Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([N+:17](CCCC)(CCCC)CCCC)CCC.[C-]#N.[Na+]>O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:13]#[N:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(CC#N)cc1

Procedure:
A mixture consisting of 107 g p-tert.butylbenzyl bromide, 2 g tetra butyl-ammonium jodide and 37 g NaCN in 50 ml water was heated during 1 hour at 100° C. After cooling the reaction mixture, the organic layer was separated and distilled in vacuo with a yield of 78 g of the desired cyanide. Then this product was fractionated in vacuo. Yield of p-tert.butylbenzyl cyanide: 65 g (80%): boiling point: 118° C./0,7 kPa: nD =1,5110. This cyanide has a very strong odor which reminds one of algae, seaweed and ozone with ambergris-like, fatty and animal notes.
Reaction SMILES: [BH4-].[CH2:2]([C:9]1[N:10]([CH3:15])[C:11]([SH:14])=[N:12][N:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][O:17][C:18](=[O:43])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:22][CH:21]=1>O1CCCC1.C(O)C>[CH3:16][O:17][C:18](=[O:43])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:14][C:11]3[N:10]([CH3:15])[C:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:13][N:12]=3)=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:24][CH:25]=1
Reactant: CCCCCCCc1nnc(S)n1C
Reactant: CCCCCCCOc1cc(I)ccc1COc1ccc(CC(=O)OC)cc1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCOc1cc(Sc2nnc(CCCCCCC)n2C)ccc1COc1ccc(CC(=O)OC)cc1
Reaction time: 8 h

Procedure:
979 mg (2.45 mmol, 3 eq) of resin-supported borohydride and 11 mg (0.02 mmol, 0.03 eq) of bis(bipyridine)dibromonickel (II) are added to a solution of 244 mg (1.22 mmol, 1.5 eq) of 5-heptyl-4-methyl-4H-[1,2,4]-triazole-3-thiol in 4 ml of tetrahydrofuran/ethanol 5/5. To the suspension obtained there is added a solution of 405 mg (0.82 mmol, 1 eq) of [4-(2-heptyloxy-4-iodobenzyloxy)phenyl]acetic acid methyl ester in 4 ml of tetrahydrofuran/ethanol 5/5. The reaction mixture is stirred overnight under reflux. After returning to room temperature, the reaction medium is filtered and then concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate: gradient from 70/30 to 50/50). After concentration, 427 mg (92%) of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH2:27][CH3:28]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCCC(F)(F)F)nc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (Step-1, single enantiomer) and propionyl chloride according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=1>C1COCC1>[CH:1]1([CH2:4][O:5][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[N:10]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a solution of cyclopropylmethanol (3.87 g, 47.7 mmol) in THF (50 mL) was added sodium hydride (oil, 60%, 2.08 g, 52.1 mmol), and the mixture was stirred at room temperature for 20 min. To this solution was added 2,6-difluoropyridine (5.00 g, 43.4 mmol) and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1 to 4:1) to give the title compound (5.69 g, yield 78%) as an oil.
Reaction SMILES: [C-:1]#[N:2].[K+].S(O[CH2:9][CH2:10][CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=O)(=O)C>CS(C)=O>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][CH:13]=[C:12]2[CH2:11][CH2:10][CH2:9][C:1]#[N:2])=[CH:17][CH:18]=1
Reactant: COc1ccc2cccc(CCCOS(C)(=O)=O)c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2cccc(CCCC#N)c2c1

Procedure:
In a 100-cm3 flask, the 3-(7-methoxy-1-naphthyl)propyl mesylate obtained in stage D is dissolved in DMSO. KCN is added and the mixture is brought to reflux for 2 h. It is allowed to cool. It is poured into a water/ice mixture. The resulting mixture is extracted with ether. The organic phase is washed with water, dried over CaCl2 and evaporated. The product obtained is recrystallized.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[N:4][CH:3]=1.Cl.Cl[CH2:17][C:18]1[C:19]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[N:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:14][O:13][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[C:7]([C:2]([O:1][CH2:17][C:18]2[C:19]([C:24]3[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=3)=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:3][N:4]=1)[CH:8]=[O:9]
Reactant: COCCOc1cc(C=O)c(O)cn1
Reactant: Cn1nccc1-c1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)c(OCc2cccnc2-c2ccnn2C)cn1
Temperature: 60 °C
Yield: 25.4 %

Procedure:
A mixture of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (125 mg, 0.63 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride salt (120 mg, 0.63 mmol, 1 eq.), and Cs2CO3 (410 mg, 1.26 mmol, 2 eq.) in DMF (3.0 mL) was heated at 60° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (59 mg, 25%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.59 (dd, J=4.7, 1.6 Hz, 1H), 7.87 (dd, J=7.9, 1.3 Hz, 1H), 7.73 (s, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.27 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (s, 1H), 6.25 (d, J=1.9 Hz, 1H), 5.02 (s, 2H), 4.26 (dd, J=5.4, 3.9 Hz, 2H), 3.80 (s, 3H), 3.57 (dd, J=5.4, 3.9 Hz, 2H), 3.28 (s, 3H). LRMS (M+H+) m/z 387.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: CCOC(=O)CCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazole-2-one was treated with ethyl 3-bromo-propionate and potassinm carbonate in butanone to give after work-up the title compound. m.p. 111°-112 ° C. Found: C. 76.0;H, 5.9;N, 6.7%;C26H24N2O3 requires:C, 75.7;H, 5.9;N, 6.8%
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>N1C=CC=CC=1>[C:1]1([S:7]([NH:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
8.1 g of phenylsulphonyl chloride were added at 0° C. to a solution of 10 g of (1b) in 100 ml of pyridine. After a reaction time of 15 min, 6.3 ml of triethylamine were added and the mixture was stirred at room temperature. After 5 h, it was concentrated, treated with 1 N HCl, extracted with dichloromethane, dried over MgSO4 and concentrated. Chromatographic purification (dichloromethane/methanol=5:1) yielded 11.4 g of a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[C:3]1=[N:10][O:11][C:12](=[O:15])[NH:13][CH3:14].C(OO)(=[O:19])C>C(OC(=O)C)C>[CH3:1][C:2]1([CH3:16])[S:6](=[O:19])[C:5]2=[N:7][CH:8]=[CH:9][N:4]2[C:3]1=[N:10][O:11][C:12](=[O:15])[NH:13][CH3:14]
Reactant: CC(=O)OO
Reactant: CNC(=O)ON=C1n2ccnc2SC1(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)ON=C1n2ccnc2S(=O)C1(C)C
Reaction time: 24 h
Yield: 70 %

Procedure:
A 2.0 g (8.32 mmol) quantity of 2,2-dimethyl-3-[O-(methyl carbamoyl)oximino]-2,3-dihydroimidazo[2,1-b]thiazole was dissolved in 300 ml of ethylacetate. The solution was cooled to -15° before 1.33 g (17.5 mmol) of peracetic acid was added. The reaction mixture was allowed to warm to 25° and stirred for 1 d, followed by concentration to ca. 100 ml and placing in the freezer overnight. The precipitate was collected to give 1.5 g (70%) of product. m.p. 147.5°-149°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18](=[O:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:33]([O:35][CH:36]1[CH:41]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:39][CH:38]([CH3:45])[CH2:37]1)=[O:34]>C1COCC1>[CH:38]1([CH3:45])[CH2:39][CH2:40][CH:41]([CH:42]([CH3:44])[CH3:43])[CH:36]([O:35][C:33]([CH:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:21])[C:18]2=[O:19])=[O:34])[CH2:37]1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: O=C1Cc2ccccc2C(=O)N1Cc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a cold (-78° C.) solution of 2-[(4-bromo-2-fluorophenyl)methyl]-1,3(2H, 3H)-isoquinolinedione (9.0 g, 25.86 mmol) in anhydrous THF (120 mL) was added lithium bis(trimethylsilyl)amide (1.0M solution in THF, 56.91 mL, 56.91 mmol), dropwise over a 10 minute period. After stirring for 3 hours, (-)menthyl chloroformate (8.48 mL, 38.79 mmol) was added and the reaction was allowed to warm up to room temperature. The mixture during that period turned a dark color. It was stirred an additional 30 minutes and quenched with H2O. The dark solution was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid-washed silica gel (5% H3PO4 in MeOH) gave a clear oil (10.2 g).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][OH:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][O:37][CH2:3][CH:2]=[CH2:1])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h
Yield: 86.4 %

Procedure:
Allyl bromide (2.91 g.) was added dropwise to a stirred suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.), N,N-dimethylformamide (100 ml.) and potassium carbonate (4.54 g.) under ice cooling over 5 minutes, and stirred at the same temperature for 4 hours. After adding water (200 ml.) to the resultant solution, the solution was extracted with diethyl ether twice. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with a solution of n-hexane and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 9.4 g.), mp. 130° to 132° C.
Reaction SMILES: P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:20]Br.[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35]O)=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][Br:20])=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)C(C)(C)C(Cc1ccc(CCO)cc1)O[SiH](C)C
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)C(C)(C)C(Cc1ccc(CCBr)cc1)O[SiH](C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a stirred solution of (C6H5)3P (9.03 g, 34.4 mmol) in 220 ml of toluene at 0° C. was added bromine (1.76 ml, 34.4 mmol) over 10 minutes. To this stirred slurry was then added a solution of p-(2-thexyldimethylsilyloxyethyl)phenethyl alcohol (10.6 g, 34.4 mmol) and pyridine (2.78 ml, 34.4 mmol) in 50 ml of toluene over 10 minutes. This mixture was stirred at room temperature for 4 hours and diluted with 300 ml of saturated NaHCO3 solution. The resulting mixture was extracted with ether (4×300 ml). The combined ether extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated in 200 ml of hexane-ether 4:1 and filtered. The filtrate was concentrated and distilled under vacuum to give 9.9 g of p-(2-thexyldimethylsilyloxyethyl)phenethyl bromide (78%) as an oil.
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[Br:12][C:13]1[C:14](=O)[CH2:15][CH2:16][C:17]2([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]=1[C:24]1[C:19](=[CH:20][C:21]([OH:26])=[CH:22][CH:23]=1)[CH2:18]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:12][C:13]1[C:14](=[CH2:2])[CH2:15][CH2:16][C:17]2([CH2:27][CH2:28][CH2:29][CH3:30])[C:25]=1[C:24]1[C:19](=[CH:20][C:21]([OH:26])=[CH:22][CH:23]=1)[CH2:18]2
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(O)cc1C2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CCC2(CCCC)Cc3cc(O)ccc3C2=C1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (373 mg, 1.04 mmol) in anhydrous tetrahydrofuran (2 mL) was cooled in an ice bath and stirred under a nitrogen atmosphere while 2.5 N nBuLi in hexane (0.36 mL, 0.90 mmol) was added by syringe. The mixture was stirred at 0° C. for 10 minutes to complete formation of the methylenetriphenylphosporane reagent. A solution of 4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-fluoren-3-one (50 mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added to the reaction mixture and the ice bath was removed. The resulting mixture was stirred at room temperature for 3.2 hours, then at 50° C. for 1.5 hour, and finally at room temperature for an additional 17 hours. The mixture was partitioned between saturated aqueous NH4Cl (5 mL) and EtOAc (9 mL). The organic phase was acidified with 2N HCl (0.2 mL), washed with brine (4 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (90. mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate using 3:1 hexanes-EtOAc as developing solvent. The UV visible band at Rf 0.50-0.63 was eluted with EtOAc. The eluant was concentrated under vacuum to a residue which was lyophilized from benzene to afford 4-bromo-9a-butyl-3-methylene-2,3,9,9a-tetrahydro-1H-fluoren-7-ol.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.Cl>C(#N)C>[CH2:5]([O:4][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[O:3])[CH3:6]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 3.5 g of ethyl chloroformate in 10 ml of anhydrous acetonitrile is dropwise added to a solution of 5.5 g of 2-aminobenzenesulfonamide and 2.5 g of pyridine in 80 ml of anhydrous acetonitrile at room temperature during 2 hours. After stirring at room temperature, the mixture is poured into ice water and acidified with 100 ml of 2N-hydrochloric acid solution. The mixture is extracted with ethyl acetate twice, washed with an aqueous saturated sodium hydrogen carbonate and then with a saturated brine, and dried over anhydrous sodium sulfate. Then the mixture is concentrated under reduced pressure. The residue is crystallized from chloroform to give 6.6 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([C:8]3=O)[CH2:6]1)[CH2:12]2)=[O:4].[NH3:16].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH2:16])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Reaction time: 18 h

Procedure:
5 g of 4-oxoadamantane-1-carboxylic acid methyl ester are placed in 26 ml of methanol under nitrogen. 86 ml of a 7N solution of ammonia in methanol are added. The reaction medium is stirred for 18 h, 4 g of sodium borohydride are then added at 0° C. and the reaction medium is stirred for a further 3 h. After concentrating to dryness under reduced pressure and adding water and ethyl acetate, the aqueous phase is extracted three times in ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of heptane/acetone/methanol/NH4OH solvent from 1/0/0 to 4/5/1/0.1. 1.5 g of 4-aminoadamantane-1-carboxylic acid methyl ester are obtained in the form of a mixture of cis/trans (1/3) isomers.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1.[Cl-].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH:12]([N:10]1[CH:11]=[C:7]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:8]=[N:9]1)([CH3:14])[CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)n1cc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
n-Butyllithium (2.5M in hexanes, 1.38 mL, 3.45 mmol) was added over 15 min to a solution of 4-bromo-1-isopropyl-1H-pyrazole (500 mg, 2.65 mmol) in diethyl ether (10 mL) at −78° C. After 30 min, a solution of tri-n-butylstannane chloride (920 μL, 3.45 mmol) in diethyl ether (1 mL) was added and the resultant reaction mixture was left to stir at −78° C. for 1 h, then allowed to warm to ambient temperature. The reaction mixture was diluted with diethyl ether (40 mL) and washed with water (20 mL), then brine (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford the title product as a colourless oil (98 mg, 94%) which was used without further purification. 1H NMR (CDCl3, 400 MHz): 7.46-7.42 (m, 1H); 7.28 (t, J=4.2 Hz, 1H); 4.59-4.43 (m, 1H); 1.58-1.42 (m, 12H); 1.39-1.24 (m, 6H); 1.02-0.77 (m, 15H).
Reaction SMILES: Cl.Cl.Cl.[N+:4]([C:7]1[CH:48]=[CH:47][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH2:45])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].CCN(CC)CC.[C:56](Cl)(=[O:58])[CH3:57]>C(Cl)Cl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][C@H:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([N:23]4[C:43]5[C:38](=[C:39]([CH2:44][NH:45][C:56](=[O:58])[CH3:57])[CH:40]=[CH:41][CH:42]=5)[C:25]5([CH2:30][CH2:29][N:28]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH2:27][CH2:26]5)[CH2:24]4)[C:17]=3[C@H:16]([CH3:46])[CH2:15]2)=[O:12])=[CH:47][CH:48]=1)([O-:6])=[O:5]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)C[C@H]2OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
To a stirred solution of (5R,7R)-4-(4-(aminomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate trihydrochloride (30 mg, 0.042 mmol) and Et3N (0.034 mL, 0.19 mmol) in DCM (1 mL) was added acetyl chloride (0.0033 mL, 0.046 mmol) at about 0° C. under N2. The reaction was stirred at about 0° C. for about 30 minutes and diluted with DCM. The reaction mixture was washed with saturate aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (2% MeOH/DCM) to give (5R,7R)-4-(4-(acetamidomethyl)-1′-benzylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (28 mg, 68%) as an oil. LCMS (APCI+) m/z 647 [M+H]+; Rt=3.21 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:24])[CH2:19][C:20]([O:22]C)=[O:21])=[N:16][CH:17]=2)=[O:10])=[CH:4][C:3]=1[OH:25].[C:26]1([N:32]=[C:33]=S)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[C:26]1([NH:32][C:33]2[O:25][C:3]3[CH:4]=[C:5]([CH2:8][C:9]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([CH:18]([CH3:24])[CH2:19][C:20]([OH:22])=[O:21])=[N:16][CH:17]=4)=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc(N)c(O)c2)cn1
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Product: CC(CC(=O)O)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4)oc3c2)cn1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A solution of (RS) methyl 3-{5-[2-(4-amino-3-hydroxy-phenyl)-acetylamino]-pyridin-2-yl}-butyrate (41.2 mg, Reference Example 24) in ethanol (1 mL) was treated with a solution of phenyl isothiocyanate (16.23 mg) in ethanol (2 mL). The mixture allowed to stand at room temperature for 48 hours, then heated at 70° C. for 16 hours and then evaporated. The residue, (RS) methyl 3-{5-[2-(3-hydroxy-4-(3-phenylthioureido)-phenyl)-acetylamino]-pyridin-2-yl}-butyrate, was dissolved in dry dimethylformamide (1 mL) and the solution was treated with a solution of dicyclohexylcarbodiimide (74.2 mg) in dry dimethylformamide (2 mL). This mixture was heated at 70° C. for 12 hours and then evaporated. The residue was dissolved in methanol (2 mL) and the solution was treated with aqueous sodium hydroxide (600 μL, 1M). After shaking for 24 hours the mixture was filtered and the filtrate was acidified with aqueous acetic acid (1 mL, 1M). The precipitate was filtered and dissolved in dimethylformamide. This solution was evaporated and the residue was subjected to reversed phase HPLC on a Hypersil Elite C18 column (100 mm×21 mm) using 0.05% TFA in acetonitrile water to give the title compound. LC-MS: RT=2.36 minutes; MS (ES+): 431 (MH+).