triphenylphosphine, 2.81 g of (Pφ3)2PdCl2 and 0.77 g of copper(I)iodide are added under nitrogen to 61 g of 4-bromo-4'-carbethoxybiphenyl in 300 ml of absolute acetonitrile. 44.3 g of 4-ethinyl-benzoic acid tert.-butyl ester dissolved in 300 ml of absolute acetonitrile are slowly added dropwise at the reflux temperature and the reaction mixture is boiled overnight. It is then suction filtered while hot and stirred up in water and again suction filtered and the residue is dissolved in CH2Cl2 and filtered after the addition of Tonsil.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33]O)=[NH:32])=[CH:29][N:28]=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:33]=[C:31]([C:30]4[CH:35]=[CH:36][C:27]([NH2:26])=[N:28][CH:29]=4)[N:32]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) (179 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/hexane) as a yellow solid (84 mg, 35%). MS (ISP) 474.0 [(M+H)+]; mp 242° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@:13]([CH3:19])([C:16](O)=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:35]1C=CC=CC=1.[NH4+].[OH-].O>C(OCC)(=O)C.O>[C:16]([C@@:13]1([CH3:19])[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:17])[NH2:35]
Reactant: c1ccncc1
Reactant: C[C@]1(C(=O)O)CCN(C(=O)OCc2ccccc2)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@]1(C(N)=O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a mixture of (S)-1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (32.87 g, 124.8 mmol), Boc2O (29.97 g, 137.3 mmol) in ethyl acetate (200 mL) was added pyridine (12.62 mL, 156.1 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. A solution of 28-30% w/w NH4OH/water (21.79 mL, 162.3 mmol) was added. The reaction was stirred at ambient temperature for 5 hours. Water (50 mL) was added. The organic layer was separated, washed with 1N HCl (50 mL) and brine, dried and concentrated under reduced pressure to give (S)-benzyl 3-carbamoyl-3-methylpyrrolidine-1-carboxylate (31.30 g, 119.3 mmol, 95.6% yield) as an oil.