Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:18])[CH3:17]
Reactant: CC1(O)CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1(C)CCCCC1
Yield: 90 %

Procedure:
The procedure given in a product publication, "POLYDMAP(tm) POLYMER, A Guide to Its Successful Use", Reilly Industries, 1990, for testing the activity of polystyrene bound BMAP, was followed. A sample (7.0 gm) of the above silica bound catalyst was mixed with 8.2 gm (0.07 mol) 1-methylcyclohexanol. To this suspension was added 11.6 gm (0.12 mol) triethylamine and 12.8 gm (0.13 mol) acetic anhydride. The mixture was heated at reflux for 5 hours, then filtered to remove the catalyst. The catalyst was washed with 50 ml dichloromethane. The combined filtrate and washes were treated with three 50 ml portions of 9% aqueous HCl, then with three 50 ml portions of saturated aqueous sodium bicarbonate. The organic layer was then dried over anhydrous magnesium sulfate, filtered and the volatile components were removed using a rotary evaporator. The crude product was purified by vacuum distillation through a short Vigreux column. Analysis of the distilled fractions by vapor phase chromatography showed that the desired 1-methylcyclohexyl acetate was obtained in 90 % yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[C:4]=1[C:15]([O:17]C)=[O:16].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([F:12])([F:13])[F:14])[C:4]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(OC)cc(OC)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(C(=O)O)c(C(F)(F)F)n1
Yield: 82.9 %

Procedure:
A mixture of 7.0 g (0.0264 mol) of product of Example 3, 30 ml of 10% sodium hydroxide and 10 ml of methanol was held at reflux for 18 hours, cooled and extracted with ether. The aqueous layer was made acidic and the precipitate was collected and dissolved in ether. The ether solution was dried and mixture was concentrated. The residual solid was recrystallized from hexane-ether to give 5.5 g (83%) of solid, mp 194°-197.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([NH:17][C:18]([O:20][CH2:21][C:22]1C=CC=C[CH:23]=1)=[O:19])[C@H:14]([OH:16])[CH3:15])=[O:10])[C:2]1C=CC=C[CH:3]=1.[H][H].[OH-].[Na+]>CO.[Pd].O.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C@H:14]([OH:16])[CH3:15])=[O:10])[CH:2]=[CH2:3]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@@H](CNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOC(=O)NC[C@@H](NC(=O)OCC=C)[C@@H](C)O
Yield: 71 %

Procedure:
A solution of (2R,3R)-1,2-bis(benzyloxycarbonylamino)-3-hydroxybutane (80.5 g) in methanol (800 ml) was hydrogenated under atmospheric pressure of hydrogen over palladium on carbon (10%, 8 g) for 5 hours at ambient temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. To a solution of the syrup in a mixture of water (400 ml) and tetrahydrofuran (400 ml) in tetrahydrofuran (90 ml) under ice-cooling with stirring, keeping the pH between 8.5 and 9.5 with 4N aqueous sodium hydroxide. After stirring for one hour, the mixture was extracted with ethyl acetate (800 ml), washed with brine (400 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (600 g) and eluted with a mixture of methanol and chloroform (1:99, V/V) to give (2R,3R)-1,2-bis(allyloxycarbonylamino)-3-hydroxybutane (41.78 g) as a syrup.
Reaction SMILES: [CH2:1]([N:8]([CH3:13])[CH2:9][C:10]([CH3:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]([CH3:13])[CH2:9][CH:10]([OH:11])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CN(C)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CN(C)Cc1ccccc1

Procedure:
Put 8.00 g (45.13 mmol) 1-[benzyl(methyl)amino]acetone in 40 ml methanol. Add, at RT in portions with stirring, 854 mg (22.57 mmol) sodium borohydride. Stir for 30 min at RT and then for a further 30 min under reflux. Concentrate by evaporation and take up the residue in water. Extract twice with ethyl acetate, wash the combined organic phases once with satd. sodium hydrogencarbonate solution, dry over magnesium sulphate and concentrate by evaporation. 7.80 g (81.9% of theor.) of the target compound is obtained without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH2:20])[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[C:1]1([C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[N:17]=[C:18]([NH:20][C:28](=[O:31])[CH2:29][CH3:30])[S:19][C:10]=4[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1nc2c(s1)-c1nc(-c3ccccc3)ncc1CC2
Temperature: 25 °C

Procedure:
0.3 g (1.1 mmol) of the compound obtained in Example 71 are suspended in 15 ml dichloromethane, combined with 0.4 ml (2.5 mmol) triethylamine and gently refluxed. 0.2 ml (2.3 mmol) propionic acid chloride are added and the mixture is refluxed for 5 hours with stirring. After cooling to ambient temperature the reaction solution is washed with sodium hydrogen carbonate and water, dried and evaporated to dryness. The residue is stirred with diethyl ether and suction filtered. Yield: 0.2 g (m.p.: 274-275° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O>C(#N)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=CCCl
Solvent: CC#N
Product: Ic1ccc2nccn2c1
Yield: 66.1 %

Procedure:
Reflux a solution of 2-amino-5-iodo-pyridine (Tetrahedron 2002, 58, 2885-2890; 1.5 g, 6.82 mmol) and 50% aqueous chloroacetaldehyde (1.56 mL, 12.3 mmol) in acetonitrile (150 mL) for 14 h. Cool, concentrate, and dissolve the residue in 1:1 saturated aqueous sodium bicarbonate/dichloromethane. Extract the aqueous layer with dichloromethane, combine the organic layers, and concentrate. Flash chromatography using appropriate ethyl acetate/methanol mixtures gives 1.1 g (66%) of the subtitled compound as a light green solid. TOF MS ES+ exact mass calculated for C7H51N2 (p+1): m/z=244.9576; Found: 244.9564. 1H NMR (400 MHz, DMSO-d6) δ 8.9 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.40 (d, J=9 Hz, 1H), 7.36 (d, J=9.2, H).
Reaction SMILES: CS(O[CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)(=O)=O.[Li+].[Br-:18]>CC(C)=O>[Br:18][CH:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cccc(CC(C)OS(C)(=O)=O)c1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: COc1cccc(CC(C)Br)c1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A round-bottomed flask was charged with 1-methyl-2-[3-(methyloxy)phenyl]ethyl methanesulfonate (2) (90 g, 0.368 mol), LiBr (80 g, 0.92 mol), and acetone (650 mL). The reaction mixture was refluxed for 24 h under N2 and then cooled to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The product was passed through a pad of silica gel to remove inorganic impurities. The product was distilled under reduced pressure (2-3 mm Hg) at 130-135° C. to afford ˜85 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.25 (dd, J1=8.00 Hz, J2=8.00 Hz, 1H), 6.84-6.78 (m, 3H), 4.32 (sextet, J=4.00 Hz, 1H), 3.82 (s, 3H), 3.25 and 3.21 (dd, J1=16.00 Hz, J2=8.00 Hz, 1H), 3.07 and 3.04 (dd, J1=16.00 Hz, J2=8.00 Hz, 1H), 1.71 (d, J=8.00 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:9]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCC(=O)C1
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C=C(OCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a flask equipped with magnetic stirrer and Dean Stark apparatus was added 1,3-cyclohexanedione (70.0 g, 624 mmol), toluene (500 ml), ptoluenesulfonic acid monohydrate (1.68 g, 8.83 mmol) and benzyl alcohol (65.6 g, 606 mmol). The resulting solution was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature and washed with saturated aqueous sodium carbonate solution (4×50 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a brown oil which crystallised upon standing. The crude crystalline material was triturated in isopropyl ether (100 ml) and stirred at 0° C. for 2 hr. The mixture was filtered and the crystalline material was washed with ice cold isopropyl ether (3×100 ml) followed by cold petroleum ether (100 ml). The resulting solid was dried overnight under reduced pressure to furnish the title compound (85.3 g, 68%). m/z (ES+) 203 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:40])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH:17]1([C:7]2([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:11]3[CH2:12][N:13]([C:32]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:40])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CNCCN12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccccc1)N1CCN2C(=O)OC(C3CCCCC3)(C3CCCCC3)C2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.1 %

Procedure:
To a solution of 1,1-dicyclohexyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.13 g, 0.42 mmol) in tetrahydrofuran (1 mL) were sequentially added diisopropylethylamine (0.5 mL) and phenyl chlorocarbonate (0.10 g, 0.64 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=7:3), crystallized from diisopropyl ether and dried to obtain the title compound (88 mg, yield 49%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.O>CCOCC>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: OCCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (10.8 g, 285 mmoles) in Et2O (300 mL) was very carefully added a solution of methyl 4-(benzyloxy)phenylacetate (6, 72.8 g, 284 mmoles) in Et2O (200 mL) over 40 minutes. After an additional 30 minutes, ethyl acetate (200 mL) was added, followed by H2O (500 mL) and the mixture maintained at 0° C. The mixture was then allowed to separate into two phases. The aqueous phase was extracted with Et2O (2×500 mL). The combined extracts were dried over anhydrous Na2SO4 and evaporated to yield 1-benzyloxy-4-(2-hydroxyethyl)benzene as a white solid, (7, 64.5 g, mp=85° C.). NMR (CDCl3)δppm: 7.33(s, 4H); 6.97(q, 4H); 4.97(s, 2H); 3.67(t, 3H); 4.43(t, 3H); 4.27(s, 1H). (Scheme II, Step 2.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]2)=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: OC1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: OC1CCN(c2ccc(F)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (10 g), 3-hydroxypyrrolidine (3.56 g), palladium(II) acetate (462 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.57 g) and cesium carbonate (26.8 g) in toluene (220 ml) was stirred under an argon gas atmosphere at 90° C. for 16 hr. After cooling to room temperature, the reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washing were combined and the solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20-25:75) to give the title compound (5.91 g, yield 58%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36](Cl)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:37][C:36]([C:22]#[C:21][C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:23])[CH:4]=4)=[N:9][C:10]=23)=[N:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ncc(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (135 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (162 mg, 57%). MS (ISN) 568.1 [(M−H)−]; mp 217° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C@@H:12]([NH:36]C(=O)OC(C)(C)C)[C:13](=[O:35])[NH:14][C:15]1[CH:16]=[C:17]2[C:33](=[O:34])[NH:32][N:31]=[CH:30][C:19]3=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21][C:22]([CH:23]=1)=[C:18]23.[ClH:44]>O1CCOCC1>[ClH:44].[NH2:36][C@H:12]([CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:13]([NH:14][C:15]1[CH:16]=[C:17]2[C:33](=[O:34])[NH:32][N:31]=[CH:30][C:19]3=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21][C:22]([CH:23]=1)=[C:18]23)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc2ccccc2c1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 99 %

Procedure:
Preparation of example 176 from the title compound of Example 154 (59 mg, 0.103 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner afforded the title compound (52 mg, 0.102 mmol) as an orange/yellow powder in 99% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH:6]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)([CH3:5])[CH3:4].[ClH:19]>CO>[ClH:19].[CH3:18][N:2]([CH3:1])[C:3]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)([CH3:5])[CH3:4]
Reactant: CN(C)C(C)(C)C1CCN(Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: CN(C)C(C)(C)C1CCNC1
Yield: 76.3 %

Procedure:
N,N-Dimethyl-2-[1-(phenylmethyl)-3-pyrrolidinyl]-2-propanamine (2.089 g, 8.47 mmol) was dissolved in a mixture of MeOH (50 mL) and 1N HCl (18.65 mL, 18.65 mmol), degassed and placed under argon. 10% Pd/C (625 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure N,N-dimethyl-2-(3-pyrrolidinyl)-2-propanamine hydrochloride (1.245 g, 76%). LCMS: (M+H)+: 157.2.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]([C:17]1[S:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+].Cl>C(O)C>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]([C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A suspension of methyl 5-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carbamoyl]thiophene-2-carboxylate (0.110 g) in ethanol (10 ml) was added with 2 N aqueous sodium hydroxide (1 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.093 g, yield: 89%) as pale yellow powdery crystals (melting point: 281-283° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][NH2:6])[CH3:2].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4][CH2:5][NH:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCN(CCN)CCCCC(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCN(CCCCC(C)C)CCNc1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 1 react N-ethyl N-(5-methylhexyl)-1,2-ethanediamine with 4-fluoro-1-nitrobenzene to obtain the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[CH2:32]([O:31][C:29](=[O:30])[C:28]([CH3:35])([CH3:34])[CH2:27][NH:26][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[CH3:33]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O

Procedure:
7-(4-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (21 mg, 0.06 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (34 mg, 0.24 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 20 mg. 1H NMR (CDCl3, 200 MHz): δ=8.41 (d, 1H, J=9.0 Hz), 8.32 (t, 1H, J=6.6 Hz), 7.60-7.39 (m, 4H), 7.12-7.06 (m, 2H), 4.24 (q, 2H, J=7.0 Hz), 3.61 (d, 2H, J=6.6 Hz), 1.37 (t, 3H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[ClH:15].C([O:18]CC)C.CO>>[ClH:15].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([NH2:13])=[O:18])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C#N)cc1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(N)=O)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 2-(4-isobutylphenyl)propionitrile (0.2 g; 1.07 mmol) in a (1:1) diethyl ether/methyl alcohol mixture (20 mL) is cooled at T=0-5° C. and gaseous HCl is bubbled into the solution for 1 h. Then the temperature is left to arise to r.t. and the mixture stirred overnight. After solvent evaporation under reduced pressure, the crude is dissolved in methyl alcohol (10 mL) and cooled at T=0-5° C. Ammonia is bubbled into for 1 h and the resulting mixture is left stirring overnight at r.t. After solvent evaporation under reduced pressure, the crude is suspended in diethyl ether (15 mL) and left stirring at r.t. for 2 h. The 2-(4-isobutylphenyl)propionamide hydrochloride (I) is isolated by filtration in vacuo as white solid (0.193 g; 0.80 mmol). Yield 75%. 1H-NMR (DMSO-d6): δ 8.80-8.50 (bs, NH3+Cl−); 7.40 (d, 2H, J=7 Hz); 7.15 (d, 2H, J=7 Hz); 3.98 (q, 1H, J=8 Hz); 2.42 (d, 2H, J=8 Hz); 1.90 (m, 1H); 1.57 (d, 3H, J=8 Hz); 0.88 (d, 6H, J=8 Hz).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][N:15]1[CH:19]2[CH2:20][C:21]([CH2:23][CH:16]1[CH2:17][CH2:18]2)=O>O1CCOCC1>[C:1]([CH:3]=[C:21]1[CH2:23][CH:16]2[N:15]([CH3:14])[CH:19]([CH2:18][CH2:17]2)[CH2:20]1)#[N:2]
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1C2CCC1CC(=CC#N)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 1.95 g of diethyl cyanomethylphosphonate in 40 ml of dioxane was cooled to 10° C., followed by the addition of 0.44 g of sodium hydride (60%) in an argon gas atmosphere. A solution of 1.39 g of tropinone in 25 ml of dioxane was added dropwise to the resulting mixture at the same temperature, followed by stirring at room temperature for 1.5 hours. After the solvent was evaporated, water was added to the residue. The resulting mixture was extracted with chloroform, followed by drying over anhydrous potassium carbonate. The solvent was then evaporated, whereby 1.66 g of 3-cyanomethylene-8-methyl-8-azabicyclo[3.2.1]octane was obtained as the oily form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:19])([CH3:20])[CH2:13][CH:12]2[OH:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC1(C)CC(O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A solution of 20.0 g (71 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-one and 2.94 g (78 mmol) of sodium borohydride in 100 ml of methanol and 300 ml of ethanol was stirred at RT for 3 h. The reaction mixture was then poured into 1300 ml of ice-water, and the precipitate was filtered off with suction and dried under reduced pressure. This procedure gave 19.3 g of 6-benzyloxy-2,2-dimethylchroman-4-ol, m.p. 83-84° C.