Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:39])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:39])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][C:35]([F:37])([F:38])[F:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCC(F)(F)F)c1
Yield: 29 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 50 mg (1.25 mmol, 13 eq) of sodium hydroxide and 50 mg (0.096 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3,3,3-trifluoropropoxy)biphenyl-4-yl]propanoate in 3 ml of a tetrahydrofuran/methanol mixture (8/2) at room temperature for 2 hours, and after crystallization from pentane/isopropyl ether, 14 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(3,3,3-trifluoropropoxy)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=90° C.). Yield=29%
Reaction SMILES: [O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9]O.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>>[O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[CH2:11][N:35]1[C:31](=[O:41])[C:32]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]2[C:34]1=[O:36]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K]
Product: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O

Procedure:
According to Scheme 2, (25R)-16β-26-dihydroxycholesterol (2) is selectively oxidized at the C-16 position to produce (25R)-16-oxo-26-hydroxycholesterol (9). Compound (9) is then converted to the monotosylate (25R)-16-oxo-26-hydroxycholesterol 26-tosylate (8) directly or by indirect means by solvolysis of (25R)-16-oxo-26-hydroxycholesterol 3β,26-diotsylate (7) derived from Compound 9. The C-26 tosylate of compound (8) is then displaced with potassium phthalimide to produce key compound (5) as described above. ##STR2##
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:38])[F:39])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.31 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide are dissolved in 100 ml tetrahydrofuran and to this solution 1.1 ml of tetra-n-butylammonium fluoride (˜75% in H2O) are added at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Cl.[CH2:18]([NH2:20])[CH3:19]>CN(C)C=O.[Cu]Br>[CH2:18]([NH:20][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[CH3:19]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCN
Agent: [Cu]Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCNc1ncccc1C(=O)O
Temperature: 100 °C

Procedure:
Potassium carbonate (9.21 g, 66.6 mmol) was added to a mixture of 2-chloronicotinic acid (5.0 g, 31.7 mol), ethylamine hydrochloride (5.18 g, 63.4 mmol) and copper (I) bromide (450 mg, 3.17 mmol) in N,N-dimethylformamide (50 ml), and the reaction heated at 100° C. for 1.5 hours, then cooled. The resulting solid was removed by filtration, and the filtrate evaporated under reduced pressure. The residual blue/green solid was triturated with acetone, and the resulting solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CO.CN(C)C.[Pd]>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Oc1cccc(-c2ccccc2)c1
Agent: [Pd]
Agent: CN(C)C
Solvent: CO
Product: COC(=O)Cc1c(C)ncnc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[6-methyl-2-chloro-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate is dissolved in methanol/trimethylamine (50 ml/10 ml) and hydrogenated over Pd on charcoal (0.2 g). The reaction mixture is evaporated. Addition of potassium carbonate, ether extraction and chromatography on silica gel gives pure methyl α-[6-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate. 1H (CDCl3):8.58 (s, 1H); 7.65-7.05 (m, 9H); 3.86 (s, 2H); 3.77 (s, 3H); 2.55 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1[NH:15]CC1C=CC=CC=1)([O:3][CH3:4])=[O:2]>CO.[Pd]>[C:1]([C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C@@H:6]1[NH2:15])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=C(NCc2ccccc2)CCc2ccccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1c2ccccc2CC[C@@H]1N
Reaction time: 72 h
Yield: 15.7 %

Procedure:
To a suspension of 1-carbomethoxy-2-benzylamino-3,4-dihydronaphthalene (1.46 g) in methanol (30 mL) at room temperature, was added 10% palladium on carbon (200 mg). The resulting mixture was shaken under a hydrogen atmosphere at 40 psi for 3 d using a Parr apparatus. The catalyst was filtered, and the filtrate was evaporated under vacuum to obtain crude product. The crude product was purified by reverse phase preparative HPLC to obtain predominantly cis 1-carbomethoxy-2-amino-1,2,3,4-tetrahydronaphthalene (160 mg) as a cis-trans mixture (10:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[SH:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (3) (2.62 g, 9.84 mmol) in 1,4-dioxane (21 mL) and methanol (10 mL) was added lithium hydroxide (825 mg, 19.7 mmol) in water (21 mL). The reaction was stirred at 50° C. overnight and the organic solvents were removed in vacuo. The mixture was acidified with 1M HCl until a white solid crashed out of the solution. The solid was collected by vacuum filtration and washed with water to afford 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylic acid (4).
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16](COCC[Si](C)(C)C)[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)[OH:14])OCC[O:4]1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:14][CH:13]([C:15]1[NH:19][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:17][N:16]=1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3](=[O:4])[CH2:1][CH3:2]
Reactant: CCC1(CCCCCC(O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)CCCCCC(O)c1ncc(-c2ccc3ccccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The alcohol F2 was dissolved in TFA/DCM (1:1) and stirred for 4 hr at RT. The reaction was quenched with sat. aq. NaHCO3 solution and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and solvent was removed under reduced pressure. The crude product was purified by flash chromatography, using EtOAc/petroleum ether as eluents and the product was obtained as a white solid. 1H NMR (300 MHz, DMSO) δ: 8.30 (1H, s), 7.97-7.75 (6H, m), 7.58-7.41 (2H, m), 5.81 (1H, br s), 4.75 (1H, m), 2.37 (4H, m), 1.80 (2H, m), 1.51-1.19 (6H, m), 0.88 (3H, t, J=7.3 Hz). MS (ES) C22H26N2O2 requires: 350, found: 351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34]O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCC#CCOCc1ccccc1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCOCc3ccccc3)cc2)CCSC1(C)C
Yield: 637.6 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.211 g (1.2 mmol) of 4-(benzyloxy)-2-butyn-1-ol provided 3.211 g (42%) of methyl 4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 504.2 (M+H)+.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[F:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=1
Reactant: O=c1ncc(F)c[nH]1
Reactant: OCc1cccs1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(F)cn1Cc1cccs1
Temperature: 80 °C

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.76 ml) was added to a stirred suspension of 5-fluoropyrimidin-2-one (456 mg) and 2-hydroxymethyl thiophene (0.7 ml) in dry N,N-dimethylformamide (8 ml) under nitrogen and the mixture was then heated at 80° C. After 1 h the reaction mixture was evaporated to a brown solid which was crystallised twice from ethyl acetate to give white crystals of the title pyrimidinone (230 mg), m.p. 161°-163° C., λmax (EtOH) 222.5 nm (ε 10,890), 333.5 nm (ε 3,660).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([CH2:14][CH3:15])([OH:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[CH2:27]([N+:31](CCCC)([CH2:36][CH2:37]CC)[CH2:32][CH2:33]CC)[CH2:28][CH2:29]C.Cl.C(N(CC)CCCCl)C>C(C(C)=O)C(C)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([CH2:14][CH3:15])([OH:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][CH2:28][CH2:27][N:31]([CH2:36][CH3:37])[CH2:32][CH3:33])=[CH:8][CH:7]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCC(O)(c1ccc(O)cc1)c1ccccc1OC
Agent: CCN(CC)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)C
Product: CCN(CC)CCCOc1ccc(C(O)(CC)c2ccccc2OC)cc1
Reaction time: 4 h

Procedure:
12.9 g. of 2-methoxy-4'-hydroxy-α-ethyl-benzhydrol are dissolved in 100 ml. of methyl isobutyl ketone, 23 g. of anhydrous potassium carbonate 0.4 ml. of a 40% tetrabutyl ammoniumhydroxide solution and 10.3 g. of 3-diethylamino-propyl chloride hydrochloride are added, and the solution is heated up to the boiling point. The reaction mixture is boiled for 4 hours, and the solvent is distilled off under reduced pressure. To the residue water is added, and it is extracted with benzene. The benzene phase is washed with a 5% potassium hydroxide solution and subsequently with water. After drying over anhydrous potassium carbonate, benzene is distilled off under reduced pressure, and the residue is fractionated in vacuo to yield 13.2 g. of the title compound, boiling at 200° to 203° C./13.3 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[NH:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19](=[O:27])[C:18]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:17]1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][N:24]1[CH2:25][CH2:26][CH:21]([N:20]2[C:19](=[O:27])[C:18]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[NH:17][C:16]2=[NH:15])[CH2:22][CH2:23]1
Reactant: COc1ccc(C2(c3ccc(OC)cc3)NC(=N)N(C3CCNCC3)C2=O)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2(c3ccc(OC)cc3)NC(=N)N(C3CCN(Cc4cc(Cl)ccc4O)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-Chlorosalicylaldehyde (0.24 g, 1.53 mmol), sodium cyanoborohydride (0.33 g, 5.25 mmol) and 2-imino-5,5-bis(4-methoxyphenyl)-3-(piperidin-4-yl)imidazolidin-4-one (0.41 g, 1.04 mmol) were dissolved in ethanol and the solution was stirred at room temperature overnight. The mixture was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified over a silica column (MeOH/DCM=1/20) to give the title compound as a white solid (0.18 g, 33% yield).
Reaction SMILES: [CH:1]1([C:6]([OH:33])([CH2:23][C:24]2[O:25][C:26]([CH3:32])([CH3:31])[O:27][C:28](=[O:30])[CH:29]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:16]#[N:17])=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]([OH:33])([CH2:23][C:24]2[O:25][C:26]([CH3:31])([CH3:32])[O:27][C:28](=[O:30])[CH:29]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH2:18][CH3:19])([CH2:20][CH3:21])[C:16]#[N:17])=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(C#N)(CC)c1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CCC(C#N)(CC)c1ccc(CCC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F

Procedure:
The desired product was prepared analogously to example A(86) step 6, substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile (0.900 g, 2.0 mmol) from step 2 above in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 0.841 g, 92%. MS (ESI): 456 (M−H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](OCC)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][OH:11]
Reactant: CCOC(=O)C1Cc2ccccc2N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of 5.12 g of ethyl indoline-2-carboxylate (prepared as described in Preparation 1) in 20 ml of anhydrous tetrahydrofuran was added dropwise, whilst ice-cooling, to a mixture of 1.20 g of lithium aluminum hydride and 80 ml of anhydrous tetrahydrcfuran, and the resulting mixture was stirred at room temperature for 2 hours. After this, an excess of sodium sulfate decahydrate was added to the mixture, which was then stirred for 20 minutes. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.81 g of the title compound having Rf=0.16 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: CC(C)CCC(=O)C(OCC)=O.N[C@H](C(N1CCC[C@H]1C(O)=O)=O)C.C([BH3-])#N.[Na+].[CH2:30]([O:32][C:33]([CH:35]([NH:41][C@H:42]([C:44]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([OH:50])=[O:49])=[O:45])[CH3:43])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH3:31]>C(O)C>[CH2:30]([O:32][C:33]([C@@H:35]([NH:41][C@H:42]([C:44]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([OH:50])=[O:49])=[O:45])[CH3:43])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH3:31]
Reactant: CCOC(=O)C(CCC(C)C)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)C(=O)CCC(C)C
Agent: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Solvent: CCO
Product: CCOC(=O)[C@H](CCC(C)C)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Ethyl 5-methyl-2-oxohexanoate (3.44 ) and L-alanyl-L-proline (0.74 g) is stirred in 15 ml of ethanol with 6 of powdered 4 A molecular sieves. Sodium cyanoborohydride (0.23 g) in ethanol is added dropwise over the course of several hours. The ethanol is then removed under vacuum, the product is absorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water to yield 1.08 g. of N-(1-ethoxycarbonyl-4-methylpentyl)-L-alanyl-L-proline. A portion is purified by LH-20 chromatography for spectral analysis. The nmr is in accord with structure. The mass spectrum shows a peak at 414 (silylated molecular ion -15). Chromatography affords the desired isomer.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8].Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:3]
Reactant: ClCCCBr
Reactant: N#Cc1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCl)c(O)c1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
NaH (0.20 g; 8.14 mmol) was added to a room temperature solution of 3,4-dihydroxybenzonitrile (1.00 g; 7.40 mmol) in DMF. After stirring for 15 minutes, 1-bromo-3-chloropropane (1.3 g; 8.14 mmol) was added to the mixture. The reaction was stirred for 40 h at room temperature, and then quenched with water and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (4×100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting crude product was chromatographed on a column of silica (5 cm×18 cm) eluting with a mixture of EtOAc and hexanes (1:4). Fractions containing the desired product were combined and concentrated in vacuo to afford the sub-title compound as an oil (0.5 g; 32%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC1CCCc2ccc(Br)cc21

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-naphthalen-1-one (CAS#32281-97-3, 3.5 g, 0.015 mol) in methanol (7 mL) and dichloromethane (10 mL) at 0° C. is added sodium borohydride (1.47 g, 0.038 mol) in one portion. The cooling bath is removed and after 1.5 hours, the mixture is poured into water and the volatile organics are removed in vacuo. Extraction with dichloromethane, drying over sodium sulfate, filtering through a cotton plug and concentration in vacuo affords 7-bromo-1,2,3,4-tetrahydro-naphthalen-1-ol. 1H NMR (400 MHz, CDCl3) δ ppm 1.72 (d, J=6.3 Hz, 1 H), 1.74-1.90 (m, 2 H), 1.92-2.07 (m, 2 H), 2.62-2.71 (m, 1 H), 2.73-2.82 (m, 1 H), 4.73-4.77 (m, 1 H), 6.98 (d, J=8.2 Hz, 1 H), 7.31 (dd, J=8.2, 2.1 Hz, 1 H), 7.61 (d, J=2.1 Hz, 1 H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C([O-])=O.[CH2:22]([O:24][C:25]([CH2:27][O:28][C:29]1[C:33]2[S:34][C:35]3[CH:36]=[C:37]([NH3+:41])[CH:38]=[CH:39][C:40]=3[C:32]=2[S:31][C:30]=1[C:42]([O:44][CH3:45])=[O:43])=[O:26])[CH3:23].[O:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1.C(O)(=O)C>ClCCCl.C(Cl)Cl>[CH3:45][O:44][C:42]([C:30]1[S:31][C:32]2[C:40]3[CH:39]=[CH:38][C:37]([NH:41][CH:49]4[CH2:50][CH2:51][O:46][CH2:47][CH2:48]4)=[CH:36][C:35]=3[S:34][C:33]=2[C:29]=1[O:28][CH2:27][C:25]([O:24][CH2:22][CH3:23])=[O:26])=[O:43]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc([NH3+])ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(NC3CCOCC3)ccc12
Temperature: 50 °C
Reaction time: 17 h
Yield: 94.2 %

Procedure:
Sodium triacetoxyborohydride (90 mg, 0.42 mmol, 2.5 equiv) was added to a mixture of 1-ethoxycarbonylmethoxy-2-methoxycarbonyl-3,8-dithia-cyclopenta[a]inden-6-yl-ammonium trifluoroacetate (85 mg, 0.17 mmol), tetrahydropyran-4-one (24 μl, 0.2 mmol, 1.2 equiv), and acetic acid (5 μl) in DCE (4 ml) and stirred at 50° C. for 17 hr. DCM (20 ml) was added and the mixture was washed with sat. NaHCO3, dried over MgSO4, filtered, and the solvent was reoved in vacuo. Purification by column chromatography yielded 72 mg (94%) of 1-ethoxycarbonylmethoxy-6-(tetrahydropyran-4-ylamino)-3,8-dithiacyclopenta[a]indene-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].Br[CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([CH2:13][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH2:15][CH2:16]1
Reactant: FC1(F)CCC(CBr)CC1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
1.2 g of 2-(3,3,3-trifluoropropyl)malononitrile and 0.76 g of 4-bromomethyl-1,1-difluorocyclohexane were dissolved in 10 ml of N,N-dimethylformamide, 0.99 g of potassium carbonate was added, and the mixture was stirred at room temperature overnight. Thereafter, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.51 g of 2-(4,4-difluorocyclohexyl)methyl-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (83)).