Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1SC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](O)(=O)C.[Mn]([O-])(=O)(=O)=O.[K+].[S:33](=[O:36])(O)[O-:34].[Na+]>O>[CH2:1]([N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[S:33]([CH3:23])(=[O:36])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])O
Reactant: CC(=O)O
Reactant: CSc1nc2cnc3cccnc3c2n1Cc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1nc2cnc3cccnc3c2n1Cc1ccccc1

Procedure:
To 1-benzyl-2-methylsulfanyl-1H-imidazo[4,5-c][1,5]naphthyridine (1 g, 3.2 mmol) was added acetic acid (15 mL), and the white suspension was stirred for a few minutes. To this suspension was added potassium permanganate solution (0.87 g, 5.5 mmol, in water (15 mL)) in a dropwise manner, and the reaction was stirred at room temperature for 2 hours. To the reaction mixture was added sodium bisulfite (0.83 g) and the white suspension was stirred for several minutes. Water was added to this suspension and the reaction mixture was transferred to a separatory funnel. The product was extracted from the aqueous layer with several batches of dichloromethane. The dichloromethane layers were combined, dried (MgSO4), filtered, and evaporated, and the resultant solid washed with ether to afford 1-benzyl-2-methanesulfonyl-1H-imidazo[4,5-c][1,5]naphthyridine as a white solid (0.9 g), mp 187-191° C.; MS (ESI) m/z 339 (M+H); Anal. Calcd for C17H14N4O2S: C, 60.34; H, 4.17; N, 16.56. Found C, 60.45; H, 3.97; N, 16.52.
Reaction SMILES: [NH:1]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:10]1[CH:11]=[CH:12][C:2]2[NH:1][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCc2ccccc2N1
Agent: O=S(=O)(O)O
Product: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Reaction time: 0.5 h

Procedure:
A solution of 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (1.42 g, 8.81 mmol) in conc. H2SO4 (25 mL) was treated with fuming HNO3 (414 μL, 8.81 mmol) at −5 to −10° C. (ice/MeOH). The resulting solution was stirred at the same temperature for 30 minutes. The reaction was quenched with the addition of crushed ice. The resulting suspension was diluted with H2O (50 mL) and filtered. The solid was washed with 4×50 mL H2O, collected and dried under reduced pressure overnight. Yield: 1.0 g, 55.1%. 1H-NMR (DMSO-d6) δ 10.08 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 8.11 (dd, J=2.4, 8.7 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 2.83-2.79 (m, 2H), 2.26-2.13 (m, 4H). MS (EI): 206 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:14][C:5]2[S:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[C:3]1=[O:15].C1COCC1.C(O)C.[OH-].[Li+]>O>[CH3:1][C:2]1([CH3:16])[CH2:14][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[C:3]1=[O:15]
Reactant: CCOC(=O)c1cc2c(s1)CC(C)(C)C2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2sc(C(=O)O)cc2C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 8 (310 mg, 1.30 mmol), THF (2 mL) and ethanol (2 mL). A solution of lithium hydroxide (125 mg, 5.21 mmol) in water (2 mL) was added, and the mixture was stirred at 50° C. for 2 h. After this time, the organic solvents were removed under reduced pressure, water (6 mL) was added, and the pH was adjusted to 3.0 with 2 N hydrochloric acid. The resulting suspension was filtered and the filter cake washed with water (2 mL). The filter cake was dried to constant weight under vacuum at 40° C. to afford a 100% yield (292 mg) of 9 as a white solid: mp 124-125° C.; 1H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 3.10 (s, 2H), 1.34 (5, 6H); MS (ESI+) m/z 211.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].NCCC(O)=O.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C.O>[CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=Cc1ccccc1
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1
Yield: 84.7 %

Procedure:
A suspension of 100 kg of 4-methyl-3-oxo-N-phenylpentanamide (Example B) in 660 kg of hexanes is treated with agitation under nitrogen with 8 kg of β-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension is heated to reflux with removal of water for 20 hours. An additional 396 kg of hexanes and 3 kg of glacial acetic acid is added and reflux continued with water removal for one hour. The reaction mixture is cooled to 20°-25° C. and the product is isolated by filtration. The product is purified by slurrying in hexanes at 50°-60° C., cooling, and filtration. The product is slurried twice with water at 20°-25° C., filtered, and dried in vacuo to yield 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7°-154.4° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:18][C:5]1[C:6]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH2:8][C:9]#[N:10])[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: N#CCc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#CCc1c(F)ccc(N)c1Nc1ccccc1
Yield: 55.6 %

Procedure:
(6-Fluoro-3-nitro-2-phenylaminophenyl)acetonitrile (463 mg, 1.70 mmol), iron powder (194 mg, 3.41 mmol), and ammonium chloride (263 mg, 5.12 mmol) in methanol (10 mL) and water (3 mL) were heated at 90° C. for 1 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as brown solid (228 mg, 55%). 1H NMR 400 MHz δ (CDCl3): 7.23-7.17 (2H, m), 6.95 (1H, t, J=8.9 Hz), 6.83 (1H, tt, J=7.4, 1.0 Hz), 6.77 (1H, dd, J=8.9, 5.5 Hz), 6.61-6.56 (2H, m), 5.12 (1H, br s), 3.79 (2H, br s), 3.59 (2H, d, J=1.2 Hz).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[S:13][N:12]=1.CC([O-])(C)C.[K+].BrCCCOC>C1COCC1.C(OCC)(=O)C>[CH3:29][O:28][CH2:26][CH2:25][CH2:24][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: CC(C)(C)[O-]
Agent: COCCCBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
(S)-Methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (105 mg, 0.19 mmol) was dissolved in THF (5 ml) and KOtBu (65 mg, 0.58 mmol) was added. The mixture was agitated for 30 minutes and 1-bromo-3-methoxypropane (37 mg, 0.24 mmol) was added. The mixture was agitated for 1 hour, diluted with ethyl acetate, washed with sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica gel (60-75% ethyl acetate/hexanes) to afford (S)—N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (85 mg, 83% yield) as glassy colorless solid.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][CH2:1][C@H:2]2[O:7][CH:6]([O:8][C@:9]3([CH2:18][O:19][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:13][C@H:12]([CH2:14][O:15][C:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:11]([OH:16])[C@@H:10]3[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]2[OH:22])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:27]=1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O[C@@H]1[C@H](O)[C@@H](O)C(O[C@]2(COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@@H]2O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.8 %

Procedure:
The procedure of Hough, Mufti, and Khan, Carbohydrate Res., Vol. 21, pp. 144-147 (1972), is modified as shown below. To a solution of 15 g of sucrose (43.82 mmol) in 225 ml of pyridine, a solution of 54.95 g of trityl chloride (197.1 mmol, 4.5 equiv.) in 50 ml of pyridine is added dropwise over a period of 30 minutes. The reaction mixture is then stirred at room temperature for 4 days. After 4 days, the solution is concentrated to a brown syrup, which is dissolved in methylene chloride. This solution is further washed successively with 1M hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous sodium sulfate. The methylene chloride solution it then concentrated in vacuo and the residue applied on a column of silica gel packed in methylene chloride:acetone (4:1) and eluted with that solvent. The 1',6,6'-tri-O-tritylsucrose is obtained (28.59 g) in 58.8% yield as an off-white solid with a melting point of 127° to 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH2:34]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:32]=3[F:31])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(F)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 2,4-difluoroaniline (CAS Reg. No. 367-25-9) in the presence of DMAP to give [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-N-(2,4-difluoro-phenyl)-acetamide as yellow oil. MS: m/e=484.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]([C:57]([NH2:59])=[O:58])[NH:48]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47]2)=[O:15])=[CH:6][CH:7]=1
Reactant: NC(=O)C1Cc2ccccc2CN1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2Cc3ccccc3CC2C(N)=O)cc1
Reaction time: 2 h
Yield: 22.1 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 1,2,3,4-tetrahydroisoquinoline-3-carboxamide (18 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H19N3O3: 361.1426, found 361.1418.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH3:13])=C(C)[CH:5]=[CH:4][CH:3]=1.O.C1(C)C=C[C:19]([S:22](O)(=O)=O)=CC=1.O1[CH2:32][CH2:31]OCC1>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[C:19]2=[S:22])=[C:31]([CH3:32])[CH:5]=[CH:4][CH:3]=1
Reactant: CNCCCNc1c(C)cccc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(Cl)c1N1CCCN(C)C1=S
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a solution of the diamine of Step A (4.16 g) in dioxane (110 mL) was added under nitrogen 1,1′-thiocarbonyl-di-1,2,4-triazole (7.12 g). After 30 minutes, para-toluenesulfonic acid monohydrate (15.1 g) was added and the reaction mixture was heated at reflux for 20 hours. More para-toluenesulfonic acid monohydrate (4.0 g) was added at this point, and after an additional 2.5 hours at reflux, the reaction was cooled and filtered. The filtrate was concentrated in vacuo to give an orange oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 20% ethyl acetate in hexane provided a white solid which was triturated with diethyl ether to give the title product (2.0 g, 40.3%) as a white solid, m.p. 164-165° C.
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:14])[CH3:13])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1coc(Cn2cccc2)c1
Reactant: CC(=O)Cl
Product: CC(=O)c1cccn1Cc1ccco1

Procedure:
1-Furfuryl-2-acetyl-pyrrole was prepared starting from 1-furfuryl-pyrrole described by Reichstein in Helv. 15, 1450 (1932) as well as Gianturco et al. in Tetrahedron 20, 1763 (1964). Acetylation by reaction of the Grignard intermediate with acetyl chloride [cf. Chem. Ber. 47, 1416 (1914)] led to the desired ketone. (A small amount of the 3-isomer was also obtained, separable by fractional distillation). The product boils at 100°-102°C./0.03 mm Hg. and crystallizes on standing. Recrystallization from a mixture of methylene dichloride and petroleum ether gave a white crystalline product with a m.p. of 42°-43°C.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:21](O)=[O:22])[CH3:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].O=S(Cl)Cl.[NH2:28][C:29]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][C:30]=1[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C([O-])(O)=O.[Na+]>C(O)C.C(Cl)(Cl)Cl>[C:31]([C:30]1[CH:39]=[C:40]([N+:43]([O-:45])=[O:44])[CH:41]=[CH:42][C:29]=1[NH:28][C:21](=[O:22])[CH:19]([NH:18][C:1](=[O:2])[O:3][CH2:4][CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:20])(=[O:32])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Temperature: 50 °C
Yield: 98 %

Procedure:
Commercially-available (S)-Fmoc-alanine (2.98 g, 0.96 mmol) was suspended in ethanol-free CHCl3 (30 mL) and SOCl2 (7 mL) was added under N2. The mixture was heated at 50° C. for 1 h, then the solvent was removed under vacuum, the residue was dissolved into CHCl3 (30 mL), commercially-available 2-amino-5-nitro-benzophenone (2.32 g, 0.96 mmol) was added, and the mixture was heated for 2 h at 60° C. After cooling, a saturated solution of NaHCO3 was added, the organic phase was collected and dried (Na2SO4), then the solvent was removed under vacuum obtaining (9H-fluoren-9-yl)methyl 1-(2-benzoyl-4-nitrophenylamino)-1-oxopropan-2-ylcarbamate (98% yield). This compound was dissolved in CH2Cl2 (40 mL), Et3N (10 mL) was added and the mixture was heated at 40° C. for 30 h under N2. The solvent was removed under vacuum and the residue was partitioned between 2N HCl and ethyl acetate; the aqueous layer was made alkaline with 10% NaOH and extracted with CH2Cl2. After drying (Na2SO4) and removal of solvent, the residue was purified by flash chromatography (cyclohexane/ethyl acetate 6:4 as eluent) yielding (S)-3-methyl-7-nitro-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one in 25% yield.
Reaction SMILES: [CH2:1]([C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:4]1)[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:27]([NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1/[CH:38]=[CH:39]/[C:40](O)=[O:41])(=[O:29])[CH3:28]>C(Cl)Cl>[Cl:37][C:35]1[CH:34]=[CH:33][C:32](/[CH:38]=[CH:39]/[C:40]([N:8]2[CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:4][C@H:3]2[CH2:1][CH3:2])=[O:41])=[C:31]([NH:30][C:27](=[O:29])[CH3:28])[CH:36]=1
Reactant: CC[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)/C=C/c1ccc(Cl)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
(R)-3-Ethyl-1-(4-fluorobenzyl)-piperazine (44.4 mg, 0.2 mmol), EDC1 (76 mg, 0.4 mmol), HOBT (55 mg, 0.4 mmol) and (E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid (47.8 mg, 0.2 mmol) were dissolved in 5 ml DCM and this mixture was stirred at room temperature overnight. The mixture was diluted with 50 ml DCM and extracted 3 times with water and once with saturated sodium chloride solution. The title compound, purified by chromatography (SiO2, ethyl acetate/MeOHINH3conc, 98/2/0.2) and was isolated as pale solid (81 mg, 91%)
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1O)[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[O:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1)[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (40 g, 0.11 mol) was added to a suspension of ethyl 3-methoxy-4-hydroxybenzoate (19.6 g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) in dry DMF (200 ml). After stirring at 95° C. for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The resulting oil was crystallised from petroleum ether and the suspension was stored overnight (at 5° C.). The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35 g, 89%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:9]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[C:10]2[CH2:16][CH:15]3[NH:17][CH:12]([CH2:13][CH2:14]3)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O.CC1C=CC=CC=1[CH:33]=[O:34]>>[CH3:33][O:34][C:8]1[CH:7]=[CH:6][C:5]([C:9]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[C:10]2[CH2:16][CH:15]3[N:17]([CH2:28][C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: COc1cccc(C(=C2CC3CCC(C2)N3)c2ccsc2)c1
Reactant: Cc1ccccc1C=O
Product: COc1ccc(C(=C2CC3CCC(C2)N3Cc2cccs2)c2ccsc2)cc1

Procedure:
Following the protocol for Example 15, and substituting 3-[(4-methoxy-phenyl)-thiophen-3-yl-methylene]-8-aza-bicyclo[3.2.1]octane for 3-[(3-methoxy-phenyl)-thiophen-3-yl-methylene]-8-aza-bicyclo[3.2.1]octane and thiophene-2-carboxaldehyde for 2-methylbenzaldehyde the title compound was obtained; MS m/z (MH+) 408; 1H NMR 300 MHz (CDCl3) δ 6.81-7.29 (m, 10H), 3.79 (s, 2H), 3.78 (s, 3H), 3.24-3.33 (m, 2H), 2.22-2.54 (m, 4H), 1.91-2.04 (m, 2H), 1.58- 1.64 (m, 2H).
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:26][OH:27])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:27][CH2:26]2)[C:12]1=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in Example 1, and making non-critical variations using 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (80%) as a white solid: mp 85-87° C.; 1H NMR (300 MHz, CDCl3) δ 7.28 (t, 1H), 7.15 (d, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.84 (dd, 2H), 4.77 (ABq, 2H), 3.85-3.62 (m, 2H), 1.76-1.66 (m, 2H), 1.40-1.33 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 155.9, 148.8, 142.4, 142.3, 132.5, 128.9, 123.9, 119.6, 108.6, 103.0, 101.5, 93.6, 80.5, 58.2, 40.4, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 352 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:27][C:26]2[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[N:4][C:3]=1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: N#Cc1ccc(-c2nc(CBr)sc2Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
To a solution of 4-(5-Bromo-2-bromomethyl-thiazol-4-yl)-benzonitrile (0.43 g, 1.20 mmol) in 5 ml of anhydrous DMF was added 2,6-difluoro-3-hydroxy-benzamide (0.20 g, 1.20 mmol) and potassium carbonate (0.58 g, 4.20 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (30:70) as the eluent to provide the title compound as a white solid (0.35 g, 66%). 1H NMR (DMSO-d6, 400 MHz): δ 5.57 (s, 2H), 7.13 (m, 1H), 7.44 (m, 1H), 7.89 (br s, 1H), 8.0 (d, J=8.40 Hz, 2H), 8.10 (d, J=8.40 Hz, 2H) and 8.17 (br s, 1H). MS ES+(450.09), HPLC (method I) Rt=16.127 min.