Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.018 ml propionyl chloride (0.2 mmol). After 2 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 87 mg yellow solid (98%). MS (ISP) 557.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH3:17])[NH:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:12]2[CH:13]([CH3:17])[CH2:14][CH2:15][CH2:16][CH:11]2[CH3:10])=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CC1CCCC(C)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1CCCC(C)N1C(=O)c1csc(Br)n1
Yield: 86.2 %

Procedure:
A solution of 2-bromothiazole-4-carboxylic acid (Intermediate 3; 2 g, 9.6 mmol), 2,6-dimethylpiperidine (1.18 mL, 8.8 mmol), HATU (4.18 g, 11.0 mmol) and DIEA (2.1 mL, 12.1 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. Ethyl acetate (20 mL) was added and the solution was washed with 0.2 M HCl (2×10 mL), water (10 mL), and brine (10 mL), then it was dried (MgSO4), filtered, evaporated, and purified by flash column chromatography (10-40% ethyl acetate/hexanes) to give (2-bromo-thiazol-4-yl)-(2,6-dimethyl-piperidin-1-yl)-methanone (2.3 g, 86%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[N+:17]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[C:11]=1[NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of beta-alanine ethyl ester hydrochloride (911 mg, 5.39 mmol), 2-chloro-1,3-dinitrobenzene (1.00 g, 4.94 mmol), triethylamine (2.07 mL, 14.9 mmol) and tetrahydrofuran (50 mL) was stirred at room temperature for 2 hr. To the reaction mixture were added beta-alanine ethyl ester hydrochloride (455 mg, 2.96 mmol) and triethylamine (1.03 mL, 7.39 mmol) at room temperature and the resultant mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (1.39 g, 4.92 mmol, 99.6%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][OH:14]>[Ag-]=O>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH3:13]
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Agent: O=[Ag-]
Product: COCc1cc([N+](=O)[O-])ccc1F
Temperature: 54 °C
Reaction time: 2.5 h

Procedure:
Under argon, 250 g (1.07 mol) of 2-(bromomethyl)-1-fluoro-4-nitrobenzene were introduced as initial charge in 2.5 l of methanol, 371 g (1.60 mol) of silver(I) oxide were added and the mixture was stirred for 2.5 h at 52-56° C. After cooling to RT, suction filtration over kieselguhr was carried out, followed by after-washing with methanol, and the solvent was removed on a rotary evaporator. The crude product was purified by distillation on a short-path evaporator at a jacket temperature of 104° C. and 0.56 mbar. This gave 184.5 g (93%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17](=[O:18])[NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3.78 g (10 mmol) 4-tert-Butoxycarbonylamino-piperidine-1,4-dicarboxylic acid monobenzyl ester (commercially available), 1.76 g (13 mmol) 4-isopropyl-aniline (commercially available), 2.1 g (11 mmol) EDCI and 1.36 g (11 mmol) DMAP in 50 mL THF was stirred at room temperature over night. After concentration of the mixture ethyl acetate and water was added. The mixture was extracted with ethyl acetate and the combined organic fractions were dried with MgSO4 and evaporated. The residue was purified over silica eluting with a gradient formed from ethyl acetate and hexane to afford after evaporation of the product containing fractions 2.85 g (57%) of the title compound as white solid. MS (m/e): 496.3 [(M+H)+].
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[NH:17])[NH2:16].[C:24](O[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>O1CCCC1.O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:10]1)(=[NH:7])[NH2:8].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:20][CH2:19]1)(=[NH:16])[NH2:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N=C(N)N1CCNCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.4 %

Procedure:
2.50 g of 1-amidinopiperazine hemisulfate were dissolved in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and a solution of 3.40 g of di-t-butyl dicarbonate in 10 ml of tetrahydrofuran was added to the resulting solution, after which the mixture was stirred at room temperature for 2.5 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure, the insolubles were filtered off and the filtrate was evaporated to dryness under reduced pressure. The resulting residue was extracted with ethanol (twice, each time with 50 ml) and methanol (twice, each time with 50 ml). The extract was evaporated to dryness to obtain 2.48 g of the title compound, as crystals, melting at 278° C. (with decomposition).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15]([O:19][CH2:20][CH3:21])=[CH:16][CH:17]=[O:18])[CH2:6]1)(=O)C.C(=O)(O)[O-].[K+].O>C(O)C>[CH2:20]([O:19][C:15]([C@@H:14]1[C@:22]2([CH3:31])[C@H:11]([C@H:10]3[C@H:25]([C:24](=[O:30])[CH2:23]2)[C@:26]2([CH3:29])[C@H:7]([CH2:6][C@H:5]([OH:4])[CH2:28][CH2:27]2)[CH2:8][CH2:9]3)[CH2:12][CH2:13]1)=[CH:16][CH:17]=[O:18])[CH3:21]
Reactant: CCOC(=CC=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=CC=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 34.1 %

Procedure:
A solution of 3α-acetoxy-20-ethoxy-21-formyl-5α-pregn-20-en-11-one (500 mg) in ethyl alcohol (15 ml) was treated with potassium bicarbonate (450 mg) and the mixture was refluxed, under nitrogen, for 7 hours, then poured into water. The product was extracted with methylene chloride, and the extract washed with water, dried and evaporated. Purification of the residue (37 mg) by preparative t.l.c. and crystallisation from methyl acetate/petrol gave title compound (154 mg) m.p. 175°-178°, [α]D - 115.9°, λmax. 258 nm (ε 18,780).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].BrC[CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18].[C:22](=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH:4]([C:3]1[C:2]([O:1][CH3:22])=[CH:9][CH:8]=[CH:7][C:6]=1[O:10][CH2:11][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:5]
Reactant: COc1cccc(O)c1C=O
Reactant: CCOC(=O)CCCCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(OCCCCC(=O)O)c1C=O
Reaction time: 16 h

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (16.875 g., 0.111 M), ethyl 5-bromopentanoate (23.25 g., 17.6 ml., 0.111 M), anhydrous potassium carbonate (16.5 g.), sodium iodide (0.675 g.) and 95% ethanol (150 ml.) were refluxed with stirring (16 hrs). The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The ethereal layer was separated and washed with 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (300 ml.) and 0.66 N sodium hydroxide solution (450 ml.) and stirred at ambient temperature (4 hrs). The reaction mixture was evaporated to half volume and diluted with water. The mixture was extracted once with ether and the aqueous layer acidified with concentrated hydrochloric acid with cooling. The crystalline solid formed was filtered off and washed well with water. Recrystallisation from ethyl acetate-petrol gave 5-(2-formyl-3-methoxyphenoxy)pentanoic acid, m.p. 99°-101° C. (Found: C, 61.98; H, 6.58. C13H16O5 requires C, 61.89; H, 6.39%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1.[Li]C(C)(C)C.CN([CH:26]=[O:27])C.C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH:26]=[O:27]
Reactant: c1ccc(CCn2cnc3ccccc32)nc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nc2ccccc2n1CCc1ccccn1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of Ar, 1-(2-pyridin-2-yl-ethyl)-1H-benzimidazole (0.46 g, 2.1 mmol) (Ichikawa, M. et al. Chem. Pharm. Bull. 1981, 29, 3042-7) was dissolved in anhydrous THF (10 mL), cooled to −40° C., and treated with tert-BuLi (1.5 mL, 1.7M, 2.5 mmol) for 30 minutes. DMF (0.80 mL, 10.3 mmol) was then added and the solution slowly warmed to room temperature. After 1 hour, water (10 mL) and saturated aqueous NaHCO3 solution (10 mL) were added and the medium was extracted with EtOAc (3×25 mL). The combined organic phases were then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography with silica gel (50:1:0.1 MeOH:NH4OH:CH2Cl2) to afford 1-(2-pyridin-2-yl-ethyl)-1H-benzimidazole-2-carbaldehyde as a brown liquid that was used immediately in the next reaction (147 mg, 28%).
Reaction SMILES: [C:1]1(=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].O.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>O.C1C=CC=CC=1.C(O)C>[C:1]1(=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14]
Reactant: O=C(O)CCCCCCC1CCCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCCC1CCCCC1=O

Procedure:
A solution of 232 g of 7-(cyclohexan-1-on-2-yl)heptanoic acid in 2500 ml. of ethanol is refluxed for 4.5 hours with 3.8 g of p-toluenesulfonic acid monohydrate. The solution is diluted with 200 ml. of benzene, and boiling is continued for 2 hours as 200 ml. of distillate is removed. The volume of the solution is concentrated to 500 ml. After dilution with 500 ml. of ether the solution is extracted with a solution prepared from 50 ml. of saturated sodium bicarbonate, 50 ml. of saturated sodium chloride, and 100 ml. of water. The extract is washed with saturated sodium chloride, dried, and evaporated. The product is purified by distillation to give a liquid, IR 1740 cm-1 (ester carbonyl) and 1715 cm-1 (ketone carbonyl).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1cccc(Br)c1
Product: O=S(=O)(NCCO)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.34) (252 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 61%). MS (ISP) 555.1 [(M+H)+]; mp 213° C.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH2:8][CH2:7][CH:6]=[CH2:4])[CH2:11][CH2:10]2)=[N:13][CH:14]=1
Reactant: CON(C)C(=O)C1CCN(c2ccc(Cl)cn2)CC1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=O)C1CCN(c2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 185.3 %

Procedure:
While under a nitrogen atmosphere, a solution of 5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid, methoxy-methyl-amide (1.0 g, 3.5 mmol), in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with 4-butenylmagnesiun bromide (0.5 M in THF, 17.6 mL, 8.8 mmol) dropwise. After stirring for 1 hour at 0° C. and room temperature overnight the reaction mixture was poured into water, acidified to pH 3-4 with 1N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave 1-(5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-pent-4-en-1-one as a colorless oil (904 mg, 93%); 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J=2.5 Hz, 1H), 7.42 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 6.62 (d, J=9.0 Hz, 1H), 5.80 (m, 1H), 5.04 (m, 2H), 4.23 (m, 2H), 2.92 (m, 2H), 2.59 (m, 3H), 2.36 (m, 2H), 1.98 (m, 2H) and 1.70 (m, 2H); MS (+CI): m/z for C15H19ClN2O: expected 278.1. found 279.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].CC([O-])=O.[Na+].[Cl:18][CH:19](C(=O)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>Cl.O.C(O)C>[Cl:18][C:19](=[N:9][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Temperature: 2.5 °C
Yield: 73.4 %

Procedure:
Part A: To a stirred solution of 4-chloroaniline (15.68 gram, 0.123 mol) in ice (30 ml) and concentrated hydrochloric acid (30 ml) is slowly added a solution of NaNO2 (9.0 gram, 0.13 mol) in water (16 ml) and the resulting solution is stirred for 1Hour at 0-5° C. and subsequently added to a cold mixture of NaOAc (32 gram, 0.39 mol), ethanol (520 ml) and ethyl 2-chloro-3-oxobutanoate (16.6 ml, 0.12 mol). After stirring the resulting mixture for 1 hour the formed precipitate is collected by filtration, washed with ethanol and dried in vacuo to give ethyl 2-chloro[(4-chlorophenyl)hydrazono]acetate (22.99 gram, 73% yield). Melting point: 147.5-149.5° C. 1H-NMR (200 MHz, CDCl3): 1.40 (t, J=7 Hz, 3H), 4.39 (q, J=7 Hz, 2H), 7.16 (br d, J=8 Hz, 2H), 7.30 (br d, J=8 Hz, 2H), 8.31 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([O-:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN[O:27][CH3:28].C1C=CC2N(O)N=[N:35][C:33]=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:13](=[O:15])[NH:35][CH2:33][O:27][CH3:28])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)CC(CCCOCc1ccccc1)C(=O)[O-]
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCNC(=O)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-tert-Butyl 2-(3-benzyloxypropyl)succinate (80 g), triethylamine (48.4 mL) and DMF (400 mL) were mixed. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (31.5 g), HOBt.H2O (45.6 g) and WSC.HCl (57.1 g) at ice temperature. The mixture was stirred at RT overnight. To the reaction mixture was added water (400 mL), and the mixture was extracted with hexane (480 mL, 480 mL, 240 mL). The combined organic layer was washed with aqueous 10 w/v % sodium carbonate (240 mL×3), aqueous 10 w/v % potassium hydrogen sulfate (240 mL), water (240 mL) and brine (240 mL), then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (84.1 g) as a crude product.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:13]([OH:17])(=[O:16])[CH:14]=[O:15].Cl.[CH2:19]([N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>O.COC(C)(C)C>[OH:15][CH:14]([C:5]1[C:6]2[S:10][CH:9]=[CH:8][C:7]=2[C:2]([OH:1])=[CH:3][CH:4]=1)[C:13]([O-:17])=[O:16].[CH2:28]([NH+:23]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH3:31]
Reactant: O=CC(=O)O
Reactant: Oc1cccc2sccc12
Reactant: CCCCN(CCCC)CCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC[NH+](CCCC)CCCC
Product: O=C([O-])C(O)c1ccc(O)c2ccsc12
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A 2 L reactor equipped with a mechanical stirrer, a thermometer, a dropping funnel, a sensor connected to a pH-meter and an argon inlet was charged under argon with 76.2 g (500 mmol) of 4-Hydroxybenzothiophene and 617.1 g (1100 mmol) of a 10% KOH aqueous solution. To the dark solution were added at 0-5° C. within 30 min ca. 85.91 g (580 mmol) of a 50% glyoxylic acid solution in water. If necessary, more glyoxylic acid is added such that the pH of the solution at the end of the addition was 11.5. After stirring for 3 h at 0-5° C., 200 ml of tert-butyl methyl ether were added to the reaction mixture followed by ca. 70 ml of 25% HCl solution in water such that the pH was ca. 7.0. The biphasic mixture was filtered through Speedex, then ca. 70 ml of 25% HCl solution in water were added to the aqueous phase such that the pH was ca. 2.0. After addition of 450 ml of tert-butyl methyl ether the organic phase was separated at room temperature and the aqueous phase washed with tert-butyl methyl ether. The combined organic phases were concentrated to a volume of ca. 300 ml and the residue was diluted with 50 ml of tert-butyl methyl ether and 100 ml of acetonitrile. To the resulting clear solution was added portionswise at 20-30° C. within 1 h a solution of 93.6 g (500 mmol) of tributylamine in 100 ml of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30° C. and then filtered off. The filter cake was washed with 160 ml of tert-butyl methyl ether/acetonitrile 3:1 and the crystals dried over night at 60° C./10 mbar to afford 108.9 g (53.1%) of tributylammonium hydroxy-(4-hydroxy-benzo[b]thiophen-7-yl)-acetate as white crystals with a m.p. of ca. 200° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][C:16](=[O:26])[CH:17]([C:23](=O)[CH3:24])[C:18](=O)[CH2:19][O:20][CH3:21])[CH3:14]>>[CH2:13]([O:15][C:16]([C:17]1[C:18]([CH2:19][O:20][CH3:21])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[C:23]=1[CH3:24])=[O:26])[CH3:14]
Reactant: CCOC(=O)C(C(C)=O)C(=O)COC
Reactant: NNc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1c(COC)nn(-c2cccc(C(F)(F)F)c2)c1C
Yield: 25 %

Procedure:
In analogy to the procedure described in Example 38A], 3-(trifluoromethyl)phenylhydrazine and rac-2-acetyl-4-methoxy-3-oxo-butyric acid ethyl ester gave after purification by flash column chromatography (CH2Cl2 to 5% Et2O/CH2Cl2) 5-methoxymethyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester and in 25% yield as light brown solid. MS: 343.0 (MH+) and 3-methoxymethyl-5-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester and in 36% yield as orange oil. MS: 343.0 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[OH:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23](O)=[CH:24][CH:25]=3)[CH:20]([CH3:31])[C:19]=2[CH:18]=1.B(O)(O)O>C1(C)C(C)=CC=CC=1>[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][C:23]2[CH:24]=[CH:25][C:26]3[C:27]4[C:19](=[CH:18][C:17]([O:16][C:11](=[O:12])[C:10]5[CH:14]=[CH:15][C:7]([OH:6])=[CH:8][CH:9]=5)=[CH:29][CH:28]=4)[CH:20]([CH3:31])[C:21]=3[CH:22]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: CC1c2cc(O)ccc2-c2ccc(O)cc21
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: CC1c2cc(OC(=O)c3ccc(O)cc3)ccc2-c2ccc(OC(=O)c3ccc(O)cc3)cc21
Yield: 70 %

Procedure:
In a nitrogen atmosphere, concentrated sulfuric acid (0.2 mL) was added to a mixture of 4-hydroxybenzoic acid (13.0 g), 2,7-dihydroxy-9-methylfluorene (10.0 g), boric acid (0.3 g) and xylene (120 mL), and the mixture was heated under reflux for 6 hours while removing water. A solid matter thus deposited was collected by filtration under reduced pressure, and rinsed with toluene. The solid matter was recrystallized from a mixed solvent of ethanol (75 mL) and acetone (75 mL) to provide 2,7-bis(4-hydroxybenzoyloxy)-9-methylfluorene (compound [H1]) (14.9 g) in the form of pale rose crystals.