Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[CH3:14][C:15]1[NH:20][C:19](=O)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[N:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[C:18]([N+:22]([O-:24])=[O:23])=[C:19]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])[N:20]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc(N2CCC(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nc(OCC(F)(F)F)c([N+](=O)[O-])c(N2CCC(c3ccccc3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
0.591 g (2.55 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added slowly at room temperature to a suspension of 0.200 g (0.636 mmol) of the 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3H-pyrimidin-4-one (example 5) and 0.135 g (1.27 mmol) of sodium carbonate in 5.0 ml of acetone. After stirring of the reaction mixture for 2 hours, 0.136 g (0.99 mmol) of potassium carbonate were added and stirring continued for 18 hours. Additional 0.296 g (1.27 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added and stirring continued for 4 hours. The reaction mixture was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 1:1 v/v gradient of hexane and ethylacetate as the eluent giving 0.077 g (0.194 mmol, 30.5% of theory) of the 2-methyl-5-nitro-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine as a light yellow solid; m.p. 114-117° C.; MS: [M+H]+=397; and 0.166 g (0.419 mmol, 65.8% of theory) of the 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one as yellowish solid;
Reaction SMILES: [NH4+]=S.[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([N+:13]([O-])=O)[C:7]=2[S:6][CH:5]=1>C(O)C.O>[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([NH2:13])[C:7]=2[S:6][CH:5]=1
Reactant: Cc1csc2c([N+](=O)[O-])cc([N+](=O)[O-])cc12
Solvent: O
Solvent: CCO
Product: Cc1csc2c(N)cc([N+](=O)[O-])cc12
Temperature: 0 °C

Procedure:
453 ml of a 20% strength ammonium sulphide solution (1.33 moles of (NH4)2S) are added dropwise to a suspension of 0.4 mole of 3-methyl-5,7-dinitrobenzothiophene in 1,400 ml of ethanol at 55°-60° C. in the course of 45 minutes, and the mixture is then heated at the boiling point for 15 minutes. The mixture is then diluted with 1,400 ml of water and cooled to 0° C. and the crystalline product is filtered off with suction. For purification, the crystals are dissolved in methylene chloride and the solution is filtered over a silica gel column (eluting agent: methylene chloride/cyclohexane 9:11). The substance obtained from the combined eluates is recrystallised from isopropanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][CH:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)=[CH:18][C:12]=3[N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[N:14]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:13]3[CH:15]=[CH:16][C:17]([N:19]4[CH2:20][CH2:21][CH:22]([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)=[CH:18][C:12]=3[N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CN(C)C1CCN(c2ccc3[nH]c(C(=O)c4ccnc(Br)c4)nc3c2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc3c(c2)nc(C(=O)c2ccnc(Br)c2)n3COCC[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
(2-Bromo-pyridin-4-yl)-[5-(4-dimethylamino-piperidin-1-yl)-1H-benzoimidazol-2-yl]-methanone (11.9 g, 27.8 mmol) was dissolved in 200 mL of dry THF. This solution was cooled at 0° C. and NaH 60% dispersion (1.34 g, 33.3 mmol) was added in portions. The mixture stirred at 0° C. for 30 minutes and then the 2-(trimethylsilyl)ethoxymethyl chloride (5.56 g, 33.3 mmol) was added dropwise. The mixture was allowed to warm at room temperature while stirring overnight. 2M Aqueous HCl (300 mL) was carefully added and then the aqueous mixture was washed with EtOAc (3×100 mL). The aqueous phase was then neutralised with saturated aqueous NaHCO3 and then extracted with CHCl3/iPrOH (3:1; 3×250 mL). The combined CHCl3/i-PrOH fractions were dried (Na2SO4) and then evaporated to dryness. Purification by SiO2 chromatography (dichloromethane/NH3 2.0M in MeOH; 98:2 to 90:10) gave the title compound as a dark red oil (11.2 g, yield 72%; as a mixture of two regioisomers). MS(ESI) m/z 558, 560.2 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:12]1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:33][C:32]=1[O:41][CH2:42][O:43][CH3:44])C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[CH3:44][O:43][CH2:42][O:41][C:32]1[CH:33]=[C:34]([O:37][CH2:38][O:39][CH3:40])[CH:35]=[CH:36][C:31]=1[C:12]1[N:11]([CH2:10][CH2:9][OH:8])[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]=1[CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCOC)cc3OCOC)n(CCOCc3ccccc3)c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCOC)cc3OCOC)n(CCO)c2n1

Procedure:
To a solution of ethyl 1-(2-benzyloxyethyl)-2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (727 mg, 1.20 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 7.5% palladium carbon (225 mg), and the mixture was stirred at atmospheric pressure and in a hydrogen atmosphere at room temperature for 12 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give ethyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate as a crude product. The obtained compound was used in Step 7 without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([CH3:25])[CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]([CH3:25])[CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(CCOc1ccccc1)c1cccc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CCOc1ccccc1)c1cccc(O)c1
Reaction time: 2 h

Procedure:
A solution of 3-(3-benzyloxyphenyl)-1-phenoxybutane (11.2 g., 33.5 mM) in a mixture of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the presence of 10% palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-10% ethyl acetate. The middle fractions are combined and concentrated to give the title product as an oil.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:15]2[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2.C(N(CC)CC)C.[CH2:27]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:27]([C:39]1[CH:40]=[CH:41][C:42]([S:45]([O:1][N:2]=[C:3]2[C:4]3[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:47])=[O:46])=[CH:43][CH:44]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)ON=C2c3ccc(OC)cc3-c3cc(OC)ccc32)cc1
Yield: 51.4 %

Procedure:
As described under 11.3., 5.1 g (0.02 mol) of 9-hydroxyimino-3,6-dimethoxyfluorene are reacted at 0° C., in the presence of 3.0 g (0.03 mol) of triethylamine in 100 ml THF, with 5.6 g (0.022 mol) of 4-dodecylbenzenesulfonyl chloride. The crude product obtained after isolation is purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 4:1). 5.8 g (51.3%) of 9-(4-dodecyl-phenylsulfonyloxyimino)-3,6-dimethoxyfluorene are obtained in the form of a viscous yellow oil. The UV spectrum (acetonitrile) of the substance shows absorption bands with a maximum at 315 nm (ε=21100) that extend to 443 nm. Elemental analysis: C33H41NO5S (563.76)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:9]/[CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])[CH:3]=1.[CH:17]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH2:18]>C1COCC1.C([O-])(=O)C.[Ag+]>[C:22]1([S:19]([CH:17]2[CH2:18][C:10]3([CH2:14][CH2:13][N:12]([CH3:15])[C:11]3=[O:16])[NH:9][CH:8]2[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(/N=C/c2cc(Br)ccn2)C1=O
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CN1CCC2(CC(S(=O)(=O)c3ccccc3)C(c3cc(Br)ccn3)N2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[(E)-(4-bromo-2-pyridyl)methyleneamino]-1-methyl-pyrrolidin-2-one (which may be prepared as described in Description 1) (564.3 mg, 2 mmol) and phenyl vinyl sulfone (339.8 mg, 2.02 mmol) in THF (10 mL) was treated with silver acetate (333.99 mg, 2 mmol). The mixture was stirred at room temp for 2 hours, filtered through Celite and concentrated to give the title compound (D2) as a brown gum;
Reaction SMILES: [N:1]([C@H:4]([CH2:15][OH:16])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C@H:4]([CH2:15][OH:16])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: [N-]=[N+]=N[C@H](CO)C(=O)NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 27.5 °C

Procedure:
In an autoclave charged (2R)-2-azido-N-benzyl-3-hydroxypropanamide (68.0 gms) in ethyl acetate (680 ml). Charged catalyst 5% Pd-C (6.85 gms) and closed the autoclave. Applied 3.8 kg Hydrogen pressure maintaining temperature at 25-30° C. and maintained the reaction mixture at 25-30° C. for 1.0 hour. After completion of the reaction, released Hydrogen pressure and flushed the autoclave with Nitrogen gas. Filtered the reaction mass through hyflo bed and washed hyflo bed with ethyl acetate. Concentrated filtrate under reduced pressure at 30-35° C. till two volumes of ethyl acetate remains in the reaction mixture. Removed vacuum and cooled the reaction mass to 0-5° C. and maintained for 2.0 hours. The reaction mass was filtered and washed with cold ethyl acetate (2×40 ml). Dried the product (2R)-2-amino-N-benzyl-3-hydroxypropanamide under vacuum at 25-30° C. till constant weight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH2:9][OH:10])[CH:3]=1.F[C:12]1[CH:13]=[CH:14][C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH:19]=1)[NH:17][CH3:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:13]=[CH:14][C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH:19]=2)[NH:17][CH3:18])=[C:4]([CH2:9][OH:10])[CH:3]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(Sc2ccc(Cl)cc2CO)ccc1[N+](=O)[O-]
Yield: 87.1 %

Procedure:
The solution of 4-chloro-2-(hydroxymethyl)thiophenol (1.0 g) from Example 16, 5-fluoro-N-methyl-2-nitroaniline (1.0 g) and K2CO3 (0.81 g) in DMF (20 ml) was heated at 90° C. for 15 minutes. After leaving the solution to stand at room temperature, water was added to the solution prior to extraction in ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by chromatography on a silica gel column (methylene chloride) to give the title compound (1.62 g; 85%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:35]3[CH2:40][CH2:39][C@@H:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[C:11]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[CH3:47][N:44]1[CH2:43][CH2:42][N:41]([C@@H:38]2[CH2:39][CH2:40][C@H:35]([N:16]3[C:12]4=[N:13][CH:14]=[N:15][C:10]([NH2:9])=[C:11]4[C:18]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][CH2:26][CH2:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:23][CH:24]=4)=[N:17]3)[CH2:36][CH2:37]2)[CH2:46][CH2:45]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)Cc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NCCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
Cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-2-phenylacetamide diacetate (0.200 g, 0.00031 mol) was suspended in anhydrous tetrahydrofuran (15 mL), the suspension was cooled to 0° C. and lithium aluminum hydride (0.177 g, 0.00416 mol) was added at once. The resulting mixture was warmed up to ambient temperature and stirred under an atmosphere of nitrogen for 18 hours. It was quenched by dropwise addition of water, the solvents were removed under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(phenethylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.039 g, 0.0000619 mol) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: COC(=O)c1cc2ccccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), methyl 2-hydroxy-3-naphthoate (271 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (7 mg, yield 4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)Cl>[Br:17][CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:16]
Reactant: CC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
To a solution of 1-[4-(4-bromophenyl)phenyl]ethanone (5 g, 18.17 mmol) in CH2Cl2 (40 mL) is added bromine (983 μL, 19 mmol). The resulting mixture is stirred for 48 hours at room temperature. The mixture is diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate and concentrated. The crude solid is triturated with ether to give 2-bromo-1-[4-(4-bromophenyl)phenyl]ethanone (5.7 g, 88.6%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1>CN1CCCC1=O.O>[N+:8]([C:7]1[C:2]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([NH2:18])=[CH:12][CH:13]=2)=[N:3][CH:4]=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cncnc1Cl
Reactant: Nc1ccc(N)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Nc2ncncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A mixture of 4-chloro-5-nitropyrimidine (380 mg) and benzene-1,4-diamine (257 mg) in N-methylpyrrolidone (5 mL) was stirred overnight at ambient temperature. After this time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated sodium bicarbonate (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 3:97 methanol/methylene chloride) to afford N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (260 mg) as a brown oil.
Reaction SMILES: C1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:8]([O:12][CH2:13][CH:14]=C)[CH2:9][CH:10]=C)C=CC=CC=1>C1C=CC=CC=1>[CH:7]([C@@H:8]1[CH2:9][CH:10]=[CH:14][CH2:13][O:12]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCO[C@@H](CC=C)C(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: C1=CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 176.2 %

Procedure:
Into a solution of (2S)-1,1-Diphenyl-2-Allyloxy-Pent-4-ene 26a (0.19 g, 0.68 mmol) in dry benzene was added Grubb catalyst (0.028 g, 0.034 mmol, 5%) and the solution was refluxed under N2 for 20 h. The solvent was removed, and the residue was purified by flash chromatography (hexane/ether=9:1) to give 0.15 g (2S)-2-benzhydryl-3,6-dihydro-2H-pyran, 27a (88%, [α]D=(−)79.3, c=1, MeOH).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)[CH3:3].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:29](Br)=[N:28][C:27]([Br:31])=[CH:26][N:25]=1)(=[O:22])=[O:21]>>[Br:31][C:27]1[N:28]=[C:29]([O:11][CH2:10][C:8]2[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[C:24]([NH:23][S:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])(=[O:22])=[O:21])=[N:25][CH:26]=1
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl
Product: CN(C)Cc1ccc(COc2nc(Br)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 31 using (5-dimethylaminomethyl-2-furanyl)methanol (0.2 g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (Example 31a) (0.2 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures and recrystallised from acetonitrile. Yield 0.058 g.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([CH3:30])=[CH:20][CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-p-tolyl-acrylic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:15][C:2]1([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4](=[O:6])[CH2:3]1
Reactant: CC(C)(CCc1ccccc1)CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CCc2ccccc2C(=O)C1
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
82 g of 3,3-dimethyl-5-phenylvaleric acid are treated with 57 ml of thionyl chloride and heated to reflux for half an hour. Thereafter, the excess reagent is evaporated, finally under a high vacuum for 1.5 hours. The acid chloride prepared, dissolved in 300 ml of methylene chloride, is added within 3.5 hours under an argon atmosphere to 79 g of aluminum trichloride in 650 ml of methylene chloride. Thereafter, the reaction mixture is stirred for an additional 10 minutes and poured on to ice. The organic phase is washed with water dried and evaporated. After chromatography on silica gel with petroleum ether (low-boiling)/ethyl acetate (98:2), there are obtained 62 g of 6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocycloheptene-5-one.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ccnc(CO)c2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccnc(COS(C)(=O)=O)c2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-yl]-methanol (177 mg, 0.91 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.16 mL, 1.17 mmol) followed by DMAP (11 mg, 0.09 mmol) and Ms-Cl (0.09 mL, 1.14 mmol). After stirring at rt for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl ester as a red oil. The crude material (246 mg) was dissolved in acetone (12 mL) under inert atmosphere (N2). 4-Nitro-1H-pyrazole (114 mg, 0.90 mmol) was added followed by K2CO3 (628 mg, 4.50 mmol) and TBA bromide (58 mg, 0.18 mmol). The reaction mixture was stirred overnight at rt and concentrated to dryness. The residue was partitioned between water (5 mL) and EA (10 mL). The layers were separated and the aq. layer extracted with EA (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1:1 hept-EA)=0.10. LC-MS-conditions 02: tR=0.85 min, [M+H]+=291.31.