Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CCN(CC)CC)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.[CH3:22][N:23]([CH3:29])[CH2:24][CH:25]([CH3:28])[CH2:26]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:26][CH:25]([CH3:28])[CH2:24][N:23]([CH3:29])[CH3:22])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CC(CCl)CN(C)C
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Agent: Cl
Product: CCCC(=O)c1ccc(OCC(C)CN(C)C)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1 Step A is replaced by an equimolecular quantity of 3-dimethylamino-2-methylpropyl chloride hydrochloride. The product is obtained as a colorless oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][S:6][C:7]1[C:8](=[O:15])[O:9][C:10]([CH3:14])=[CH:11][C:12]=1[OH:13].C(OO)(=[O:22])C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][S:6]([C:7]1[C:8](=[O:15])[O:9][C:10]([CH3:14])=[CH:11][C:12]=1[OH:13])=[O:22]
Reactant: Cc1cc(O)c(SCc2ccc(Cl)c(Cl)c2)c(=O)o1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)Cc2ccc(Cl)c(Cl)c2)c(=O)o1

Procedure:
3-(3,4-Dichlorobenzylthio)-4-hydroxy-6-methyl-2-pyrone (12.0 g., 0.037 mole) and 40% peroxyacetic acid (7.2 g., 0.0378 mole) were dissolved in glacial acetic acid (200 ml.). After a day there was no peroxide left and a solid had crystallized. The mixture was diluted with water and extracted with methylene chloride. The extract was dried (MgSO4) and evaporated to dryness leaving 11.9 g. (95 percent) of an off-white solid. Recrystallization from benzene gave the pure product as a white solid, m.p. 144°-146°C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:5]=1
Reactant: CC(=O)N1CCOc2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CCOc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the crude 1-(6-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone (0.86 g, 3.89 mmol) in EtOAc (8 mL) was added SnCl2.2H2O (4.3834 g, 19.4 mmol) and the mixture was heated under reflux with stirring. After 1.5 h, the mixture was cooled to rt. To the mixture was added 2 M aqueous Na2CO3 (20 mL) followed by EtOAc (50 mL). The resulting white precipitate was filtered off and washed the white solid with EtOAc (50 mL). The filtrated was separated in a reparatory funnel. The aqueous layer was extracted with EtOAc (30 mL×1). The combined organics were washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give dark syrup. The dark syrup was purified by column chromatography on a silica gel column using 0 to 100% gradient of DCM-MeOH—NH4OH (89:9:1) in DCM as eluent to give 1-(6-amino-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone as a red syrup: Mass Spectrum (ESI) m/e=193.1 (M+1).
Reaction SMILES: [CH:1]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:23]CCCC>CCOCC.CCCCCC>[C:11]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:1]2([Li:23])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [Li]CCCC
Reactant: C1=CC(P(c2ccccc2)c2ccccc2)c2ccccc21
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]C1(P(c2ccccc2)c2ccccc2)C=Cc2ccccc21
Reaction time: 8 h
Yield: 87.3 %

Procedure:
(1H-Inden-1-yl)diphenylphosphine (5.00 g, 16.65 mmol) was dissolved in a mixture of 60 mL of ether and 60 mL of hexane. n-BuLi (7.35 mL, 18.31 mmol) was added to the mixture within 10 minutes. After stirring overnight no precipitate appeared. Solvent was removed under reduced pressure leaving a waxy yellow residue. This residue was triturated with 120 mL of hexane for 15 minutes The hexane solution was decanted and the residue was dried under reduced pressure to give 4.45 g of off-white solid. Yield 87 percent.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7](=[O:15])[C:6]2[CH:16]=[C:17]([CH2:20][C:21]([O:23]C)=[O:22])[CH:18]=[CH:19][C:5]1=2)[CH2:2][CH3:3].[OH-].[Na+].CO>O>[CH2:1]([N:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7](=[O:15])[C:6]2[CH:16]=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:18]=[CH:19][C:5]1=2)[CH2:2][CH3:3]
Reactant: CCCN1Cc2ccccc2C(=O)c2cc(CC(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN1Cc2ccccc2C(=O)c2cc(CC(=O)O)ccc21
Yield: 79.4 %

Procedure:
A mixed liquid of methyl 5,6-dihydro-5-n-propyl-11-oxodibenz[b,e]azepine-2-acetate (0.5 g), sodium hydroxide (2 g), methanol (20 ml) and water (10 ml) was treated in the same manner as described in Example 21 to afford the desired compound (0.38 g) as yellow powdery crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:7]([CH2:13][CH3:14])[C:8](OCC)=[O:9]>>[N:1]1([CH:7]([CH2:13][CH3:14])[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCOC(=O)C(Br)CC
Product: CCC(CO)N1CCCC1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield for 2 steps from pyrrolidine and ethyl 2-bromobutyrate by essentially following the procedure detailed in Example 121, Part A.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][C:2]1=[O:7].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:26][C:27]([F:34])([F:33])[C:28]([F:32])=[C:29]([F:31])[F:30]>>[F:30][C:29]([CH:6]1[CH2:5][CH2:4][O:3][C:2](=[O:7])[O:1]1)([F:31])[CH:28]([F:32])[C:27]([F:34])([F:33])[F:26]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=C1OCCCO1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1OCCC(C(F)(F)C(F)C(F)(F)F)O1
Temperature: 73 °C

Procedure:
Example 6 was prepared by combining 1,3-dioxan-2-one (240 g, 2.35 moles) (Richman Chemical Inc., Lower Gwynedd, Pa.) with benzoyl peroxide (5 g, 0.02 moles) in a 600 mL Parr reactor. The reactor was heated to 73° C. and hexafluoropropene (16 g, 0.1066 moles) was fed into the reactor over a 24 h period. The reactor was maintained at the set temperature for an additional 24 h. The reactor contents were collected and analyzed by GC/MS.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH:7]1([NH2:10])[CH2:9][CH2:8]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]1([NH:10][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:9][CH2:8]1
Reactant: O=C(O)C1CC1
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1CC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) and cyclopropylamine (0.995 g, 1.5 eq) in 8 mL of methylene chloride was added DMAP (4-dimethylaminopyridine, 2.13 g, 1.5 eq) followed by EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.34 g, 1.5 eq). The reaction was stirred at room temperature for 2 h after which time it was diluted with 50 mL of methylene chloride and washed twice with 0.5 N aqueous HCl followed by water, saturated aqueous sodium bicarbonate, then brine. The solvent was removed under reduced pressure and the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate to afford N-cyclopropylcyclopropanecarboxamide (2-A).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([O:20]C(C)C)=[O:19])[CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[CH:24](I)([CH3:26])[CH3:25]>CN(C)C=O>[CH:24]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC(C)OC(=O)c1cc(-c2cnc3cc[nH]c3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2ncc(-c3ccnc(C(=O)O)c3)cc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
Sodium hydride (55 mg, 60% in mineral oil, 1.4 mmol) was added to a solution of isopropyl 4-(1H-pyrrolo[3,2-b]pyridin-6-yl)picolinate (250 mg, 0.89 mmol) in N,N-dimethylformamide (3 mL). After stirring for 10 minutes, isopropyl iodide was added and the reaction was stirred for 3 hours at room temperature. Solvent was removed from the reaction mixture under reduced pressure, and the residue dissolved in 2M HCl (3 mL) and heated at 100° C. overnight. The crude reaction mixture was purified by reverse-phase HPLC to give 4-(1-isopropyl-1H-pyrrolo[3,2-b]pyridin-6-yl)picolinic acid (50 mg, 20%). 282.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3C(OCC3C=CC=CC=3)=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: O[C@H]1CN[C@@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (350 mg) in MeOH (15 mL) was added 10%Pd-C (wet) (50 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 1 hour. The catalyst was removed by filtration and the filtrate was evaporated to give (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-4-ol (236.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH3:23]>CN1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH3:23]
Reactant: CI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Agent: CN1CCCC1
Product: Cn1c2c(c(=O)n1-c1ccccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 66.9 %

Procedure:
A solution of (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 39; 151.5 mg, 0.5 mmol) and iodomethane (0.16 mL, 2.55 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube for 2 h. The reaction mixture was purified by preparative HPLC to give (4R,7S)-2-(2-chloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (106 mg, 67%) as an off-white solid. ES(+)-MS (M+H) 317.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:16]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:16][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:9][C:4]=1[C:3]([NH:2][CH3:1])=[O:19]
Reactant: CNC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1cc(N2CCOCC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methyl-5-morpholino-2-nitrobenzamide (256 mg) in ethanol (20 mL) was added Pd/C (10% Pd in carbon, 50 mg, 20 wt %) under argon. A hydrogen balloon was used as the hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed and the crude was purified by silica gel chromatography to obtain the desired product 2-amino-N-methyl-5-morpholinobenzamide (quantitative yield).
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].IC[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27]>>[F:30][C:25]([F:31])([C:26]([F:27])([F:28])[F:29])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:14][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCCCI
Product: C=CCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9 and the 1-iodo-6,6,7,7,7-pentafluoro-heptane prepared in Example 3, the same procedure as shown in Example 5 was repeated to give ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[CH:3]1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH3:1][N:2]1[C:6]([C:7]2[C:13]3[NH:9][C:10]([C:7]([C:6]4[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=4)=[C:10]4[N:9]=[C:13]([C:7]([C:6]5[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=5)=[C:10]5[NH:9][C:13](=[C:7]([C:6]6[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=6)[C:10]6[CH:11]=[CH:12][C:13]=2[N:9]=6)[CH:12]=[CH:11]5)[CH:12]=[CH:11]4)=[CH:11][CH:12]=3)=[CH:5][N:4]=[CH:3]1
Reactant: c1cc[nH]c1
Reactant: Cn1cncc1C=O
Solvent: CCC(=O)O
Product: Cn1cncc1-c1c2nc(c(-c3cncn3C)c3ccc([nH]3)c(-c3cncn3C)c3nc(c(-c4cncn4C)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 60 h
Yield: 21 %

Procedure:
To a refluxing solution of propionic acid (400 mL) and 1-methylimidazole-5-carboxaldehyde (53, 2.0 g, 18.16 mmol), prepared according to literature procedure (Dener, J. M.; Zhang, L-H.; Rapoport, H. J. Org. Chem. 1993, 58, 1159-1166), was added pyrrole (1.26 mL, 18.16 mmol). The reaction was covered with foil then heated under reflux for 5 h. Upon cooling, the reaction mixture was exposed to air for 60 h. The propionic acid was then removed by vacuum distillation. The residue was dissolved in 10% MeOH/CH2Cl2, then adsorbed onto silica gel (6 g). Purification by column chromatography (gradient elution, 5-10% MeOH/CH2Cl2) provided porphyrin 54 as a purple solid (600 mg, 21%): 1H NMR (300 MHz, CDCl3) δ−2.80, −2.75 (2 s, 2H, atropisomer NH), 3.42-3.58 (multiple s, 12H, atropisomer N—CH3), 7.87-7.98 (multiple s, 4H, atropisomer), 8.06 (s, 4H), 8.95-8.99 (multiple s, 8H, atropisomer).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=394.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](O)=[O:10].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1ccccc1Br
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1ccccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (2-bromophenyl)acetic acid (100 g, 0.46 mmol) in dry THF (2 L) was added NaBH4 (29 g, 0.77 mol) in portions. The contents were cooled to 0° C., and BF3. Et2O (123 mL, 0.770 mol) was added drop-wise over 1 h. The mixture was allowed to warm to 25° C. and stirred for 16 h. The reaction was cooled to 0° C. and cautiously quenched with aqueous sodium hydroxide. The contents were stirred for 3 h, and then extracted with EtOAc. The organic layer was dried and concentrated to give 2-(2-bromophenyl)ethanol. 1H-NMR (400 MHz, CDCl3) δ 7.54˜7.56 (m, 1H), 7.23˜7.28 (m, 2 H), 7.07˜7.11 (m, 1H), 3.88 (s, J=6.6 Hz, 2H), 3.03 (t, J=6.8 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[S:17])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].[C:18]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([S:17][CH3:18])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1[nH]c(=S)[nH]c1-c1ccc(F)cc1
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1nc(SC)[nH]c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a stirred solution of compound 7 (18 g, 71.0 mmol) in MeOH (200 mL) was added K2CO3 (12.0 g, 85.0 mmol), followed by the dropwise addition of a solution of MeI (8.9 mL, 143 mmol) in MeOH (200 mL) at rt. The resulting mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was treated with water (200 mL) and extracted with ethyl acetate (150 mL×3). The combined extracts were washed with brine (50 mL×2), dried over anhydrous MgSO4, filtered, and evaporated to afford product 8 (19.0 g, 100%) as a white solid. ESI MS m/z 267.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[OH-].[Na+]>Br>[N+:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[OH:2])([O-:11])=[O:10]
Reactant: COc1ccncc1[N+](=O)[O-]
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnccc1O
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
4-Methoxy-3-nitropyridine (25.0 g, 162 mmol) in 220 ml conc. hydrobromic acid (48%) was refluxed at 100° C. for 16 hrs. The reaction mixture was cooled, poured into ice water and neutralized with 155 ml conc. NaOH (32%). The suspension was stirred for 10 min. at 5° C. and filtered. The solid was washed with water and dried at 50° C. and <30 mbar for 1 hour. The desired product was obtained as a light yellow solid (20.2 g, 89%).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:8]=1)(=O)=O.[NH4+:27].[OH-]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:8]=[C:7]([CH2:6][NH2:27])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)OCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Agent: [OH-]
Solvent: C1CCOC1
Product: NCC1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Yield: 39.8 %

Procedure:
A solution of [5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]methyl methanesulfonate (58 g, 0.134 mol) in THF (200 mL) and NH4OH aq. (25%, 412 mL, 2.68 mol) was stirred at room temperature for 15 hours. The excess ammonia was removed in vacuo and EtOAc (200 mL) and sat. aq. NaHCO3 (150 mL) was added. The organic layer was separated and the aqueous phase was extracted with EtOAc, the combined organic layers were washed with sat. aq. NaHCO3 (2×150 mL), brine (200 mL) and water (1×200 mL), dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to afford the crude material (89.85 g). This material was purified by column chromatography using dichloromethane, methanol and ammonium hydroxide (97:3:1) in silica gel to yield the [5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-yl]methyl amine (18.90 g, 40%, two steps) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[CH3:13][N:14]([CH3:16])[NH2:15]>CCO>[CH3:13][N:14]([CH3:16])[N:15]=[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1]
Reactant: CN(C)N
Reactant: CC(C)CCC(=O)c1ccco1
Solvent: CCO
Product: CC(C)CCC(=NN(C)C)c1ccco1

Procedure:
A solution of 2-(4-methylvaleryl)furan (1 mmol) and N,N-dimethylhydrazine (1.5 mmol) in EtOH was heated at reflux for 24 h. Evaporation and distilation gave 2-(4-methylvaleryl)furan dimethylhydrazone as a brown oil.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[N:31]1([C:36]2[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=2)[CH:35]=[CH:34][N:33]=[CH:32]1>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:42][C:39]2[CH:38]=[CH:37][C:36]([N:31]3[CH:35]=[CH:34][N:33]=[CH:32]3)=[CH:41][CH:40]=2)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: Sc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccc(-n3ccnc3)cc2)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 4-imidazol-1-yl-benzenethiol (prepared according to patent application FR 2267101, 1975) yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(4-imidazol-1-yl-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless foam. MS: 454.2 [M+H]+.
Reaction SMILES: C(O[C:4]([CH:6]([C:28]([O:30]CC)=O)[C:7]1[C:16]2[C:11](=[C:12]([NH:17][C:18](=[O:27])[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)=[O:5])C.O.[NH2:34][NH2:35]>C(O)C>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:6]1[C:28]([OH:30])=[N:34][NH:35][C:4]=1[OH:5])=[O:27]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: CCO
Solvent: O
Product: O=C(Nc1cccc2c(-c3c(O)n[nH]c3O)ccnc12)c1c(Cl)cccc1Cl

Procedure:
A mixture or 4-[bis(ethoxycarbonyl)methyl]-8-(2,6-dichlorobenzoylamino)quinoline (200 mg) and hydrazine monohydrate (211 mg) in ethanol (2 ml) was refluxed overnight. After cooling, the resulting precipitates were collected by the filtration, and the residue was washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(3,5-dihydroxypyrazol-4-yl)quinoline as a solid. The obtained solid was treated with ethanol solution of hydrogen chloride, and the precipitates were collected and recrystallized from isopropyl alcohol to give 8-(2,6-dichlorobenzoylamino)-4-(3,5-dihydroxypyrazol-4-yl)quinoline hydrochloride (95 mg).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[CH2:9]=[O:10]>C1(C)C=CC=CC=1>[OH:10][CH2:9][N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2]
Reactant: CCc1nc(C)c[nH]1
Reactant: C=O
Solvent: Cc1ccccc1
Product: CCc1nc(C)cn1CO
Yield: 92.9 %

Procedure:
110 g of 2-ethyl-4-methylimidazole are dissolved in 400 ml of toluene at 50° C. 30 g of paraformaldehyde are introduced into this solution, whilst stirring. The mixture is then stirred for 16 hours at 50°-55° C. and is cooled in an icebath, and the crystal slurry is filtered off. The resulting crude product is recrystallized from 300 ml of acetone. 130 g of 1-hydroxymethyl-2-ethyl-4-methylimidazole (corresponding to a yield of 92.9% of theory), of melting point 83.1°-86.3° C., are obtained.