Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([F:1])=[CH:3][C:4]=2[C:26]([F:29])([F:27])[F:28])[CH:8]=[CH:9]3)/[S:21][C:20]1=[O:22]
Reactant: CN(C)CCCl
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: CN(C)CCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-3-[2-(Dimethylamino)ethyl]-5-[(1-{[4-fluoro-2-(trifluoromethyl)-phenyl]methyl}-1H-indol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 249) and 2-(dimethylamino)ethyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([Cl:15])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][OH:14])[CH:7]=1>CO.C1COCC1.[Pt]>[NH2:16][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][OH:14])=[C:5]([Cl:15])[CH:4]=1
Reactant: Nc1cc(N2CCC[C@@H]2CO)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Cl)c(N2CCC[C@@H]2CO)cc1N

Procedure:
The sub-title compound was prepared from (R)-1-(5-amino-2-chloro-4-nitro-phenyl)-2-hydroxymethyl-pyrrolidine (220 mg, 0.8 mmol) and Pt/C (50 mg) in MeOH (6 mL) and THF (6 mL) in analogy to example 1 step (f).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: OC1(c2ccc(F)c(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(O)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Example 2: 3-(3-chloro-4-fluorophenyl)pyrrolidin-3-ol (0.31 g, 1.46 mmol), acetonitrile (3 mL), potassium carbonate (0.20 g, 1.46 mmol), iodoethane (0.12 mL, 1.5 mmol). Microwave irradiation at 100° C. for 20 minutes. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 55:45). Yield: 0.19 g. The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 157-158° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 9), 228 (9), 157 (13), 129 (10), 71 (bp).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.I[CH2:28][CH3:29]>CN(C=O)C>[CH2:28]([N:10]1[CH2:9][CH2:8][N:7]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:12][CH2:11]1)[CH3:29]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
Potassium carbonate (0.2 g, 1.36 mmol) was added in one portion to a stirred solution of N-[4-(piperazine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.34 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 5 minutes before iodoethane (0.03 ml, 0.44 mmol) was added drop wise and the resulting mixture heated to 60° C. and stirred under a nitrogen atmosphere for 18 hours. The crude reaction mixture was concentrated under vacuum and the residue was purified by Prep HPLC to give the title compound (0.015 g, 11% yield) as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][F:15])[C:7]=12.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][F:15])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(C)n(CCF)c2c(Cl)nncc12
Product: Cc1c(C)n(CCF)c2c(OCc3ccccc3)nncc12
Yield: 76.2 %

Procedure:
The title compound was prepared as white crystals in 76.2% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-(2-fluoroethyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [O:1]([CH:8]=[CH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(C(OO)=[O:24])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[O:1]([CH:8]=[CH:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]2[O:24][CH:15]2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1ccccc1
Reactant: C(=COc1ccccc1)Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C(=COc1ccccc1)CC1=CC2OC2C=C1
Reaction time: 120 h
Yield: 40 %

Procedure:
To 6.3 g of p-phenoxyallylbenzene was added 45 ml of chloroform solution containing perbenzoic acid prepared from 11 g of benzoylperoxide, and the resulting mixture was allowed to stand at about 5° C for 5 days. The thus obtained solution was washed with 10% sodium hydroxide solution, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue. This was chromatographed over a silica gel, and eluted with chloroform, and there was obtained 2.7 g (yield 40%) of p-phenoxyallylbenzene oxide as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.Cl.[CH3:13][NH:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:14]([CH3:15])[CH3:13]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])cc1Cl
Yield: 101.1 %

Procedure:
A solution of 3-chloro-4-fluoronitrobenzene (3.0 g, 17.1 mmol), dimethylamine hydrochloride (1.53 g, 18.8 mmol) and K2CO3 (4.96 g, 35.9 mmol) in Me2SO (20 mL) was heated in a sealed tube at 105° C. for 18 h. On cooling the reaction mixture was poured into water (200 mL) and extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, filtered, and evaporated to give 3.47 g of 3-chloro-4-(dimethylamino) nitrobenzene as a yellow solid. An aliquot of this (3.4 g, 16.95 mmol) was dissolved in 20 mL of EtOH/AcOH (1:1, v/v) with warming. Iron powder (−325 mesh, 9.5 g, 170 mmol) was added in small portions. The mixture was then heated on a steam bath for 30 min. The mixture was cooled, filtered through a pad of celite and the filtrate was evaporated to give 3.33 g of 3-chloro-4-(dimethylamino)aniline as a dark solid. A solution of this compound in EtOH (10 mL) was treated with HNO3 (69% aq, 2.6 mL, 40.6 mmol) dropwise, followed by cyanamide (50% solution in water, 5.3 mL, 67.78 mmol). After heating for 18 h at reflux the reaction mixture was cooled to room temperature, poured into Et2O (100 ml) and basified with NaOH solution (2 N, 100 mL). The ethereal layer was separated. The aqueous phase was extracted with Et2O. The combined organic phases were washed with brine, dried on MgSO4, filtered, and evaporated to give a black oil, which solidified on standing to afford 1.6 g of the title compound. RP-HPLC: tR=12.7 min (10-70% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>95%). 1H-NMR (CD3OD) δ: 2.68 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.75 (s, 6H, CH3), 7.05 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=8.8 Hz, pyrimidinyl-H), 7.49 (dd, 1H, J=8.8, 2.4 Hz, Ph-H), 7.94 (d, 1H, J=2.4 Hz, Ph-H), 8.43 (d, 1H, J=5.4 Hz, pyrimidinyl-H). MS (ESI+) m/z=393 [M+Na] (C17H18N6O2S requires 370.4).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=2[F:20])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[C:47](=[O:59])[N:48]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:49]=[CH:50][CH:51]=1.CCN(CCO)CC>CN(C=O)C.CO>[F:20][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[NH:45][C:46]2[C:47](=[O:59])[N:48]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[CH:49]=[CH:50][CH:51]=2)[CH:18]=[CH:19][C:11]=1[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: Nc1cccn(-c2ccc(F)cc2)c1=O
Reactant: NC(=O)c1cc(Oc2ccc(C(=O)O)cc2F)ccn1
Agent: CCN(CC)CCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1cc(Oc2ccc(C(=O)Nc3cccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
To a solution of 4-(2-carbamoylpyridin-4-yloxy)-3-fluorobenzoic acid (0.3 mmol, 83 mg) in DMF (2 mL), were added HATU (Perspective Biosystems, 0.45 mmol, 171 mg), 3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (0.3 mmol, 61.2 mg) and DEEA (Aldrich, 0.2 mL). The reaction mixture were heated at 50° C. for 5 h. After cooling to room temperature, 5 mL of methanol was added. The product was purified by preparative HPLC. The desired fractions were combined, neutralized to pH 7-8 with aq. K2HPO4, and concentrated in vacuo. The precipitate that formed was collected by filtration, rinsed with water, and dried under vacuum to give the desired product (78 mg, 57% yield). MS(ESf+) m/z 463.25 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:22][NH:23][C:24]([NH2:26])=[O:25].C[O-].[Mg+2].C[O-].CO>>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:4]([NH:26][C:24]([NH:23][CH3:22])=[O:25])=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (1.27 g, 4.36 mmol) and methyl urea (647 mg, 8.73 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 9.36 mL, 6.54 mmol) was refluxed at 100° C. for 8.5 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-nitro-phenyl)-propionyl]-3-methyl-urea (183.6 mg, 13.2%) as a white solid: mp 179-183° C.; EI-HRMS m/e calcd for C16H21N3O4(M+) 319.1532, found 319.1527.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:14]1([CH3:18])[CH:15]=[CH:16][CH:17]=[C:12]([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH:13]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: Cc1cccc(-c2nccnc2C2CNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 260 %

Procedure:
To a solution of 2-azetidin-3-yl-3-m-tolyl-pyrazine hydrochloride (131 mg, 0.05 mmol) and 2-chloro-quinoline (82 mg, 0.05 mmol) in DMF (10 mL) was added Cs2CO3 (325 mg, 1.0 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×2). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% EtOAc in petroleum ether) to give 2-[3-(3-m-tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (44 mg, 0.13 mmol, 25%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[S:3]([O:6][C:7]1[C:8]([N+:27]([O-])=O)=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=[O:5])=[O:4]>CCO.CC(O)=O.CCOC(C)=O.[Fe]>[F:31][C:2]([F:1])([F:30])[S:3]([O:6][C:7]1[C:8]([NH2:27])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=[O:5])=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 100 °C
Yield: 84 %

Procedure:
Iron (211 mg, 3.79 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (350 mg, 0.757 mmol) in EtOH (8.4 mL) and AcOH (8.4 mL) at rt and then was heated to 100° C. for 10 min. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl followed by 1M NaOH and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a white solid which was 1:1 starting material:product. It was resubjected to the reaction conditions for 15 min and re-worked up to give the titled compound (275 mg, 84%). LC-MS retention time: 1.47 min; m/z (MH+): 433. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: COc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccnc(F)c2)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
50 mg of 2-fluoro-4-iodopyridine, 33 mg of p-anisidine, 108 mg of K2CO3, 1 mg of Pd(OAc)2 and 6 mg of BINAP were charged into a microwave vial and 2 mL of dry toluene were added and the vial was sealed, evacuated and flushed with Argon. The mixture in the vial was irradiated at 180° C. in a CEM Explorer™ microwave unit for 30 minutes with stirring and the mixture obtained was cooled to r.t. From the mixture obtained solid material was filtered off and washed with 10 mL of CH2Cl2 and solvent from the combined filtrate and washing solvent was evaporated off. The evaporation residue obtained was subjected to flash column chromatography. (2-Fluoro-N-(4-methoxyphenyl)pyridin-4-amine in the form of yellow crystals was obtained.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg+2].[Cl-].[Cl-].[CH2:19]=[O:20].Cl>C(#N)C>[OH:15][C:11]1[CH:10]=[C:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH2:8])[CH:14]=[CH:13][C:12]=1[CH:19]=[O:20]
Reactant: C=C(c1ccccc1)c1cccc(O)c1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: C=C(c1ccccc1)c1ccc(C=O)c(O)c1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A mixture of the phenol from step 2 (4.15 g, 21.1 mmole), MgCl2 (3.02 g, 31.7 mmole), TEA (11.1 mL, 79.3 mmole) and paraformaldehyde (4.29 g, 143 mmole) in anhydrous acetonitrile (100 mL) was refluxed for 17 h. Additional MgCl2 (1.5 g, 15.8 mmole), TEA (5.6 mL, 40 mmole) and paraformaldehyde (2.23 g, 74 mmole) were then added and reflux was continued for 2 h. The mixture was then cooled, acidified with 1N HCl and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by filtration through a silica-gel plug (9:1 hexanes:EtOAc) to give 4.28 g (91% yield) of the product as a yellow oil: EIHRMS m/z 224.0837 (M+, C15H12O2, Calc'd 224.0837).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:18])=O>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([Cl:18])=[O:15])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCC[C@H]1CC[C@H](CC(=O)O)CC1
Product: CCCCC[C@H]1CC[C@H](CC(=O)Cl)CC1

Procedure:
For conversion into the acid chloride, trans-4-pentylcyclohexylacetic acid (12.0 g, 0.0566 mol) was reacted for about 1 hour on an oil bath at 80° C. with thionyl chloride (50 ml). The solution obtained was evaporated under reduced pressure, treated with absolute toluene (50 ml) and once more evaporated under reduced pressure.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([C:21]([OH:23])=[O:22])[S:13][C:14]=1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:21]([OH:23])=[O:22])[S:13][C:14]=1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[Cl:1]
Reactant: Cn1nccc1-c1sc(C(=O)O)cc1Br
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Br
Temperature: 70 °C
Yield: 0.1 %

Procedure:
N-chlorosuccinimide (NCS) (299 mg, 2.194 mmol) was added in portions to a 30 mL sealed tube reactor containing 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (503 mg, 1.23 mmol) in tetrahydrofuran (THF) (6 mL) at room temperature. The mixture was heated to 70° C. for 2 hours. Upon completion, the reaction mixture was partitioned between CHCl3 and H2O, the organic layer dried with Na2SO4, solvents removed by vacuum distillation affording the title compound (0.54 mg, quant.) which was used without further purification. LC-MS (ES) m/z=321 (M+H)+
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH:11](O)[CH3:12])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9](=[O:10])/[C:8](=[CH:11]/[CH3:12])/[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(C(C)O)C1=O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C/C=C1\NC(=O)N(CCCC)C1=O

Procedure:
A solution of (1' RS, 5 SR)-3-n-butyl-5-(1-hydroxyethyl)hydantoin (7.7 g 0.039 mole) in toluene (150 ml) containing methane sulphonic acid (2.5 mole 0.039 mole) was heated under a Dean and Stark apparatus for 48 hours during which time 0.65 ml of water collected (94% of theory). The mixture was cooled to room-temperature and washed with dilute sodium bicarbonate and dried (MgSO4). Removal of the solvent gave a solid which was crystallised from cyclohexane to give the title compound as prisms m.p. 127° C. Yield=3.3 g=46.5%. The following Examples 14-20 illustrate pharmaceutical formulations containing the compound 3-n-butyl-5-methylenehydantoin.
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:7]2[C:6]3[S:19][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=3[C:10](=[O:11])[N:9]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:18])=[CH:27][CH:26]=1)#[N:35]
Reactant: CCc1cc2c(=O)n(C(C)C(=O)OC)c(=O)[nH]c2s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(C(C)C(=O)OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A mixture of methyl 2-(6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)propanoate (9.9 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (11.5 g), potassium carbonate (9.7 g) and acetonitrile (500 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (15 g, 90%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=[O:39]>C1C=CC=CC=1>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([O:19][C:38]([CH2:37][Cl:36])=[O:39])[CH2:17][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)CCl)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C
Yield: 66.1 %

Procedure:
A solution of cholesterol (1.93 g, 5 mmol) and triethylamine (0.51 g, 5 mmol) in benzene (25 mL) was added dropwise to an 8°-10° C. solution of chloroacetyl chloride (0.57 g, 5 mmol) in benzene (20 mL). The solution was heated under reflux at 80° C. for 24 hours, cooled to room temperature and worked up. Recrystallization (absolute EtOH) afforded the title compound (1.53 g, 66%) as a white solid (mp 160°-161° C.).
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]1.[NH4+].[Cl-]>CCO.O.[Fe]>[F:18][C:4]([F:3])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]1
Reactant: CC(F)(F)CCCCn1cc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)CCCCn1cc(N)cn1
Temperature: 75 °C
Reaction time: 0.67 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-(5,5-difluoro-hexyl)-4-nitro-1H-pyrazole (400 mg, 1.72 mmol), iron powder (290 mg, 5.15 mmol) and NH4Cl (463 mg, 8.58 mmol) in a mixture of EtOH (8.0 mL) and water (4.0 mL) was stirred at 75° C. for 40 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (30 mL) was added followed by 1M NaOH (30 mL). The aq. layer was extracted with CH2Cl2 (2×30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep red oil. LC-MS-conditions 02: tR=0.60 min; [M+H]+=204.27.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1
Reactant: Cc1nc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylthiazol-4-yl)methyl)oxazolidine-3-carboxylate (0.100 g, 0.219 mmol) was dissolved in THF (4 mL) and cooled to 0° C. Next, TBAF (0.547 ml, 0.547 mmol) was added dropwise and the reaction was stirred 1 hr. and then quenched with saturated ammonium chloride and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. Purification by column chromatography (2.5:1 Hexanes/EtOAc) afforded the title compound.