Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[CH:23][S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:24]([CH3:25])=[CH:23][S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccno3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=O.C(N(CC)CC)C.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([N:34]=[N+:35]=[N-:36])=[O:12]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1ccccc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1ccccc1Cl
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of (E)-3-(2-chlorophenyl)acrylic acid (13 g, 71.2 mmol) in benzene (100 ml) was added triethylamine (14.4 g, 141 mmol) followed by DPPA (19.5 g, 71.2 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as pale yellow solid (14 g, 95%). 1H NMR (400 MHz, CDCl3): δ ppm 8.19-8.15 (d, J=16 Hz, 1H), 7.63-7.61 (d, J=8 Hz, 1H), 7.44-7.42 (m, 1H), 7.36-7.26 (m, 2H), 6.44-6.40 (d, J=16 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH:28]=[CH:29][C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33]>>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31]#[C:30]/[CH:29]=[CH:28]/[CH2:27][N:3]([CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH2:1][CH3:2]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CCNCc1cccc(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(C(C)=O)c1
Yield: 62.4 %

Procedure:
The procedure described in Example 13 was repeated, except that 3′-(N-ethylaminomethyl)acetophenone (1.24 g; 7 mmol), sodium carbonate (instead of potassium carbonate) (745 mg; 7 mmol), and 1-bromo-6,6-dimethyl-2-hepten-4-yn (1.41 g; 7 mmol) were used, to thereby yield 1.30 g of the target compound (yield: 62.5%).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>O.O1CCCC1.CCCCCC>[N:16]1[CH:21]=[CH:20][C:19]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:18][CH:17]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cncnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.8 ml of a hexane solution containing 2.52 mol of n-butyllithium was slowly added dropwise into a solution of 20 ml of tetrahydrofuran containing 2.5 ml of 2,2,6,6-tetramethylpiperidine. After stirring at 0° C. for 30 minutes, a mixture of 0.98 ml of pyrimidine, 4.6 ml of tri-n-butyltin chloride and 20 ml of tetrahydrofuran was slowly added dropwise thereinto. After stirring at −78° C. for 4 hours, water was added to the reaction solution and then extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. Then, the residue was subjected to silica gel column chromatography to elute with hexane/ethyl acetate (10:1), to give 474 mg of the target compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:36][CH:35]3[N:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:31]([CH2:32][O:33][CH2:34]3)[CH2:30]2)[C:9]=1Br.[CH2:56]([Sn](CCCC)(CCCC)[C:61]([O:63][CH2:64][CH3:65])=[CH2:62])[CH2:57][CH2:58][CH3:59].O1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:36][CH:35]3[N:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:31]([CH2:32][O:33][CH2:34]3)[CH2:30]2)[C:9]=1[C:61]([O:63][CH2:64][CH3:65])=[CH2:62].[CH3:53][Si:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][O:47][CH2:46][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:55])([CH3:54])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH:31]3[N:37]([C:38]([O:40][CH2:56][CH2:57][CH2:58][CH3:59])=[O:39])[CH:35]([CH2:34][O:33][CH2:32]3)[CH2:36]2)[C:9]=1[C:78]([O:77][CH2:76][CH3:75])=[CH2:79]
Reactant: C1COCCO1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(c1nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(OCC)c1c(C2CC3COCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Product: C=C(OCC)c1c(C2CC3COCC(C2)N3C(=O)OCCCC)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (150 mg, 0.176 mmol) in dioxane (2 mL) was treated with Pd(PPh3)4 (20.3 mg, 0.0.176 mmol) and tributyl(1-ethoxyvinyl)tin (0.18 mL, 0.528 mmol) under argon and the mixture was heated at 100° C. for 16 h. Upon cooling, the mixture was filtered through a pad of 10% KF—SiO2 and the filtrate was evaporated off under reduced pressure to give a residue which was purified by column chromatography (SiO2, 0-40% hexane-EtOAc) to provide desired compound tort-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate. HPLC-MS tR=3.65 min (UV254 nm). Mass calculated for formula C45H66N6O6Si2 842.4; observed MH+ (LCMS) 843.2 (m/z).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl.[NH2:27][NH:28][C:29]([NH2:31])=[O:30].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20](/[C:23](=[N:27]/[NH:28][C:29]([NH2:31])=[O:30])/[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 1-(3-(1-(7-fluoroquinolin-6-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (60 mg, 0.18 mmol) in methanol (10 ml) was added semicarbazide hydrochloride (40 mg, 0.36 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 38 mg (yield: 54%) title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1H), 8.84 (d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 7.96 (d, 1H), 7.77 (m, 3H), 7.44 (q, 1H), 6.69 (b, 2H), 5.03 (t, 1H), 2.07 (s, 3H), 1.83 (d, 3H). LCMS (method A): [MH]+=392, tR=4.88 min.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12].C(=O)([O-])O.[Na+]>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:11]([N:10]([CH3:14])[CH3:9])=[O:12])=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C)C(=O)Nc1ccc(O)cc1

Procedure:
This is made as described in British Patent Spectification No. 999 862. Thus, p-aminophenol (30 g), dimethylcarbamoyl chloride (30 g), sodium hydrogen carbonate (28 g), and dry acetone (600 ml) are stirred and heated under reflux for 3 hours. The mixture is filtered hot and the filtrate is allowed to cool overnight. The crystals which form are filtered off to give the desired urea, m.pt. 205° C. (decomp.). as measured on a Kofler bench (British Patent Specification No. 999 862 reports m.pt. 205°-206° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:12]([O:14][C:15](=[O:31])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29]Br)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][O:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(ccn4C)c3)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a solution of 1-methyl-1H-indol-5-ol (44.0 mg, 0.30 mmol) (Example 47) and ethyl[(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 100 mg, 0.29 mmol) in DMF (4.0 mL) were added Cs2CO3 (114.6 mg, 0.35 mmol) and water (3 drops). The reaction mixture was stirred at 40° C. for 16 h, then cooled to rt, and concentrated under reduced pressure. Water was added and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:13) yielded 55 mg (46%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.28 (t, 3H), 1.76 (m, 1H), 2.26 (m, 2H), 2.39 (m, 2H), 2.71 (dd, 1H), 2.88 (m, 2H), 3.50 (m, 1H), 3.78 (s, 3H), 4.18 (m, 6H), 6.38 (d, 1H), 6.72 (dd, 1H), 6.80 (s, 1H), 6.89 (d, 1H), 7.02 (s, 1H), 7.06 (d, 1H), 7.10 (s, 1H), 7.20 (d, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:8][CH2:9][CH2:10][OH:11].O>N1C=CC=CC=1>[S:2]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[OH:6])([CH3:1])(=[O:4])=[O:3]
Reactant: OCCCC(O)c1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCC(O)c1ccc2ccccc2c1

Procedure:
Methanesulfonyl chloride (0.77 g was added slowly with stirring to a cooled (-40° C.) solution of rac-delta-hydroxy-2-naphthalenebutanol (1.45 g) in dry pyridine (6 mL). The mixture was stirred at -40° C. for 5 hours, then was poured into water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed in turn with water (2×10 mL), saturated magnesium sulfate solution (3×15 mL) and brine, then were dried (MgSO4) and evaporated. The resulting oil was purified by HPLC (ethyl acetate-hexane; 2:3) to provide 1.25 g of rac-alpha-(3-mesyloxypropyl)-2-naphthalenemethanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:24])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C(=O)C)=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:28])[CH3:27].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:24])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:27])[CH3:28]
Reactant: CC(=O)Oc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.7 g of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-acetoxyphenylimino)-3-methyl-4-thiazoline (Example 8) in 30 ml of ethanol and 20 ml of water is brought to pH 11-12 with 2 N caustic soda and stirred at room temperature for 3 hours. After neutralization with 2 N hydrochloric acid, and repeated extraction with methyl acetate, the organic phases are dried, evaporated and the residue recrystallized from ethyl acetate/ethanol. Beige-colored crystals of m.p. 188°-190° C., identical with the product obtained by the method (a)-(c) by thin layer comparison.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O.O[CH2:10][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:3]=1.[Na+:15]
Reactant: O=S(=O)([O-])CO
Reactant: Nc1cccnc1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CNc1cccnc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 58.9 %

Procedure:
A mixture of 3-aminopyridine (2.82 g) and sodium hydroxymethanesulfonate monohydrate (9.12 g) in water (40 ml) was stirred for 1.5 hours at 80° C. The solution was concentrated to yield a precipitate and stood for several hours. The resulting precipitate was filtered, washed with ethanol and dried to give sodium 3-pyridylaminomethanesulfonate (3.71 g), mp 211° to 220° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].ClCCl.CO.N>C(OCC)(=O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCCN(CC)CC
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cc(N)ccc1OCCN(CC)CC

Procedure:
Prepared analogously to Example 3.1.b. from 0.30 g ethyl 2-(2-diethylaminoethoxy)-5-nitrobenzoate in ethyl acetate. Yield: 0.27 g (100% of theory); C15H24N2O3 (M=280.37); calc.: molecular ion peak (M+H)+: 281; found: molecular ion peak (M+H)+: 281; Rf value: 0.40 (silica gel, dichloromethane/methanol/ammonia (39:1:0.1)).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Br:21]Br>C1(C)C=CC=CC=1>[Br:21][CH2:9][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: BrBr
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(CBr)C(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 4.20 g. of 1,1-diphenyl-2-propanone in 25 ml. of acetic acid is heated at 60°-70° C. and 1.0 ml. of bromine in 8 ml. of acetic acid is added dropwise. The reaction mixture is held at 60°-70° C. for one hour and then poured into ice. Toluene is added. The toluene layer is separated, washed with water, dried over magnesium sulfate and concentrated to obtain 1-bromo-3,3-diphenyl-2-propanone.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[S:7][C:8]([CH2:10][CH:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][NH:28][C:27](=[N:30]C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[NH:26][CH2:25]4)=[CH:19][CH:18]=3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:5]=2[CH:4]=1)#[N:2].[Cl-:46].[NH4+]>C(O)C.[C].[Pd]>[ClH:46].[C:1]([C:3]1[CH:45]=[CH:44][C:6]2[S:7][C:8]([CH2:10][CH:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH:24]4[CH2:25][NH:26][C:27](=[NH:30])[NH:28][CH2:29]4)=[CH:21][CH:22]=3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2s1)c1ccc(OC2CNC(=NC(=O)OCc3ccc([N+](=O)[O-])cc3)NC2)cc1
Reactant: [Cl-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2s1)c1ccc(OC2CNC(=N)NC2)cc1
Product: Cl
Reaction time: 2 h
Yield: 86.3 %

Procedure:
In 100 ml portion of ethanol was dissolved 1.5 g of ethyl 3-(5-cyanobenzo[b]thien-2-yl)-2-[4-[[2-(p-nitrobenzyloxycarbonylimino)hexahydropyrimidin-5-yl]oxy]phenyl]propionate obtained in the above step c). To the thus prepared solution were added 0.5 g of ammonium chloride and 0.5 g of 10% palladium carbon catalyst (50% wet type). The resulting mixture was subjected to 2 hours of catalytic hydrogenation under normal pressure. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a chloroform/ethanol mixture as an elution solvent, thereby obtaining 1.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[C:14]2[CH:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([C:28]#[C:29][Si](C)(C)C)=[CH:22][CH:23]=5)[C:18]([CH3:35])([CH3:34])[C:17]=4[CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([NH:36][C:37](=[O:39])[CH3:38])=[CH:6][CH:7]=2.I[C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1>>[CH3:1][C:2]1([CH3:40])[C:14]2[CH:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([C:28]#[C:29][C:42]6[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=6)=[CH:22][CH:23]=5)[C:18]([CH3:35])([CH3:34])[C:17]=4[CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([NH:36][C:37](=[O:39])[CH3:38])=[CH:6][CH:7]=2
Reactant: CC(=O)Nc1ccc2c(c1)C(C)(C)c1cc(-c3ccc4c(c3)C(C)(C)c3cc(C#C[Si](C)(C)C)ccc3-4)ccc1-2
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: CC(=O)Nc1ccc2c(c1)C(C)(C)c1cc(-c3ccc4c(c3)C(C)(C)c3cc(C#Cc5ccc([N+](=O)[O-])cc5)ccc3-4)ccc1-2

Procedure:
FIG. 3 shows a synthetic scheme (30) for the production of compound 20 (FIG. 2), where X is hydrogen. Compound 31, 7′-bromo-9,9,9′,9′-tetramethyl-9H,9′H-[2,2′]bifluoreny-7-ylamine, is acetylated and subsequently coupled with trimethylsilylacetylene to provide N-(9,9,9′,9′-tetramethyl-7′-trimethylsilanylethynyl-9H,9′H-[2,2′]bifluorenyl-7-yl)-acetamide 32. Trimethylsilyl derivative 32 is subjected to an organometallic cross-coupling reaction in the presence of 4-iodo-nitrobenzene to afford N-[9,9,9′,9′-tetramethyl-7′-(4-nitro-phenylethynyl)-9H,9′H-[2,2′]bifluoreny-7-yl]-acetamide 33. Acetylene 33 is converted to ketone 34—2-(7′-amino-9,9,9′,9′-tetramethyl)-9H,9′H-[2,2′]bifluoreny-7-yl]-1-(4-nitro-phenyl)-ethanone—through the addition of H2O, which also effects the hydrolysis of the terminal acetamide. Alkylation of 34 provides the desired compound 35, 2-[7′-(2-mercapto-ethylamino)-9,9,9′,9′-tetramethyl-9H,9′H-[2,2′]bifluoreny-7-yl]-1-(4-nitro-phenyl)-ethanone.
Reaction SMILES: BrC1C(OC)=C(C=CC=1CSC1C=CC=CC=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35]Br)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].[Br:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1[SH:47]>>[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35][S:47][C:41]2[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:40]=2[Br:39])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: Fc1ccc(S)c(Br)c1
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Product: COC(=O)c1c(CSc2ccc(F)cc2Br)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-bromo-4-fluorothiophenol and used without further characterization.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:16][CH2:15][CH2:14][CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: ClCCCBr
Reactant: Cn1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCCl)c2ccccc21
Temperature: 65 °C
Yield: 84.7 %

Procedure:
A mixture of 1-methyl-1H-benzo[d]imidazol-2(3H)-one (2 g, 13.5 mmol, 1 equiv), 1-bromo-3-chloropropane (3.98 ml, 40.5 mmol, 3 equiv), and potassium carbonate (2.79 g, 20.25 mmol, 1.5 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and diluted with ethyl acetate. After being washed with water and brine, the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified using the Biotage chromatography system (SNAP 100 g cartridge, Rf=0.6, gradient—10%-50% ethyl acetate/hexanes) to afford 1-(3-chloropropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one as a clear oil (2.57 g, 85%); 1H NMR (400 MHz, DMSO-d6): δ 2.05-2.12 (m, 1H); 2.14-2.21 (m, 1H); 3.32 (s, 3H); 3.53 (t, 1H, J=6.8 and 6.4 Hz); 3.66 (t, 1H, J=6.4 Hz); 3.92-3.97 (m, 2H); 7.05-7.09 (m, 2H); 7.12-7.16 (m, 1H); 7.17-7.21 (m, 1H); MS for C11H13ClN2O m/z 226.07 (M+H)+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.NC(C1C=[C:20]([CH:24]=[C:25]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31]C)=[O:28])C=1)[C:21]([OH:23])=O)=O.Cl.[NH2:37][C@@H:38]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:39]([OH:67])[CH2:40][N:41]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([I:66])[CH:61]=1)[C:42](=[O:58])[O:43][CH2:44][CH:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2.CN1CCOCC1>CN(C=O)C>[F:76][C:71]1[CH:70]=[C:69]([CH2:68][C@H:38]([NH:37][C:21](=[O:23])[CH2:20][CH2:24][CH2:25][C:27](=[O:28])[N:29]2[CH2:30][CH2:31][CH2:35][CH2:34][CH2:33]2)[C@H:39]([OH:67])[CH2:40][N:41]([CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([I:66])[CH:61]=2)[C:42](=[O:58])[O:43][CH2:44][CH:45]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:51]=3[C:52]3[C:57]2=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH:74]=[C:73]([F:75])[CH:72]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN(Cc1cccc(I)c1)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CCCC(=O)N1CCCCC1)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN(Cc1cccc(I)c1)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
HOBt (81 mg, 0.6 mmole) and EDC (105 mg, 0.55 mmole) are added to 1-carboxy-5-piperdinylglutaramide (IX, 100 mg, 0.5 mmole) in DMF (2 ml). The acid is activated 60 minutes then treated with 1-9H-fluoren-9-ylmethyl (2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3-iodobenzyl)carbamate hydrochloride (XXXV, EXAMPLE 590, 300 mg, 0.43 mmole) and NMM (0.19 ml, 1.72 mmole). The reaction is stirred 3 hours then concentrated under reduced pressure. The residue is partitioned between ethyl acetate and saturated aqueous bicarbonate. The organic phases are washed with aqueous potassium bisulfate, saline, dried over sodium sulfate and finally concentrated under reduced pressure to give crude product. Purification via flash chromatography with ethyl acetate/hexane (50/50) then methanol/ethyl acetate (10/90) gives the title compound, M+H=838.