Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N+:18]([C:21]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](F)=[CH:24][C:22]=1[NH2:23])([O-:20])=[O:19]>O.C(O)C>[N+:28]([C:26]1[CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[C:22]([NH2:23])=[CH:24][C:25]=1[NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O-:30])=[O:29]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(NCCc2c[nH]c3ccccc23)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitro-5-fluoroaniline in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.57) which is well resolved from the starting materials under the same conditions
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[S:17][C:18]([Cl:21])=[CH:19][N:20]=2)(=[O:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][C:16]2[S:17][C:18]([Cl:21])=[CH:19][N:20]=2)(=[O:13])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61818.2 %

Procedure:
To a solution of methyl 2-chloro-4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}benzoate (Preparation 36, 410 mg, 1.1 mmol) in dioxane (4 ml) was added a solution of sodium hydroxide (93 mg, 2.32 mmol) in water (1.5 ml) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 ml), added to concentrated HCl (10 ml) and stirred for 10 minutes at room temperature for 15 minutes. The resultant precipitate was collected by filtration to yield the title compound (239 mg, 0.68 mol, 62%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)=O>ClCCCl.C(O)(=O)C>[CH3:26][CH:25]([CH3:27])[CH2:24][C@@H:16]([NH:15][CH2:28][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)C[C@@H](N)C(=O)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(C)C)C(=O)N3CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and (R)-2-amino-4-methyl-1-(pyrrolidin-1-yl)pentan-1-one (91 mg, 0.493 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (160 mg, 93%). [M+H] calc'd for C25H36N4O5, 473; found, 473.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH3:17])[CH:9]=2)=[CH:5][CH:4]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([CH3:17])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2ccc(N)c(C)c2)cc1
Yield: 100.2 %

Procedure:
A mixture of 4-(4-methoxy-phenoxy)-2-methylnitrobenzene (3.5 grams, mmol) and methanol (200 mL) was treated with 200 miligrams of 10% palladium on carbon and was shaken under 50 psi of hydrogen gas for 3 hours. Filtration through a pad of celite and concentration in vacuo afforded 3.1 grams of 4-(4-methoxy-phenoxy)-2-methyl-phenylamine as a tan solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8](OC2C=CC=CC=2)=[N:9][C:10]#[N:11])=[CH:3][CH:2]=1.[NH2:19][NH2:20]>CO>[NH2:11][C:10]1[N:9]=[C:8]([O:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[NH:20][N:19]=1
Reactant: NN
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CO
Product: Nc1n[nH]c(Oc2ccccc2)n1
Reaction time: 2 h

Procedure:
Diphenylcyanocarbonimidate (9.53 g) and methanol (150 ml) were cooled to 0° C. and hydrazine (1.5 ml) was gradually added dropwise thereto. The mixture was stirred at 0° C.-room temperature for 2 hours. Methanol was distilled away under reduced pressure and the residue was subjected to silica gel column chromatography (chloroform-methanol) to quantitatively give white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH2:13][N:12](CC4C=CC(OC)=CC=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:45][C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=1)CCC>>[S:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:13][NH:12][C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Product: O=C1NCC2(CCNCC2)c2[nH]c(-c3ccnc(-c4nc5ccccc5s4)n3)cc21

Procedure:
The title compound was prepared following the general procedure reported for Example 9—1 using A5 and 2-(tributylstannyl)benzo[d]thiazole, purified by semi-preparative HPLC (Method A) and isolated as TFA-salt. 1H NMR (400 MHz, DMSO-D6, 300K): δ=1.92 (2H, d J=14.1 Hz), 2.30 (2H, dt, J1=3.9 Hz, J2=14.5 Hz), 3.12 (2H, t, J=12.5 Hz), 3.31 (1H, s), 3.53 (2H, d, J=2.3 Hz), 7.42 (1H, s), 7.45 (1H, s), 7.60 (2H, m), 8.01 (1H, d J=5.5 Hz), 8.21 (2H, t, J=8.6 Hz), 8.91 (1H, d, J=5.5 Hz), 11.93 (1H, s); MS (ES) C22H20N6OS requires: 416. found: 417.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH2:27][CH2:28][F:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16]2)[C@@H:12]([OH:30])[C@@H:11]1[OH:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[CH2:35]([O:31][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH2:27][CH2:28][F:29])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[S:16]2)[C@H:12]1[O:30][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
A solution of tert-butyl (3aR,5R,6S,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (2.0 g, 4.2 mmol) in N,N-dimethylformamide (30 mL) was treated with sodium hydride (510 mg, 21 mmol) for 10 min at 10° C. in a nitrogen atmosphere, and followed by addition of 1-(bromomethyl)benzene (2.2 g, 13 mmol). After stirred for 15 min, the reaction was quenched with saturated aqueous NH4Cl and extracted with dichloromethane (3×30 mL). The organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 1.5-3% ethyl acetate in petroleum ether to provide compound 70 as a yellow oil (0.7 g, 25%). (ES, m/z) [M+H]+ 660.8; 1H NMR (300 MHz, CDCl3) δ 7.28-7.43 (m, 10H), 6.11-6.13 (d, J=6.3 Hz, 1H), 4.60-4.74 (m, 4H), 4.30-4.41 (m, 6H), 3.73-3.75 (m, 3H), 3.37-3.44 (m, 1H), 1.54 (s, 9H), 0.90 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2N3C(CNCC#C)=NN=C3CN=[C:7]([C:20]3[C:25](F)=[CH:24][CH:23]=[CH:22][C:21]=3F)[C:6]=2[CH:28]=1.C=[O:30]>C(O)=O>[C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:30])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:28]=1
Reactant: C#CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Reactant: C=O
Solvent: O=CO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 1, 8-chloro-1-[[(2propynyl)amino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated in formic acid with aqueous formaldehyde to give 5-chloro-2',6'-difluoro-2-[3-[[(2propynyl)methylamino]methyl]-5-(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C

Procedure:
To a solution of 25.0 g (0.18 mol) of 1-fluoro-4-nitrobenzene and 19.5 g (0.2 mol) of 1-methylpiperazine in 300 mL of acetonitrile, add 48.9 g (0.35 mol) of anhydrous potassium carbonate. Heat the reaction mixture to 60° C. for 20 h under nitrogen. After this time, add 100 mL of water and concentrate mixture to 200 mL volume. Add another 100 mL of water and extract with 3×200 mL of methylene chloride. Extract the combined methylene chloride extracts with 100 mL of 6N hydrochloric acid solution and 3×200 mL of water. Make the combined aqueous extracts basic (pH=14) with 50% sodium hydroxide solution and extract with 3×200 mL of methylene chloride. Dry the extracts over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo. Dissolve the residue in 150 mL of methanol and bubble hydrogen chloride gas through the solution until pH=1. Precipitate the product by addition of diethyl ether to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[N:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(F)nc2)C1
Temperature: 110 °C
Yield: 68.4 %

Procedure:
Dissolve (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.49 g, 8 mmol) in toluene (20 mL). Heat to 110° C. and add 5-bromo-2-fluoropyridine (824 μL, 8 mmol), cesium carbonate (3.9 g, 12 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (748 mg, 1.2 mmol) and tris(dibenzylidineacetone)dipalladium(0) (733 mg, 0.8 mmol). Place a nitrogen inlet and condenser on the flask and heat at reflux overnight. Cool and filter the reaction mixture through a pad of Celite® and wash the pad with dichloromethane. Concentrate and chromatograph twice on silica gel, eluting with 0:100 to 25:75 ethyl acetate:dichloromethane, then 10:90 to 40:60 ethylacetate:hexanes, to give (S)-[1-(6-fluoropyridin-3-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a brown solid (1.54 g, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:24]([OH:38])[C:25]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([F:27])[F:26])=[O:21])[C:15]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.ClC(Cl)C(O)=O.Cl>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:24](=[O:38])[C:25]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([F:26])[F:27])=[O:21])[C:15]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1c(-c2cccc(Cl)c2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)C(=O)NCc1ccccc1
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C(Cn1c(-c2cccc(Cl)c2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)C(=O)NCc1ccccc1
Yield: 76.5 %

Procedure:
To a solution of the objective compound of step (14) (69 g, 95 mmol) and WSCIHCl (99.87 g, 0.5209 mol) in DMSO (590 mL)-toluene (590 mL) was added dichloroacetic acid (15.6 mL) with drop wise over 20 minutes under ice-cooling. The resulting mixture was stirred under ice-cooling for 2.5 hours, then added to 0.5 M hydrochloric acid (1800 mL) and extracted with ethyl acetate (1800 mL, 2×800 mL). The extract was washed with saturated sodium hydrogencarbonate aqueous solution (800 mL) and saturated brine (800 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (99:1 chloroform-methanol) to give 52.95 g (77%) of 2-[5-benzyloxycarbonylamino-2-(3-chlorophenyl)-1,6-dihydro-6-oxo-1-pyrimidinyl]-N-[1-benzyl-3-[N-(benzyl)carbamoyl]-3,3-difluoro-2-oxopropyl]acetamide as a white solid.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=[O:23])C.[OH-].[Na+]>C(OO)(=O)C.O>[O:23]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]1[CH3:1]
Reactant: CC=CCCCCCCCCCCCCCCCCC
Reactant: CC(=O)O
Agent: CC(=O)OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC1OC1C

Procedure:
7 g of 2-eicosene are dissolved in 20 g of peracetic acid. The ethylenic function is oxidised into epoxide in the absence of heat. The acetic acid formed is neutralised in 10 ml of water by the addition of 1N NaOH. The aqueous solution thus obtained is extracted with ether. Removal of the ether leaves 6 g of 2,3-epoxy eicosane which is purified in the same way as described above. Mp: 40° C., bp 15 mm Hg : 200°-210° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39](=[NH:56])[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43]2>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:56]=[C:39]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[N:45]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43]4)[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CCOC(=O)CCn1ccc2cc(C(=N)NO)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ccc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 80 °C
Yield: 42.9 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (215 mg, 1.05 mmol), EDAC (219 mg, 1.14 mmol) and HOBt (156 mg, 1.14 mmol) in dry DMF (10 ml) were stirred at RT for 10 minutes. Added ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D52) (288 mg, 1.05 mmol) and stirred for 1 hour at RT. Heated at 80° C. for 7 hours. The solution was cooled and EtOAc (50 ml) added. Washed with water (50 ml), sat. sodium hydrogen carbonate (50 ml) and water (50 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from ether to yield 200 mg of the title compound as a very pale pink solid. MS (ES) C25H24N4O4 requires 444; found 445 (MH+)
Reaction SMILES: [CH2:1]([O:5][C:6]12[CH2:13][CH2:12][C:9]([CH2:14][CH2:15][CH3:16])([CH2:10][CH2:11]1)[C:8](=O)[CH2:7]2)[CH2:2][CH2:3][CH3:4].[OH-].[K+].C(O)COCCO.O.NN>>[CH2:1]([O:5][C:6]12[CH2:11][CH2:10][C:9]([CH2:14][CH2:15][CH3:16])([CH2:8][CH2:7]1)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC12CCC(CCC)(CC1)C(=O)C2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCOC12CCC(CCC)(CC1)CC2
Temperature: 180 °C
Reaction time: 2 h

Procedure:
A mixture of 4-n-butoxy-1-n-propylbicyclo(2,2,2)octane-2-one (2.08 g, 0.009 mol) hydrazine hydrate (8.4 ml, 98-100%) and potassium hydroxide (2.80 g, 0.050 mol) in diethylene glycol (40 mol) was stirred and heated under reflux for 4 h (180° C., oil bath temperature). The reaction mixture was cooled and hydrazine hydrate (4 ml) and potassium hydroxide (1.00 g) were added and the apparatus was arranged for distillation. The temperature was raised slowly to 240° C. in 2 h, and the reaction mixture was kept at this temperature for 2 h. The reaction mixture was cooled and the residue and the distillate were separately diluted with water, washed with ether (3×50 ml). All the ether washings were combined and washed with water (2×50 ml) dilute hydrochloric acid (2×50 ml) and water (2×50 ml). The ether solution was dried (MgSO4) and ether was removed to give a residue which was chromatographed on a neutral alumina column (1.5×30 cm) using light petroleum (bp 40°-60° C.) as eluent. Four fractions were collected (20 ml each) the solvent was removed to leave a residue which was distilled in a short-path distillation apparatus under reduced pressure to give the required compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.O[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(Br)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Yield: 57.6 %

Procedure:
1-Methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.71 g, 58%) was prepared as a light yellow solid from 2-bromo-5-hydroxypyridine (0.60 g, 3.45 mmol), 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (prepared as in Example 9, Step 1, 0.71 g, 3.45 mmol) and Ph3P (0.92 g, 3.45 mmol) in THF (18 mL) followed by diisopropyl azodicarboxylate (0.75 g, 94%, 3.45 mmol) in THF (6 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.04 (bs, 1H), 7.36 (d, 1H, J=8.8 Hz), 7.15-7.05 (m, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.82 (d, 2H, J=6.1 Hz), 2.85-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.90-1.75 (m, 2H), 1.35-1.15 (m, 8H); LRMS (ESI), m/z 357/359 (M+H).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[NH:32][CH:31]=[CH:30]2>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:30]2[C:29]3[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=[C:27]([F:26])[CH:28]=3)[NH:32][CH:31]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12

Procedure:
128 mg (0.58 mmol) of indium(III) chloride and 0.07 ml (0.87 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 167A and 149 mg (0.58 mmol) of the compound from Example 87A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 130 mg (65% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:21][C@@H:22]([CH3:36])[CH2:23][C@H:24]([CH3:35])[O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([O:25][C@@H:24]([CH3:35])[CH2:23][C@@H:22]([Cl:21])[CH3:36])=[CH:34][CH:33]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(C(=O)O)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(C(=O)Oc2ccc(-c3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1

Procedure:
0.30 g of (S,S)-4-[4'-(3"-chloro-1"-methylbutoxy)phenyl]phenol, 0.24q of (S,S)-4-(3'-chloro-1'-methylbutoxy)benzoic acid, 0.22 g of dicyclocarbodiimide, 0.04 g of 4-pyrrolidinopyridine and 6 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (4:1) as a developing solvent to thereby give 0.2 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([O:20][CH:21](OCC)[CH2:22][C:23](Cl)=[O:24])[CH3:19]>ClCCl>[CH2:18]([O:20]/[CH:21]=[CH:22]/[C:23]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:24])[CH3:19]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(CC(=O)Cl)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCO/C=C/C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 97 %

Procedure:
To a solution of 4-(trifluoromethyl)aniline (2.56 g, 15.9 mmol) in dichloromethane (40 ml) was added pyridine (3.77 g, 47.7 mmol). The solution was cooled to 0° C. before a solution of 3,3-diethoxypropanoyl chloride (4 g, crude) in dichloromethane (10 ml) was added dropwise with stirring. The resulting solution was stirred for 4 hours at 20° C. and then washed with water (200 ml). The resulting mixture was extracted with dichloromethane (3×80 ml) and the organic layers were combined and concentrated under vacuum. The crude residue was purified by Pre-TLC with 1-20% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford (2E)-3-ethoxy-N-(4-trifluoromethylphenyl)prop-2-enamide as a yellow solid (4.0 g). (ES, m/z): [M+H]+ 260; 1H NMR (300 MHz, DMSO): δ 10.10 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.72 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.50-7.56 (m, 1H), 5.52 (d, J=12.4 Hz, 1H), 3.90-4.01 (m, 2H), 1.15-1.30 (m, 3H).