Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:10](=[Se:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(N)cc1
Reactant: OC(=[Se])c1ccccc1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=[Se])c2ccccc2Cc2ccccc2)cc1
Reaction time: 2 h

Procedure:
A suspension of 4 g (0.013 mol) 2-benzylselenobenzoic acid in 80 ml dichloromethane is cooled to 0°-5° C. and treated with stirring with 2 g (0.015 mol) chloromethylenedimethyliminium chloride (Vilsmeir's reagent) in one portion. After 1 hour a solution of 1.47 g (0.0137 mol) 4-methylaniline and 3 g (0.03 mol) triethylamine are added dropwise in the cold and stirring continued for 2 hours at room temperature. The solution is washed successively with
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH:30][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-sulfamoylphenyl)-L-phenylalanine methyl ester (100 mg) was dissolved in anhydrous pyridine (5 mL). To this solution was added benzoyl chloride (50 μL) and the mixture was stirred for 12 h at room temperature under N2. EtOAc and satd. NaHCO3 were added to the mixture and the EtOAc phase was washed with 1 N HCl, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give N-(2,6-dichlorobenzoyl)-4-[2-(N-benzoylsulfamoyl)phenyl]-L-phenylalanine methyl ester.
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[CH:17]1([NH:23][CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCCCCC.CCOC(C)=O>[CH:17]1([N:23]([CH3:24])[C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH:7]4[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]4[CH2:5][C:4]=3[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CNC1CCCCC1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(c1ccc2c(n1)CC1CCCCC1C2=O)C1CCCCC1
Yield: 52 %

Procedure:
A mixture of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.29 g, 1.23 mmol) and cyclohexyl(methyl)amine (1.39 g, 12.3 mmol) was stirred at 110° C. for 9.5 h (TLC control; hexane-EtOAc, 2:1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.2 g, 52%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])=[N:6][CH:7]=1.[OH:15][C:16]([CH3:49])([CH3:48])[CH2:17][C@@:18]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:23][C:22](=[O:24])[N:21]([C@H:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH3:26])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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>[OH:15][C:16]([CH3:48])([CH3:49])[CH2:17][C@@:18]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:23][C:22](=[O:24])[N:21]([C@H:25]([C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[CH2:12][CH2:11][N:10]([CH3:13])[C:9]4=[O:14])=[N:6][CH:7]=3)=[CH:31][CH:32]=2)[CH3:26])[CH2:20][CH2:19]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN1CCN(c2ncc(Br)cn2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ccc(-c2cnc(N3CCN(C)C3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (1 mg) was added to a solution of 1-(5-bromopyrimidin-2-yl)-3-methylimidazolidin-2-one (10 mg), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (38.0 mg), and Na2CO3 (17 mg) in toluene (3 mL), ethanol (2 mL), and H2O (1 mL) under nitrogen at room temperature. The reaction mixture was heated to 100° C. under nitrogen and stirred at this temperature for 2 h. After cooling to room temperature, the mixture was concentrated to afford an oil, which was purified by preparative HPLC to give the title compound. Yield: 2.4 mg (12% of theory); LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=530 [M+H]+; 1H NMR (CD3OD) δ 0.88 (s, 3H), 1.32 (s, 3H), 1.48 (d, 3H), 2.05 (m, 2H), 2.12 (m, 2H), 2.41 (m, 2H), 2.81 (s, 3H), 3.42 (m, 2H), 4.01 (m, 2H), 5.52 (m, 1H), 7.02 (d, 2H), 7.26 (m, 5H), 7.31 (m, 2H), 8.67 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][C:15]([Cl:17])=[O:16])=[O:11])=[CH:5][CH:4]=1.S(Cl)(Cl)=O>ClCCl>[ClH:17].[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]2=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)CCCC(=O)Cl)cn1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N2C(=O)CCCC2=O)cn1
Product: Cl

Procedure:
The crude 4-(6-methoxy-pyridin-3-ylcarbamoyl)-butyryl chloride was redissolved in dichloromethane (25 mL). Thionyl chloride (5.95 g, 50 mmol) was added and the solution was heated to reflux overnight. The solvent and excess thionyl chloride were evaporated in vacuo, yielding 6′-methoxy-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione hydrochloride, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)=[C:13]([CH3:26])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C([O-])([O-])=[O:30].[K+].[K+]>CS(C)=O>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]([NH2:21])=[O:30])=[CH:18][N:17]=2)=[C:13]([CH3:26])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CCNCc2ccccc2)ccc1Oc1ccc(C#N)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(CCNCc2ccccc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 96.8 %

Procedure:
Combine nitrile, 6-[4-(2-benzylamino-ethyl)-2-methyl-phenoxy]-nicotinonitrile (compound of example 219, step 3) (13 mg, 0.04 mmol), H2O2 (5 μL) and K2CO3 (3 mg, 0.02 mmol) in DMSO (0.2 mL), and stir the mixture at room temperature overnight. Add water and extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Purify by flash chromatography (eluent: CHCl3/0.5% EtOH/0.05% NH4OH) to give the title compound (7 mg, 52%). Electrospray MS M+1 ion=362. 1H-NMR (methanol-d4, 300 MHz): 8.59 (d, 1H, J=2.5 Hz), 8.24 (dd, 1H, J=2.5 and 8.0 Hz), 7.33-7.21 (m, 5H), 7.15-7.07 (m, 2H), 6.98-6.93 (m, 2H), 3.78 (s, 2H), 2.83 (s, 4H), 2.09 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12].[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:13][CH2:10][CH:11]=[CH2:12])=[O:9])=[C:4]([Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: C[Si](C)(C)Cl
Reactant: C=CCN
Product: C=CCNC(=O)c1sc(Cl)cc1[Si](C)(C)C

Procedure:
The title compound was prepared from 5-chloro-2-thiophenecarboxylic acid and allylamine, followed by reaction with TMSCl using the methods of Example 248 to afford 0.7 g of the title compound as a white solid. m.p. 63-66° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([CH3:31])=[CH2:30])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: C=C(C)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(C)C)cc(C(F)(F)F)c1
Yield: 96.8 %

Procedure:
A solution of (R)-[4-(3-isopropenyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (using a method analogous to the one described for 1st step intermediate of example 11-1) (34 mg, 0.072 mmol) in methanol was hydrogenated over 10% Pd/C (6 mg) under 30 psi for 3 hours at room temperature. The reaction mixture was filtered through a glass funnel and concentrated to afford (R)-[4-(3-isopropyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (33 mg, 96.8%) as a white solid. MS cald for C21H26F3N3O4S 473, obsd. (ESI+) [(M+H)+] 474.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:17]([O:24][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1nc(SCOCc2ccccc2)ns1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCSc2nsc(OCc3ccccc3)n2)cc1
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
Into 3 g of N,N-dimethylformamide were dissolved 350 mg of 5-chloro-3-benzyloxymethylthio-1,2,4-thiadiazole and 153 mg of benzyl alcohol, 68 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes. After stirring for 2 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 260 mg of 5-bezyloxy-3-benzyloxymethythio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (43)).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:7][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1ccccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 1 h

Procedure:
20 g o-nitro benzylalcohol and 21.7 ml ethyl bromoacetate was dissolved in 250 ml dry DMF. Portions of 55-60% sodium hydride were added to this solution under stirring over one hour until a total amount of 8.5 g had been added. The mixture was left overnight at room temperature and then heated to 150° C. under stirring for 2 hours. The mixture was then evaporated and the residue was partitioned between diethylether and water. The organic phase was evaporated to give 14 g ethyl (o-nitro-benzyloxy)acetate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=[C:15]([CH2:21][OH:22])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[K+].[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>ClCCl.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][O:20][S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[N:16]=[C:15]([CH2:21][O:22][S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:26])=[O:23])[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(CO)nc(CO)c1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCc2cc(OCCCNC(=O)OC(C)(C)C)cc(COS(=O)(=O)c3ccc(C)cc3)n2)cc1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a precooled (0° C.) solution of 4-(3-tert-butoxycarbonylamino-propoxy)-2,6-bis-(hydroxymethyl)-pyridine (76 mg) in dichloromethane (0.7 mL), was added a solution of potassium hydroxide (30 mg) in water (0.3 mL). Tosyl chloride (93.7 mg) was added, and the resulting heterogenous mixture was shaken vigorously for 1 h and then washed into separatory funnel using dichloromethane and water. The layers were separated, and the aqueous layer was extracted three times with dichloromethane. The combined organic solutions were dried over magnesium sulfate, and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Interchrom Puriflash 10 g column, SiOH 15-35 μm), using gradient elution with a mixture of heptane (A) and ethyl acetate (B) (gradient: 90% A:10% B up to 50% A:50% B) to give 4-(3-tert-butoxycarbonylamino-propoxy)-2,6-bis-(tosyloxymethyl)pyridine (56 mg):
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[N:13]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([CH2:35][OH:36])[CH2:31][CH2:30]3)[N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.O.CCOC(C)=O>CS(C)=O>[N:13]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]3[CH2:30][CH2:31][CH:32]([CH:35]=[O:36])[CH2:33][CH2:34]3)[N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: OC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CC1CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 71.2 %

Procedure:
Iodoxybenzoic acid (830 mg, 2.96 mmol) was added to a solution of trans-[4-(4-benzo-triazol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanol (640 mg, 1.97 mmol) in DMSO (10 mL) and the resulting mixture was stirred at RT for 23 hours. An additional aliquot of o-iodoxy-benzoic acid (830 mg, 2.96 mmol) was then added. After a few hours, the reaction was stopped. Water was added and the resulting mixture was stirred for 20 minutes, the solid formed was filtered and the filtrate was extracted 3 times with EtOAc. The combined organic extracts were washed once with water, dried over Na2SO4 and filtered; the solvent was evaporated under reduced pressure. The white solid formed was washed several times with EtOAc and it was combined with the previous obtained solid to give 789 mg of crude residue. This crude material was purified via flash chromatography (heptane/EtOAc, with a gradient from 20% to 50% of EtOAc) to give 452 mg (70% yield) of 4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclo-hexanecarbaldehyde.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[CH3:27][O:26][C:10]1[CH:9]=[C:8]2[C:17]3[C@H:16]([CH2:15][C@H:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13][C:12]=3[C:11]=1[O:24][CH3:25])[C@H:5]([C:1]([OH:3])=[O:2])[CH2:6][CH2:7]2
Reactant: COC(=O)[C@@H]1CCc2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c3c(c1OC)C[C@@H](c1ccccc1)C[C@@H]3[C@H](C(=O)O)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Crude [1R*,8S*,9aR*]1-Carbomethoxy-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene (0.8 g., 2.1 mmol), from Step 4, was dissolved in 100 mL of methanol and 8 mL of 1N aqueous sodium hydroxide solution was added. After stirring for 3 days at ambient temperature, the methanol was removed under reduced pressure. The residue was partitioned between 50 mL of diethyl ether and 75 mL of water. The aqueous phase was acidified to pH 2 with 6M aqueous hydrochloric acid solution and extracted with 3×25 mL of 1:1 ethyl acetate/diethyl ether. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.74 g (100% yield) of the title compound as an oil; DCI MS: 253 (M+H)+. 1H NMR (CDCl3) δ: 2.0-2.3 (m, 2H), 2.65-2.85 (m, 2H), 2.9-3.1 (m, 6H), 3.2-3.3 (m, 1H), 3.73 (s, 3H), 3.83 (s, 3H), 6.56 (s, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10]I)[CH2:8][C:7]1=[O:12].[CH:19]([NH2:21])=O.[C-]#N.[Na+]>>[C:19]([CH2:10][CH:9]1[N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7](=[O:12])[CH2:8]1)#[N:21]
Reactant: COc1ccc(CN2C(=O)CC2CI)c(OC)c1
Reactant: NC=O
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc(CN2C(=O)CC2CC#N)c(OC)c1
Yield: 70 %

Procedure:
A solution of 1.2 g. (3.3 mmoles) of 1-(2,4-dimethoxybenzyl)-4-(iodomethyl)-2-azetidinone prepared according to Example 13 in 5 ml. ofddimethyl formamide is stirred with 0.35 g. (7 mmoles) of sodium cyanide for 48 hours, at room temperature. The solution is then poured onto 30 ml. of water and extracted with five 20-ml. portions of ether. The ethereal solution is dried with magnesium sulfate, decolored with activated carbon, filtered and the filtrate is evaporated in vacuo. 0.6 g. (70%) of the named compound are obtained.
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][C@@H:10]([CH3:25])[CH2:11][C:12]1[C:20]2[CH:19]=[C:18]([OH:21])[CH:17]=[CH:16][C:15]=2[N:14]2[CH2:22][CH2:23][CH2:24][C:13]=12)(C)(C)C.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34].O>CN(C)C=O.C(OCC)(=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:22][CH2:23][CH2:24][C:13]3=[C:12]([CH2:11][C@@H:10]([NH2:9])[CH3:25])[C:20]=2[CH:19]=1
Reactant: COCCOCCBr
Reactant: C[C@@H](Cc1c2n(c3ccc(O)cc13)CCC2)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOc1ccc2c(c1)c(C[C@H](C)N)c1n2CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
25 mg sodium hydride 55-65% in oil was added to a solution of 165 mg (S)-[2-(6-hydroxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester in 1.5 mL N,N-dimethylformamide. The mixture was stirred at room temperature for 30 min, then 122 mg 1-bromo-2-(2-methoxyethoxy)-ethane was added to the mixture and the mixture was stirred at room temperature for an additional 7 h. The reaction mixture was distributed between water and ethyl acetate. The phases were separated, the organic phase is washed with water, 10% citric acid, 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate=4:1. The product fractions were evaporated and the residue taken up in 1.5 mL of a 2.16 M solution of hydrochloric acid in ethyl acetate. The mixture was stirred at room temperature for 3 h. The solid was collected by filtration, neutralised with aqueous ammonium hydroxide and purified by chromatography on silica gel with dichloromethane:methanol:aqueous ammonium hydroxide=90:9:1. The product fractions are dried over magnesium sulfate and evaporated to yield 82 mg (S)-2-{6-[2-(2-methoxy-ethoxy)-ethoxy]-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl}-1-methyl-ethylamine as light brown oil. MS: M+H=333.3; M+H−NH3=316.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([O:15]CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc(OC2CCC(OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: OC1CCC(Oc2ccc(F)cc2)CC1
Yield: 74.3 %

Procedure:
A mixture of 17.1 parts of 1-fluoro-4-[[4-(phenylmethoxy)cyclohexyl]oxy]benzene and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated, yielding 8.9 parts (74.3%) of 4-(4-fluorophenoxy)cyclohexanol as a residue (139).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][N:15]1[C:19]([CH2:20][OH:21])=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[N:16]1.[CH3:26][O:27][C:28](=[O:41])[CH2:29][C:30]1[C:34]2[C:35]([F:40])=[CH:36][C:37](O)=[CH:38][C:33]=2[S:32][CH:31]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:26][O:27][C:28](=[O:41])[CH2:29][C:30]1[C:34]2[C:35]([F:40])=[CH:36][C:37]([O:21][CH2:20][C:19]3[N:15]([CH3:14])[N:16]=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:18]=3)=[CH:38][C:33]=2[S:32][CH:31]=1
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: COC(=O)Cc1csc2cc(O)cc(F)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a mixture of tri-n-butylphosphine (0.793 mL), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (187 mg), methyl(4-fluoro-6-hydroxy-1-benzothiophen-3-yl)acetate (250 mg) and THF (dry) (15 mL) was added ADDP (801 mg) at room temperature. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. To the residue was added IPE and the insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) and silica gel column chrothatography (EtOAc/hexane) to give the title compound (310 mg). The crystals were recrystallized from acetone-hexane.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:18][CH3:19])[CH2:15][N:14]([C:20]([O:22][CH3:23])=[O:21])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[I:24]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:18][CH3:19])[CH2:15][N:14]([C:20]([O:22][CH3:23])=[O:21])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[C:7]([I:24])[N:8]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)cnc1CC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(I)nc1CC
Temperature: 50 °C
Yield: 89 %

Procedure:
To a solution of the methyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate (5.25 g, 16.2 mmole) in DMF (0.3M, 54 ml) under N2 was added N-iodosuccinimide (4.57, 1.25 eq.). The reaction mixture was heated at 50° C. for 2 hours then cooled to ambient temperature. It was poured into saturated sodium thiosulfate (100 mL) and extracted with ethyl acetate (2×100 ml), dried with MgSO4, filtered and concentrated. Purification with Biotage MPLC (40 g, 10-30% ethyl acetate in heptane gradient) provided 6.45 g (89%) of methyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.06 (m, 1 H), 4.62 (m, 1 H), 4.05 (m, 1 H), 3.88 (m, 1 H), 3.73 (m, 5 H), 3.58 (m, 1 H), 3.43 (m, 1 H), 3.18 (m, 1 H), 2.80 (m, 2 H), 2.62 (q, J=15.8 Hz, 2 H), 1.26 (m, 9 H); IR (diffuse reflectance) 3432, 2976, 2969, 2498, 2461, 2388, 2350, 2337, 1697, 1550, 1535, 1457, 1451, 1392, 771 (s) cm−1 HRMS (ESI) calcd for C16H25N4O3I+H1 449.1051. found 449.1029. Anal. Calcd for C16 H25 I N4 O3: C, 42.87; H, 5.62; N, 12.50. Found: C, 43.01; H, 5.73; N, 12.43.