Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[CH3:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Phenol (28.5 g, 0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous N,N-dimethylformamide (DMF) (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce 2-phenoxypropionic acid ethyl ester, shown above, as a golden oil (48.5 g, 83%) 1H NMR (250 MHz, CDCl3): δ 7.31 (d, 2H, J=7.8), 7.02 (t, 1H, J=7.9), 6.93 (d, 2H, J=7.8), 4.79 (q, 1H, J=6.1), 4.26 (q, 2H, J=7.2), 1.66 (d, 3H, J=6.1), 1.24 (t, 3H, J=7.2). MS [EI+] 195 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:46]([N:42]1[CH2:43][CH2:44][C@@H:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCN(C(=O)c2ccccc2)C1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 40% yield. LCMS for C30H28ClN6O2 (M+H)+: m/z=539.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=S)[C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19]1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([N:18]3[CH2:19][CH:20]=[CH:21][CH2:22][CH2:23]3)[C:6]=2[CH:17]=1
Reactant: C1=CCNCC1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(N1CC=CCC1)=NC2
Reaction time: 72 h

Procedure:
A stirred mixture of 8-Chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (2.65 g., 0.01 mole) and 1,2,3,6-tetrahydropyridine (15 ml.) was refluxed for 32 hours with a slow stream of nitrogen passing through the mixture. It was then kept at ambient temperature for three days, mixed with water and extracted with methylene chloride; the aqueous layer was saturated with sodium chloride and re-extracted with methylene chloride. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from methylene chloride/ethyl acetate to give 3.41 g. of crude product. This material was chromatographed over silica gel (180 g.) with 5% methanol in methylene chloride. The first material eluted from the column was crystallized from a methylene chloride/ethyl acetate/Skellysolve® B mixture to give 0.37 g., melting point 224°-225.5° of the titled compound (Ib). The analytical sample was recrystallized from a methylene chloride/ethyl acetate and had melting point 224°-225°.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15]I.C(O)C.[S-:43][C:44]#[N:45].[K+]>C(O)(=O)C>[F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15][S:43][C:44]#[N:45]
Reactant: FC(F)(CC(CC(CC(CCI)C(F)(F)F)C(F)(F)F)C(F)(F)F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CSCCC(CC(CC(CC(F)(F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 94.4 %

Procedure:
According to scheme (27) above, in a flask that can be equipped with an agitator, thermocouple and a reflux condenser, 20 grams (27 mmol) of 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-iodotetradecane (see, e.g. Published Patent Applications), 20 ml of absolute ethanol, 3.9 grams (40.5 mmol) of potassium thiocyanate (KSCN) and 0.5 ml of glacial acetic acid (HOAc) can be placed to form a mixture. The mixture can be heated to reflux (84.7 C) and maintained stirring for overnight. The mixture can be concentrated in vacuo to afford what can be observed as a thick yellow slurry. The slurry can be extracted with 300 ml of diethyl ether and decanted twice and filtered to afford a wet cake and a filtrate. The wet cake can be washed with three 100 ml portions of diethyl ether and the filtrates combined. The combined filtrates can be concentrated in vacuo to afford 17.12 grams (94.6% yield) of the 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-thiocyanatotetradecane product that can be observed as a light yellow oil. The product structure can be confirmed by NMR and/or chromatographic analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][OH:31])([CH3:4])([CH3:3])[CH3:2].[CH3:33]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CO)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A 15 mL round bottomed flask was charged with 3-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.10 g, 0.23 mmol) and methyl iodide (0.21 mL, 2.3 mmol) in anhydrous DMF (1 mL) under a nitrogen atmosphere. The mixture was cooled in an ice bath and treated in one portion with NaH (0.018 g, 0.25 mmol, 60% oil dispersion). The reaction mixture was stirred for 2 h, concentrated, and diluted with EtOAc (40 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated. The crude product was purified using radial chromatography (EtOAc:hexanes 10:90 to 25:75) to give a yellow oil (0.060 g, 58%). MS (ES) m/e 648 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:25][O:26][CH2:27][O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=2)=[CH:31][C:30]=1[CH3:45].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH3:25][O:26][CH2:27][O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([NH:1][CH2:2][CH2:3][O:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=3)=[O:43])=[CH:38][CH:37]=2)=[CH:31][C:30]=1[CH3:45]
Reactant: CCOC(=O)C(Cc1ccc(OCCN)cc1)Oc1ccccc1
Reactant: COCOc1c(C)cc(-c2ccc(C(=O)O)cc2)cc1C
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3cc(C)c(OCOC)c(C)c3)cc2)cc1)Oc1ccccc1
Yield: 23 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-phenoxypropionate (2.07 g), which is the product of Reference example 4, 4′-methoxymethoxy-3′,5′-dimethylbiphenyl-4-carboxylic acid (1.50 g), which is the product of reference example 17(b), and carbonyldiimidazole (1.10 g) and the reaction mixture was treated to afford the desired compound (720 mg) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C1COCC1>[CH:2]1([NH:1][CH:16]2[CH2:15][CH2:14][C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1CCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NC2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
266 mg 1-aminoindane and 434 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry 1,2-dichloroethane (10 ml) and THF (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 200 mg N′-indan-1-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid (m.p. 99-101° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:37]=[CH:36][C:23]3[NH:24][C:25]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([O-])=[O:32])=[CH:29][CH:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:16][CH2:15]1>>[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:37]=[CH:36][C:23]3[NH:24][C:25]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([NH:11][C:10]5[CH:9]=[CH:8][C:7]([N:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)=[CH:13][CH:12]=5)=[O:32])=[CH:29][CH:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:16][CH2:15]1
Reactant: O=C([O-])c1ccc(-c2nc3cc(N4CCOCC4)ccc3[nH]2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(N4CCOCC4)ccc3[nH]2)cc1

Procedure:
Compound 457 was prepared from 4-morpholinoaniline and 4-(5-morpholino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C28H29N5O3: 484.23; found: 484.01.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9]C)[C:5]([NH2:6])=[CH:4][C:3]=1[Cl:11].B(Br)(Br)Br>C(Cl)Cl>[NH2:6][C:5]1[CH:4]=[C:3]([Cl:11])[C:2]([Br:1])=[CH:8][C:7]=1[OH:9]
Reactant: COc1cc(Br)c(Cl)cc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(Cl)c(Br)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
To a suspension of 4-bromo-3-chloro-6-methoxyaniline (52) (5 g, 21.1 mmol) in 50 ml DCM was added 1 M BBr3 in DCM (43 ml, 43 mmol) at 0° C. The reaction mixture was stirred at r.t. for 3 h, which turned to a light brown solution and back to a light brown suspension. After quenched with aq. sodium bicarbonate solution, the mixture was extracted with EA. The org. phase was washed with brine, dried over sodium sulfate, concentrated to dryness to give 4.746 g 53 as light brown solid. Yield: 100%, purity>95%.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1)#[N:2].[H][H].[ClH:21]>[Pd].C(O)(C)C>[ClH:21].[NH2:2][CH2:1][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: C=C(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(C(=O)OC(C)(C)C)c1ccc(CCN)cc1
Reaction time: 8 h

Procedure:
t-Butyl p-(cyanomethyl)-phenylacrylate (6.0 g) is combined with 600 mg 10% palladium on carbon in 80 ml isopropanol and 24 ml 1N HCl and treated with hydrogen at room temperature. After 8 hours at 3 atmospheres pressure, the catalyst is filtered off and the filtrate concentrated under vacuum. The residue is triturated with ether, filtered and dried under vacuum to afford t-butyl p-(2-aminoethyl)-phenylpropionate hydrochloride as a white solid. The hydrochloride salt is partitioned between ethyl acetate and 1N NaOH. The ethyl acetate extract is washed with a saturated NaCl solution and dried over MgSO4. Filtration and concentration of the filtrate affords t-butyl p-(2-aminoethyl)-phenylpropionate as a yellow oil; NMR (CDCl3): 7.1 (4H,s), 2.98 (2H,t), 2.89 (2H,t) 2.73 (2H,t), 2.5 (2H,t), 2.02 (2H,s), 1.42 (9H,s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[O-:10][Mn](=O)(=O)=O.[K+].[OH2:16]>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])=[O:16]
Reactant: O
Reactant: Cc1ccc(Cl)cc1F
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(Cl)cc1F

Procedure:
A mixture of 2-fluoro-4-chlorotoluene (25.05 g), KMnO4 (55.04 g) and water (400 ml) is heated to reflux for about 5 hr. The reaction is then worked up by filtering while hot through Celite and the filtrate is acidified with 2 N HCl. White crystals are filtered off, dissolved in ether and washed with water and brine, dried over sodium sulfate, filtered and evaporated to yield 2-fluoro-4-chlorobenzoic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].CN(C)C=O.[CH3:24][NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:30][CH2:31][CH:27]([CH2:26][NH:25][CH3:24])[CH2:28]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC)C3)cc21
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture of 1.00 g (3.95 mmole) 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml N,N-dimethylformamide, 75 ml acetonitrile, and 1.35 g (11.85 mmole) of N-methyl-3-pyrrolidinemethanamine were refluxed overnight. The reaction was cooled to room temperature and filtered The precipitate was washed with water, ethanol/ether (1:3), and finally with ether until dry to give 1.17 g of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylic acid, mp 247°-250° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[CH:14]12[O:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C1CCC2OC2C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1CCCCC1c1ccc(F)cc1
Temperature: -50 °C
Yield: 56.8 %

Procedure:
To a solution of 1-bromo-4-fluorobenzene (12.5 mL, 114 mmol) in diethylether (250 mL) at −78° C. was added BuLi (1.6 M, 68 mL, 109 mmol) under argon. After 5 min at this temperature, cyclohexenoxide (11.0 mL, 109 mmol) was added followed by the addition of borontrifluoride-diethyletherate (13.8 mL, 109 mmol) whereby the temperature increased to approx. −50° C. After 4 h at this temperature the reaction was quenched by the addition of ammonium chloride (saturated, 200 mL) and diluted with water (50 mL). The product was then extracted with diethylether (3×100 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the tide compound (11.9 g, 56%) as white crystals after trituration from hexane. MS: m/e=194.1 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][NH:14][C:15]2[N:23]=[C:22](Cl)[N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1.CCOC(C)=O>O>[ClH:1].[ClH:1].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:22]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:15]([NH:14][CH2:13][CH2:12][NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[N:23]=2)[CH2:33][CH2:32]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNS(=O)(=O)c3ccc(Cl)cc3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
The operation is carried out as in Stage 2 of Example 10 starting from 161 mg of the product obtained in Stage 1 above and 403 mg of trans-1,4-diaminocyclohexane and the reaction medium is heated to approximately 140° C. for approximately 3 hours 30 minutes left to return to 80° C., 5 ml of AcOEt then 5 ml of warm water are added, the reaction medium is left to return to ambient temperature, followed by extracting with 2×5 ml of ethyl acetate, washing with 5 ml of saturated sodium chloride, then drying. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 85/15/1.5, 5 ml of 1.4N hydrochloric acid/ethanol is added, the reaction medium is left to crystallize, followed by filtering, rinsing with 5 ml of ether and drying under vacuum. In this way 113 mg of expected product is obtained in the form of beige white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:7]3)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Temperature: 125 °C

Procedure:
60 g (228 mmole) 7-Chloro-2-cyclohexylmethyl-indan-1-one, 49 g (1.2 eq.) 4-tert-butyl-benzene boronic acid, 53 g sodium carbonate, 750 ml ethylene glycol and 150 ml water were placed in a 2 l-roundbottom flask equipped with a mechanical stirrer and a reflux condenser. The mixture was degassed three times by slight evacuation and recharging with argon. A premixed catalyst solution consisting of 103 mg (0.2 mole %) palladium acetate, 3 ml NaTPPTS (2.6 M in water, 0.8 mole %) and 2 ml of water was added and the mixture was refluxed at 125° C. until complete conversion (approx. 4 h). 300 ml of water were added and the mixture was extracted three times with 150 ml of toluene each. The combined organic layers were washed twice with 100 ml water and once with 100 ml of a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent in vacuo yielded 87.2 g (quant.) of the desired product as a yellow sticky oil. 1H-NMR (400 MHz, CDCl3): δ=7.54 (t, 1H, aromatic), 7.43, 7.38 (2×d, 4H, aromatic), 7.24 (m, 2H, aromatic), 3.30 (m, 1H, COCH), 2.80-2.67 (3×m, 2H, benzylic), 1.85-1.47 (m, 7H, aliphatic), 1.35 (s, 9H, C(CH3)3), 1.27-0.87 (m, 6H, aliphatic) ppm.
Reaction SMILES: [OH-:1].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[C:13](N1CCNCC1)=[O:14].[CH2:21]([OH:23])[CH3:22]>>[C:21]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][CH:4]([C:13]([OH:14])=[O:1])[O:3][C:8]=2[CH:9]=1)(=[O:23])[CH3:22]
Reactant: [OH-]
Reactant: CCO
Reactant: O=C(C1COc2ccccc2O1)N1CCNCC1
Agent: [Na+]
Product: CC(=O)c1ccc2c(c1)OC(C(=O)O)CO2

Procedure:
Aqueous sodium hydroxide solution (1.2 g., in 5 ml. water) was added to a stirred solution of the product (7 g.) from (A) in ethanol (25 ml.) at 15° C. The reaction temperature was maintained below 25° C. for 1/2 hour then the mixture evaporated in vacuo, the residue triturated with water, acidified with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were dried (MgSO4), evaporated in vacuo and the residue (1.46 g.) recrystallized from ethyl acetate/methanol to give 7-acetyl-1,4-benzodioxan-2-carboxylic acid, m.p. 167°-168° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[N:7]([CH3:14])[C:8]3[C:13]([C:5]2([CH3:15])[CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.F[B-](F)(F)F.[O:21]=[N+:22]=[O:23].C([O-])(O)=O.[Na+].C(Cl)Cl>C(#N)C>[N+:22]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]1[N:2]([CH3:1])[CH2:3][CH2:4][C:5]21[CH3:15])([O-:23])=[O:21]
Reactant: CN1CCC2(C)c3ccccc3N(C)C12
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a stirred solution of 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (25.0 g) in acetonitrile (500 ml) at 0° C. was added nitronium tetrafluoroborate (18.65 g) dissolved in acetonitrile (500 ml) in a dropwise manner over a period of 0.5 hour. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature for an additional hour. Ice and a dilute NaHCO3 solution were added followed by methylene chloride (800 ml). The layers were separated and the aqueous layer was extracted with methylene chloride (2×200 ml). The organic layers were combined, dried (Na2SO4), and concentrated to give an oil which was chromatographed twice on silica gel, first eluting with 2.5% methanol/ethyl acetate and then with 2% methanol/methylene chloride to give 1,2,3,3a,8,8a-hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (7.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-hydroxyproline methyl ester (30.2 g, 123 mmol) in methylene chloride (300 ml) were dropwise added successively triethylamine (41.2 ml, 0.295 mmol) and methanesulfonyl chloride (17.1 ml, 0.221 mol) at 0° C. in a nitrogen atmosphere. The mixture was stirred at 0° C. for 2 h, and saturated aqueous sodium hydrogencarbonate was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was subjected to silica gel flash column chromatography (heptane-ethyl acetate=5:5) to give (2S,4R)-N-tert-butoxycarbonyl-4-methanesulfonyloxyproline methyl ester (39.5 g, yield: 99.1%).