Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].CN(C)[CH:17]=[O:18].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[CH:17]=[O:18])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 12.96 g (60 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-3-sulfonamide in 300 mL THF under a nitrogen atmosphere cooled to -78° C. was added dropwise, at such a rate as to keep the temperature below -65° C., 52.35 mL (123 mmol) 2.35M n-butylithium in hexanes. The reaction was stirred at -78° C. for ca. 30 minutes. To the reaction mixture was added 4.64 mL (60 mmol) of N,N-dimethylformamide dropwise. The reaction mixture was allowed to warm to room temperature and stir for ca. 2 hours. The reaction mixture was cooled to 0° C. and acidified with 1N HCl. The THF phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on silica (25% ethyl acetate/80% hexanes) affording 5.72 g of the title compound as a white solid, m.p. 101.5°-103° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CCOC(C)=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a suspension of [4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenyl]-methanol (WO 2011/070368, which is incorporated herein by reference in its entirety; 3.05 g, 12.4 mmol) in aq. NaOH solution (1 M, 31 mL, 31 mmol) and EtOAc (30 mL) at RT was added 2,2,2-trichloroethyl chloroformate (1.88 mL, 13.7 mmol) over 3 min (CARE: exotherm to ˜35° C.) and the mixture stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (20 mL), then the combined organics washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a pale orange solid. Recrystallisation from hot cyclohexane-EtOAc (3:1, 30 mL) and drying in vacuo gave the title compound as a flocculent off-white solid (3.87 g, 74%). LCMS (Method 3): Rt 4.00 min, m/z 420, 422 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O>ClCCl>[NH2:20][C@H:18]([C:7]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:11])[C:10]2=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]2[N:6]=1)[CH3:19]
Reactant: Cc1ccn2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(S)-tert-Butyl (1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (950 mg, 2.58 mmol) was dissolved in 5 mL dichloromethane and trifluoroacetic acid (993 μl, 12.89 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and was partitioned between ethyl acetate and potassium bicarbonate. The organic layer was washed with water, brine and dried over sodium sulphate, filtered and concentrated under reduced pressure to give 0.55 g (78% yield) of the title compound that was used in the next step without any further purification. Purity 97%.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][OH:22])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]=[O:22])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(CO)cc2C)c(OC)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 73.1 %

Procedure:
In 50 ml of dichloromethane was dissolved 1.5 g (3.79 mmol) of [4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-2,5-dimethylphenyl]methanol, and 6.6 g of active manganese dioxide was added thereto. The mixture was stirred at room temperature for 21 hours. After the reaction mixture was filtrated and concentrated, the residue was dissolved in 50 ml of ether. 60 mg of iodine pieces were added thereto, and the reaction mixture was stirred. The reaction mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. After ether was evaporated off, the residue was purified by silica gel column chromatography to give 1.09 g of a reddish orange crystal (yield: 72.4%).
Reaction SMILES: C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:6].[P:21]([O:33][CH2:34][C@H:35]1[O:39][C@@H:38]([N:40]2[C:49]3[N:48]=[CH:47][N:46]=[C:44]([NH2:45])[C:43]=3[N:42]=[CH:41]2)[C@H:37]([OH:50])[C@@H:36]1[OH:51])([O:24]P(OP(O)(O)=O)(O)=O)(=[O:23])[OH:22].[Mg+2].[Cl-].[Cl-].C1S/C(=C2/N=C3C(S/2)=CC(=O)C=C3)/N[C@H]1C(O)=O.C(S)[C@@H](O)[C@H](O)CS>CC(O)=O.C(O)C(N)(CO)CO>[CH:41]1[N:40]([C@@H:38]2[O:39][C@H:35]([CH2:34][O:33][P:21]([OH:24])([OH:22])=[O:23])[C@@H:36]([OH:51])[C@H:37]2[OH:50])[C:49]2[NH:48][C:47]([NH2:46])=[N:45][C:44](=[O:6])[C:43]=2[N:42]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: NC(CO)(CO)CO
Agent: O=C1C=Cc2n/c(=C3\N[C@@H](C(=O)O)CS3)sc2=C1
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CC(=O)O
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]3O)c2[nH]1
Reaction time: 1 h

Procedure:
100 μl of reaction mixture should contain 50 mM TEA buffer (pH 7.4), 3 mM MgCl2, 3 mM GSH, 0.1 mM GTP, 1 mM IBMX (isobutylmethylxanthine), 0.2 mM NAD+, 0.4 mU of NAT, suitably diluted sGC enzyme solution (isolated from bovine lung as described by P. Humbert et al., Methods of Enzymology 195, 384-391 (1991)) and the test substance or solvent (for determining the basal enzyme activity). The reaction is started by adding the sGC. The reaction mixture is incubated at room temperature for 60 min and then stopped by cooling in ice and adding 50 mM EDTA, pH 8.0. For the ATP determination, 20 μl of 100 mM MgCl2 and 50 μl of ATP assay reagent (0.035 mM luciferin and 10,000 U/mL luciferase in 62.5 mM TRIS acetate pH 7.75, 1.9 mM EDTA, 0.05 mM DTT, 0.1% BSA) are added. The relative luminescence units (RLU) can be measured in a microtiter plate luminometer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Br:16]C1C=C(C=CC=1F)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([Br:16])[CH:7]=1)[Cl:13]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(F)c(Br)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3-bromo-4-fluorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1.[CH3:16][C:17]1([CH3:30])[CH2:22][CH:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][C:19]([CH3:29])([CH3:28])[NH:18]1.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:24]([N:23]([C:2]1[N:7]=[C:6]([N:23]([CH:21]2[CH2:22][C:17]([CH3:30])([CH3:16])[NH:18][C:19]([CH3:28])([CH3:29])[CH2:20]2)[CH2:24][CH2:25][CH2:26][CH3:27])[N:5]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1)[CH:21]1[CH2:20][C:19]([CH3:29])([CH3:28])[NH:18][C:17]([CH3:30])([CH3:16])[CH2:22]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CCOC(=O)CNc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCN(c1nc(NCC(=O)OCC)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Yield: 96.3 %

Procedure:
2.36 g of ethyl N-(2,4-dichloro-1,3,5-triazin-6-yl)glycinate [obtained as described in Preparation 4(A)], 4.19 g of 2,2,6,6-tetramethyl-4-(butylamino)piperidine [obtained as described in Preparation i(A)] and 2.77 g of sodium bicarbonate were heated under reflux in 20 ml of xylene for 29 hours. At the end of this time, the xylene was removed by distillation under reduced pressure, and a mixture of methylene chloride and water was added to the resulting residue, after which the mixture was shaken. The methylene chloride layer was separated, dried and concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using a 20:10:1:1 by volume mixture of hexane, diethyl ether, ethanol and triethylamine as eluent), to yield 5.46 g of the title compound melting at 40° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][N:3]1[CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17].Cl.[NH2:22][C@@H:23]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:24]([OH:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:39]([C@H:23]([NH:22][C:11]([C:6]1[C:5]2[CH2:4][N:3]([CH:14]([CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH3:20])[C:2](=[O:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13])[C@H:24]([OH:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCC(CCC)N1Cc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCC(CCC)N1Cc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2C1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
136.4 mg of 1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylic acid are dissolved in 8 cm3 of dichloromethane under an inert atmosphere at a temperature close to 20° C. 195 mg of ((2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol hydrochloride (2:1), 9.6 mg of hydroxybenzotriazole, and 108.7 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the solution. 0.308 cm3 of N,N-diisopropylethylamine is poured into the reaction medium. This is kept stirring for 20 h at 20° C. 10 cm3 of water are added to the reaction medium. The organic phase is washed with 10 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 310 mg of beige gum obtained are purified by flash chromatography over silica (column: 15 g; particle size: 20-40 μm, spherical; flow rate: 20 cm3/min; eluent: 95% dichloromethane/5% methanol). After concentrating the fractions under reduced pressure, 110 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxamide are obtained in the form of a beige foam.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[C:21]#[CH:22])[CH2:8][CH2:7]1.[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:27]([N:34]1[C@@H:39]2[C@H:40]([S:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH2:41][C@@:35]1([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:36](=[O:51])[CH2:37][CH2:38]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:34]1[C@@H:39]2[C@H:40]([S:42]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)(=[O:43])=[O:44])[CH2:41][C@@:35]1([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C@:36]([C:22]#[C:21][C:11]1[CH:12]=[C:13]([O:16][C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:15][C:10]=1[O:9][CH:6]1[CH2:7][CH2:8]1)([OH:51])[CH2:37][CH2:38]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Reactant: C#Cc1cc(OC(F)(F)F)ccc1OC1CC1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)C#Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A solution of n-butyl lithium in hexanes (1.6M, 5 ml, 8 mmol) was added dropwise to a stirred solution of 2-cyclopropyloxy-5-trifluoromethoxyphenylethyne (Description 4; 2.0 g, 8.2 mmol) in tetrahydrofuran (30 ml) at −78° C. to form an orange solution that turned violet at the end of addition. The mixture was stirred for 10 minutes and solid anhydrous cerium(III) chloride (2 g, 8.1 mmol) was added. The mixture was stirred for 30 minutes at −78° C. and a solution of (1R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-one (Description 7; 2.9 g, 6.7 mmol) in tetrahydrofuran (25 ml) was added dropwise. The reaction mixture was warmed to 0° C. over 30 minutes, stirred at 0° C. for 15 minutes, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (2.4 g, 53%) which was recrystallised from ethyl acetate:iso-hexane.
Reaction SMILES: [N:1]([C:4]1(C=CC=CC1)C=C)=[N+]=[N-].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[NH:1][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: C=CC1(N=[N+]=[N-])C=CC=CC1
Product: C1=C(c2ccccc2)N1

Procedure:
200 ml of toluene was added to the 1-azidostyrene, the mixture was heated under reflux for 1 hour, and the toluene was distilled off under reduced pressure, to obtain 11.2 g of 2-phenylazirin (C) 13.5 g of Compound (A) and 3.6 g of Compound (C) were dissolved in 50 ml of acetone, and then 0.05 g of nickel acetylacetonate was added followed by stirring for 3 hours at room temperature. After distilling the acetone off from the reaction liquid, the residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate =3/1), to obtain 12.5 g of Exemplified Coupler (60).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:18]=1)[C:9](=[O:17])O[C:11]3=[O:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]>>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:18]=1)[C:9](=[O:17])[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]3=[O:16])([O-:3])=[O:2]
Reactant: NCCCCCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Product: O=C(O)CCCCCN1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O

Procedure:
2.45 g (0.01 mmol) of 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione and 1.23 g (0.01 mmol) of 6-aminohexanoic acid was alloyed with at 210-220° C. for 35 min. The obtained crude 6-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl)hexanoic acid was recrystallized from ethanol. Yield 1.7 g (48%). The product was dissolved in 50 mL of ethanol and was added dropwise to the hot solution of 8 g of tin chloride in 9 mL of hydrochloric acid at boiling. The reaction mixture was boiled for 4 h, then poured with water and neutralized with 5% solution of sodium hydrate. Yellow sediment was filtered and purified by a column chromatography (Silica gel, chloroform). Yield 1.1 g of ethyl 6-(5-amino-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl)hexanoate (31.5% counting on 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione). M.P. 108-110° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:33])[CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C(Cl)Cl.C(Cl)CCl>[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[C@@H:29]([CH3:33])[CH2:28]1)=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
1-(tert-Butoxycarbonyl)-piperidine4-carboxylic acid (0.53 g), (S)-1-benzyloxycarbonyl-3-methylpiperazine (D19)(0.5 g), HOBt (0.29 g) and diethylaminomethyl polystyrene (1.78 g) were stirred in DCM (30 ml), then EDC (0.53 g) was added and the reaction was stirred at rt ovemight. The mixture was filtered and washed with saturated sodium hydrogen carbonate solution (3×50 ml) and brine (30 ml). The organic layer was dried (MgSO4) and evaporated to give a crude yellow oil which was purified by chromatography [silica gel; 0-100% ethyl acetate/hexane) to give the tide compound (D20) as a clear oil which crystallised on standing (0.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:34][O:35][C:36]1(OC)[CH:43]2[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:45][CH:37]1[CH2:38]3)[CH2:42]2.C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:36]3([O:35][CH3:34])[CH:43]4[CH2:44][CH:39]5[CH2:40][CH:41]([CH2:45][CH:37]3[CH2:38]5)[CH2:42]4)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1(OC)C2CC3CC(C2)CC1C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)C2CC3CC(C2)CC1C3
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
A solution of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(2-hydroxyethyl)-1-methyl-1H-imidazole (22) (345 mg, 1 mmol) prepared in accordance with the method as described in WO 96/10019 and p-toluenesulfonic acid mono hydrate (200 mg) in a mixture of tetrahydrofuran (5 mL) - toluene (50 mL) was concentrated under reduced pressure. The residue was dried with a vacuum pump on an oil bath at 50° C. for 40 minutes. The residue was dissolved in toluene (10 mL), and cooled on an ice-bath under nitrogen atmosphere. Then a solution of 2,2-dimethoxyadamantane (1.93 g, 10 mmol) in toluene (1 mL) was added thereto. After stirring at the same temperature for 30 minutes, the reaction mixture was further stirred at room temperature for 4 hours without ice-bath. Triethylamine (0.17 mL, 1.25 mmol) was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. Hexane was added to the residue and filtered off the insoluble matter. The hexane-soluble matter was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (2:1)) to give the compound 23 (227 mg, 44%). Mp 74.5-76° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O>CO>[CH3:12][O:13][CH:14]1[C:15]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC1CCCCC1=O
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC1CCCC=C1c1c[nH]c2ccccc12
Yield: 29.9 %

Procedure:
Add 5 ml dry MeOH to a flask under N2 containing indole (1 g, 8.5 mmol, 8.5 eq) and potassium hydroxide (202 mg, 3.59 mmol, 1 eq). Add to this solution 2-Methoxy-cyclohexanone (834 mg, 6.5 mmol, 6.5 eq). Heat reaction to 63° C. for 18 hours. Cool reaction and purify crude material by silica gel chromatography to give 442 mg (30% yield) of 3-(6-Methoxy-cyclohex-1-enyl)-1H-indole as a waxy yellow solid. Mass Spectrum (m/e): 228.02 (MH+).
Reaction SMILES: C([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1([CH3:14])[CH3:13])C.I[CH2:16][CH2:17][CH3:18]>>[CH3:14][C:4]1([CH3:13])[CH2:3][CH:12]([CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: CCC1Cc2ccccc2NC1(C)C
Reactant: CCCI
Product: CCCC1CC(C)(C)Nc2ccccc21

Procedure:
This compound was prepared in a manner similar to that described for (R/S)-3-ethyl-1,2,3,4,-tetrahydro-2,2-dimethylquinoline (EXAMPLE 348) but using iodopropane in place of iodoethane. (R/S)-1,2,3,4,-Tetrahydro-2,2-dimethyl-4-propylquinoline was obtained in 16% overall yield as a colorless oil. Data for (R/S)-1,2,3,4,-tetrahydro-2,2-dimethyl-4-propylquinoline: 1H NMR (400 MHz, CDCl3) 6.98 (d, J=7.4, 1H), 6.96 (t, J=7.4, 1H), 6.61 (t, J=7.4, 1H), 6.45 (d, J=7.4, 1H), 3.60 (brs, 1H), 2.87 (dd, J=16.6, 5.2, 1H), 2.42 (dd, J=16.6, 10.7, 1H), 1.66-1.49 (m, 3H), 1.40-1.25 (m, 2H), 1.21 (s, 3H), 1.05 (s, 3H), 0.92 (t, J=7.1, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Temperature: 20 °C
Reaction time: 3.75 h

Procedure:
Preparation of (3R,3aR,6S,6aS)-Benzyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (34). Ethanol (6 mL) was added dropwise to a mixture of 10% palladium on charcoal (50 mg) and anti-(33) (547 mg, 1.26 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred at 20° C. for 3.75 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (40 mL) then the solvents removed in vacuo from the filtrate to obtain (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH3:26])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([C:17]1[C:18]([CH3:26])=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:16]=1[O:15][CH3:14])=[O:9]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COc1ccc(Br)c(C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2C)c(OC)c1OC

Procedure:
63B (240 g, 1.0 mol) is reacted with 3,4,5-trimethoxytoluene (182 g; 1.0 mol) in the presence of P2O5 (1.0 kg) and dichloromethane as described in Example 6 yielding white crystals, 220 g (54% ), mp 89-91° C.