Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:49]C(OCC(C)=C)=O)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:33][O:34][C:35]([O:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:36])[N:29]([C:43]3[N:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.CN(C=O)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>[C:18]([OH:20])(=[O:17])[CH3:19].[C:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:33][O:34][C:35]([O:37][CH:38]([CH2:39][CH3:40])[CH2:41][CH3:42])=[O:36])[N:29]([C:43]3[N:44]=[CH:45][CH:46]=[CH:47][N:48]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:8]=1)(=[NH:1])[NH2:49]
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(CC)CC)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCC(CC)OC(=O)OCOc1nc([C@H](Nc2ccc(C(=N)N)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of acetic acid 2-(3-{(R)-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)-[5-(1-ethylpropoxycarbonyloxymethoxy)-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl]methyl}-2-fluoro-5-methoxyphenoxy)ethyl ester (Example 51, 266 mg), DMF (2 mL) and acetic acid (0.196 mL), tetrakis(triphenylphosphine) palladium (0) (20 mg) was added, and the resulting mixture was stirred overnight at an external temperature of 45° C. After cooling the mixture to room temperature, the reaction solution containing the captioned compound was divided into 4 equal lots, and used for the following reactions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([CH2:23][C:24](N(OC)C)=[O:25])[CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:24](=[O:25])[CH2:23][CH:20]3[CH2:22][CH2:21]3)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Reactant: CON(C)C(=O)CC1CC1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(C(=O)CC3CC3)cc21

Procedure:
Prepared from 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester and 2-cyclopropyl-N-methoxy-N-methyl-acetamide using a procedure analogous to that of Preparation 263. MS: [M+H]+=331.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:17][CH2:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[N:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:18][C:12]1[C:11](=[O:13])[N:10]2[CH2:14][CH2:15][CH2:16][NH:17][C:9]2=[N:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCN2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=c1c(Cl)c(-c2ccncn2)nc2n1CCCN2
Temperature: 90 °C

Procedure:
A suspension of 3.0 g (13.09 mmol) of 2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 60 ml of acetic acid was treated with 1.75 g (15.7 mmol) of N-chlorosuccinimide. The reaction mixture was heated at 90° C. during 18 h.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:15]4[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[CH3:21][O:20][C:16]1[C:15]2[CH:11]([NH:10][C:7]3[O:8][CH2:9][C:4]4[CH:3]=[C:2]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=5)[CH:23]=[CH:22][C:5]=4[N:6]=3)[CH2:12][O:13][C:14]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4cccc(C(F)(F)F)n4)cc3CO1)CO2
Yield: 12.3 %

Procedure:
The title compound (28 mg, 12%), light brown foam, MS (ISP): m/e=457.3 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-amine (Example 54) (188 mg, 0.5 mmol) and commercially available 2-amino-6-trifluoromethyl-pyridine (162 mg, 1.0 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[OH:15].[CH2:16](Br)[C:17]#[CH:18].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:13])([CH3:14])[CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[O:15][CH2:18][C:17]#[CH:16]
Reactant: COc1cc2c(cc1O)C(C)(C)CC2=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: C#CCOc1cc2c(cc1OC)C(=O)CC2(C)C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
6-Methoxy-3,3-dimethyl-5-hydroxy-indan-1-one (2.2 g), 1.5 g of propargyl bromide, and 3.7 g of K2CO3 in 9 ml of 1-methyl pyrrolidone was placed in a 25 ml reaction flask and stirred for one hour. Then, it was stirred further at 100° C. for one hour. The reaction mixture was distributed between water and ethyl acetate. The organic phase was washed with 1N NaOH solution and NaCl solution, dried over Na2SO4 and concentrated to yield 2.7 g of a yellow liquid. UV 310 nm (ε=18′734), MS: 244(M+), 229, 105(100%).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6](Br)[CH:5]=1.B1([C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)OCCCO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=1)[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1cc(F)cc(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(F)cc(-c2cccnc2)c1
Temperature: 120 °C
Yield: 55.5 %

Procedure:
To the solution of Methyl-3-bromo-5-fluorobenzoate (1.97 g, 8.44 mmol) in toluene (40 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphenylphoshine)palladium (O) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120° C. under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1% methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](O)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.O=P(Cl)(Cl)[Cl:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([Cl:18])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(S(=O)(=O)O)sc2ccc(F)cc12
Product: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Temperature: 60 °C
Yield: 93 %

Procedure:
A mixture of 5-fluoro-3-methylbenzothiophene-2-sulfonic acid (230 mg, 0.93 mmol) in POCl3 (5 mL) was heated at 60° C. over night. The POCl3 was evaporated and the crude product was dissolved in CH2Cl2 and washed with water. The organic phase was dried and evaporated to give 0.23 g (93%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH3:38][NH:39][S:40]([CH:43]1[CH2:45][CH2:44]1)(=[O:42])=[O:41].[Na]>C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N:39]([S:40]([CH:43]2[CH2:45][CH2:44]2)(=[O:42])=[O:41])[CH3:38])[N:7]=[C:6]([NH:11][C@H:12]([CH2:14][CH3:15])[CH3:13])[CH:5]=1
Reactant: CNS(=O)(=O)C1CC1
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(Cl)n1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(=O)(=O)C2CC2)n1
Temperature: 100 °C

Procedure:
Dissolve (S)-2-sec-butylamino-6-chloro-isonicotinic acid methyl ester (880 mg, 3.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (164 mg, 0.18 mmol), 2-(di-tert-butylphosphino)biphenyl (107 mg, 0.36 mmol) in toluene (18 mL) and THF (2 mL) in a previously nitrogen-filled sealed vessel. Add sodium cyclopropanesulfonic acid methylamide (700 mg, 4.42 mmol) into the mixture under nitrogen and flush the reactants again with nitrogen before sealing and heating overnight at 100° C. Cool the reaction to room temperature and dilute with ethyl acetate and diethyl ether and filter through a filtering agent. Concentrate and purify (silica gel chromatography, eluting with 0:100 to 08:92 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]3[N:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[CH:26][C:19]=34)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([NH:17][C:18]3[N:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[CH:26][C:19]=34)[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C[C@H]1CC[C@H](Nc2ncnc3[nH]ncc23)CC1)CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CCCC[C@H]2CC[C@H](Nc3ncnc4[nH]ncc34)CC2)cc1
Reaction time: 18 h

Procedure:
A mixture of 0.100 g of trans-[4-(4-phenyl-but-1-enyl)-cyclohexyl]-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine and 0.050 g of 10% palladium on carbon in 20 mL of ethanol was stirred under an atmosphere of hydrogen for 18 hours. The reaction was filtered to remove catalyst and concentrated under reduced pressure. Purification by C-18 reversed phase chromatography (0.1% trifluroacetic acid/water to 0.1% trifluoroacetic acid/acetonitrile) gave 0.200 g of pure product as a foam: HRMS=350.2324.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15]C)=[O:14])[CH2:7][CH2:6]2.P([O-])([O-])([O-])=O.Cl.CC(=O)OCC(COC(=O)C)OC(=O)C.[OH-].[Na+]>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2
Reactant: COC(=O)C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OCC(COC(C)=O)OC(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CC[C@@H](C(=O)O)C2
Reaction time: 4.5 h
Yield: 41.4 %

Procedure:
3 g (0.0136 mol) of methyl 6-methoxy-1,2,3,4-tetrahydro-2-naphthoate are dissolved in 100 ml of tert-butanol, and 300 ml of phosphate buffer at pH 7 are added to the solution prepared in this way. The pH of the solution, which rises to 7.3-7.5, is lowered to 7.1 by the addition of 1N HCl. 1.5 g of Sigma PPL enzyme (known as porcine pancreatic lipase type II, crude, Sigma L-3126--50 U/mg using triacetin) are added to the mixture. The pH tends to drop as the reaction progresses, but is kept constant by the addition of a 0.25N solution of NaOH, the pH being controlled by an automatic titration apparatus. After 4-5 hours, when about 22 ml of 0.25N NaOH have been consumed, sodium bicarbonate is added to the solution until the pH is 8 in order to stop the reaction by inactivation of the enzyme. Extraction is carried out with ethyl ether and the two phases are separated. The organic phase contains the unreacted ester principally of (S) configuration, which can be recovered as indicated in Example 2 below. The aqueous phase is acidified with concentrated sulfuric acid and the precipitate formed is filtered off to give 1.16 g of the title acid, which is crystallized from ethyl acetate. M.p. 130°-131° C.; [α]D20 =+57.8° (c=1.4%, CHCl3); ee 93.7% (HPLC performed under conditions (a)). This product is purer than that described in EP-A-436435, preparation (O) (i).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:15])[C:9]2=[O:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:15])[N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]2=[O:29])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CN2CCC(c3ccc(Cl)cc3)(c3ccc(Cl)cc3)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)C1=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 25E (0.920 g, 1.73 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (2.66 mL, 34.6 mmol) under nitrogen. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to remove excess trifluoroacetic acid and then diluted with CH2Cl2 (150 ml). The organic layer was washed with saturated aqueous NaHCO3 solution, water, and brine, dried with MgSO4, filtered, and concentrated. Purification by chromatography on silica gel, eluting with 7N NH3 in CH3OH/CH2Cl2, 3:97) yielded the title compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42-7.30 (m, 8H), 4.16 (s, 2H), 3.40-3.29 (m, 7H), 2.75-2.59 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[OH:11][C:12]1[C:20]2[N:19]=[N:18][NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:11])[C:20]=3[N:19]=[N:18]2)=[CH:5][CH:4]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc3c(O)cccc32)cc1
Reaction time: 1 h

Procedure:
4-Methoxy-benzylbromide (2.976 g, 14.80 mmol) was added to a stirred suspension of 4-hydroxy-benztriazole (2.0 g, 14.80 mmol) and cesium carbonate (9.645 g, 29.6 mmol) in DMF (30 mL) at room temperature and the reaction mixture was stirred for 1 hour. Aqueous ammonium chloride (30 mL) was then added to quench the reaction and the mixture was then extracted with ethyl acetate (2×100 mL). The organic fractions were combined and concentrated under reduced pressure. The resulting residue was subjected to reverse phase chromatography (5-95% MeCN/H2O, 0.1% TFA). The product fractions were combined and extracted with dichloromethane (2×100 mL). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title product. 1H NMR (DMSO d6) δ 10.67 (s, 1, H), 7.29-7.27 (m, 3H), 7.15 (d, J=8.3 Hz, 1H), 6.88-6.84 (m, 2H), 6.63 (d, J=7.6 Hz, 1H), 5.80 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([OH:15])[CH2:10]2.N1C=CC=CC=1.[Cl:22][C:23]([C:33]([F:36])([F:35])[F:34])=[CH:24][C@@H:25]1[C@H:27]([C:28](Cl)=[O:29])[C:26]1([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[Cl:22][C:23]([C:33]([F:34])([F:35])[F:36])=[CH:24][C@@H:25]1[C@H:27]([C:28]([O:15][CH:9]2[CH2:8][C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)=[O:29])[C:26]1([CH3:32])[CH3:31]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3cccs3)c2C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC1Cc2cccc(-c3cccs3)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A stirred solution of 0.54 g (0.003 mole) of 4-(2-thienyl)-2-indanol and 0.25 g (0.003 mole) of pyridine in 15 mL of toluene was cooled to 5° C., and 0.65 g (0.003 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 5 mL of toluene was added dropwise. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 16 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give an oil residue. The oil was subjected to column chromatography on silica gel, eluting with 100% hexane then 1% ethyl acetatehexane. The appropriate fractions were combined and concentrated under reduced pressure to give 0.57 g of 4-(2-thienyl)-2-indanyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as an oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[C:15]([O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:16]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[CH2:13][CH:12]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:11]=1)=O)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[NH2:8][CH2:9][C:10]1[C:19]2[C:14](=[C:15]([O:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[C:16]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[CH2:13][CH:12]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC1=CC(c2ccccc2)Cc2c1ccc(OC(=O)C(C)(C)C)c2OC(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1OC(=O)C(C)(C)C)CC(c1ccccc1)C=C2CN
Reaction time: 2 h
Yield: 90 %

Procedure:
N-t-Butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthalene (14 g, 26 mmol), from Step 2, was dissolved in 75 mL of dioxane and saturated with anhydrous hydrogen chloride. The reaction mixture was stirred for 2 h and concentrated in vacuo. The solid residue was dissolved in a minimum amount of methanol and the methanol solution was added dropwise to an excess amount (500 mL) of diethyl ether. The precipitate was filtered, washed with diethyl ether and dried to give 9.1 g (90% yield) of 1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthalene hydrochloride as a white powder, m.p. 210°-212° C.; 1H NMR (d6 -DMSO) δ: 1.25 (s, 9H), 1.28 (s, 9H), 2.61 (dd, 1H), 2.89 (dd, 1H), 3.75-3.85 (m, 1H), 3.99 (s, 2H), 6.28 (d, 2H), 7.15 (d, 1H), 7.2-7.35 (m, 5H), 7.37 (d, 1H), 8.37 (br s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1.C(N(CC)CC)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].Cl>CN(C)C=O>[Si:25]([O:1][CH2:2][C:3]1[C@H:7]2[C@H:8]([O:16][CH3:17])[O:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C@H:6]2[CH2:5][CH:4]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO)=CC[C@H]12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1=CO[C@@H](OC)[C@@H]2C(CO[Si](C)(C)C(C)(C)C)=CC[C@H]12
Reaction time: 1 h
Yield: 93.9 %

Procedure:
3 g (12.5 mmol) of methyl (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran4-carboxylate was dissoved in 50 ml of dimethylformamide and 1.9 ml (13.8 mmol) of triethylamine was added thereto under nitrogen atmosphere. The reaction solution was stirred for one hour and then 2.07 g (13.8 mmol) of t-butyldimethylsilylchloride dissolved in 10 ml of dimethylformamide was added dropwise thereto. After stirring for 3 hours, 1N-aqueous hydrochloric acid solution was added in order to stop the reaction. Organic layer was extracted by the addition of diethylether and then it was washed with saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 4.16 g (Yield 94%) of methyl (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-1 -methoxy-1,4a,5,7a-tetrahydrocyclo penta[c]pyran-4-carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C@@H:16]3[O:21]C(=O)C)([CH3:14])[C@@H:12]([O:25]C(=O)C)[CH2:11][CH2:10]4)[CH2:7][C:6](=[O:29])[C:5]=2[CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C@@H:16]3[OH:21])([CH3:14])[C@@H:12]([OH:25])[CH2:11][CH2:10]4)[CH2:7][C:6](=[O:29])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2[C@@H](OC(C)=O)C[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
The keto-diester (23) (21 mg, 0.05 mmole) was added to a degassed 10% solution of potassium hydroxide in methanol-water (19:1) (4 ml), and the solution was boiled for 15 min under nitrogen. The solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ether. The extract was washed in succession with dilute hydrochloric acid and water, dried, and evaporated to give a residue which was chromatographed on silica (1 g) eluted with ether to give the product (6A) (15 mg, 90%), m.p. 225°-6° C. (from ether-light petroleum), νmax 3460 (OH) and 1655 cm-1 (CO), δ (250 MHz) 7.61 (1 H, d, J 2.5 Hz, 4-proton), 7.37 (1 H, d, J 8 Hz, 1-proton), 7.17 (1 H, dd, J 8 and 2.5 Hz, 2-proton), 4.84 (1 H, dt, H 3 and 2.5 Hz, 11-proton), 3.85 (3 H, s, OCH3), 3.74 (1 H, dd, J 9 and 7 Hz, 17-proton) 2.78 (1 H, dd, J 15 and 2.5 Hz, 12-proton), 2.71 (1 H, dd, J 10.5 and 2.5 Hz, 9-proton), 2.44 (10 H, m), 1.04 (3 H, s, 18-CH3);
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[C:11]1([CH2:17][O:18][CH2:19][CH2:20][CH2:21]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C(OCC)(=O)C>[C:11]1([CH2:17][O:18][CH2:19][CH2:20][CH2:21][O:10][C:8]2[CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(OCCCOCc2ccccc2)c1
Reaction time: 24 h

Procedure:
To a solution of 3-hydroxyacetophenone (5.5 g) in dimethylformamide (18 mL) was added 3-bromopropyl phenylmethyl ether (9.25 g) at ambient temperature followed by cesium carbonate (17 g). The suspension was stirred for 24 h and water was added followed by ethyl acetate. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined and washed twice with 2 N sodium hydroxide, four times with brine, and concentrated in vacuo to an oil to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH3:12])[NH:9]2)=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1.[Pd]>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1CCc2ccc(N)cc2N1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: Cc1ccc2ccc(N)cc2n1
Temperature: 25 °C

Procedure:
A mixture of 7-amino-2-methyl-1,2,3,4-tetrahydroquinoline (D65) (86 mg) and wet 10% palladium/charcoal (25 mg) in xylene (20 ml) was heated at reflux for 3.5 h. After cooling to room temperature the catalyst was removed via filtration and washed with further xylene. Evaporation of the combined filtrate and washings gave the title compound as a crude off-white solid (87 mg) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.87 (d, 1H), 7.56 (d, 1H), 7.14 (d, 1H), 7.03 (d, 1H), 6.91 (dd, 1H), 4.02 (br, 2H), 2.67 (s, 3H).