Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=3[C:17]#[N:18])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].[Al]>C1COCC1>[CH3:25][O:24][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=3[CH2:17][NH2:18])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21)OC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Al]
Solvent: C1CCOC1
Product: COC(Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21)OC
Temperature: 0 °C
Yield: 97 %

Procedure:
2-(1-(2,2-Dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorobenzonitrile (3.80 g, 11.13 mmol) in THF (100 mL) was added dropwise to a stirred 0° C. suspension of lithium aluminum hydride (0.6338 g, 16.70 mmol) in THF (100 mL). The reaction mixture was maintained at 0° C. until complete addition of the starting material was achieved. The reaction mixture was warmed to room temperature and stirred until complete consumption of starting material was seen by HPLC analysis. The reaction mixture was added dropwise to a stirred room temperature solution of saturated aqueous Rochelle's salt. The two phase mixture was rapidly stirred for 30 minutes until the aluminum salts were in solution. The layers were separated and the aqueous layer extracted with more EtOAc. The combined organics were dried (MgSO4) and concentrated under reduced pressure to afford 3.73 g (97%) of the crude product, which was used without further purification. MS (APCI+) m/z 346 (M+1) was detected. 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.48 (d, 1H, J=9 Hz), 6.9-7.15 (m, 5H), 4.76 (t, 1H, J=5.3 Hz), 4.49 (d, 2H, J=5.3 Hz), 3.88 (s, 2H), 3.36 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:9]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of 1H-Imidazole-4-carboxylic acid methyl ester (1.0 g, 7.93 mmol) in N,N-dimethylformamide at 25° C. was treated with triethylamine (2.2 mL, 15.86 mmol) and triphenylmethylchloride (2.43 g, 8.72 mmol). The reaction was stirred at 25° C. for 8 h and then concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with water, a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50:50 ethyl acetate/petroleum ether) afforded 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.88 g, 98.6%) as a white foam: 1H NMR (DMSO-d6, 300 MHz) δ7.56 (s, 1H), 7.47 (m, 10H), 7.09 (m, 6H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OC)=O.[NH2:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:36])[C:28]([C:33]([OH:35])=[O:34])=[CH:29][NH:30]2)=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl.C(#N)C>[C:1]([NH:4][CH:5]([CH3:6])[C:7]([NH:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:36])[C:28]([C:33]([OH:35])=[O:34])=[CH:29][NH:30]2)=[CH:25][CH:24]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc2c(=O)c(C(=O)O)c[nH]c2c1
Reactant: CC(=O)N[C@@H](C)C(=O)O
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)NC(C)C(=O)Nc1ccc2c(=O)c(C(=O)O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of 3.93 g (30 mmol) of N-acetyl-L-alanine, 3.30 ml (30 mmol) of N-methyl morpholine, 2.33 ml (30 mmol) of methyl chloroformate, and 80 ml of acetonitrile is stirred at -10° to -20° for 30 minutes. A mixture of 4.08 g (20 mmol) of 7-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8.4 ml (60 mmol) of triethylamine, 7.6 ml (60 mmol) of chlorotrimethylsilane, and 100 ml of dichloromethane is stirred at room temperature for 30 minutes and then cooled to -20°. The cold mixed anhydride is added to the cold silylated quinoline and stirred with cooling for 3 hours and overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is treated with water. The solid is filtered to give 3.98 g of 7-[[2-(acetylamino)-1-oxopropyl]-amino]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[O:10][C:9]=2[CH:18]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O.[I-].[K+]>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:19]4[CH:23]=[CH:22][N:21]=[CH:20]4)=[CH:18][C:9]=3[O:10][C:11]=2[CH:16]=1
Reactant: ClCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)oc1cc(OCCn3ccnc3)ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
0.5 g of potassium iodide was added to 19.6 g (0.06 mole) of 1-chloro-2-(7-chlorodibenzofuran-3-yloxy)-ethane and 16.4 g (0.24 mole) of imidazole in 50 ml of dimethylformamide, and the mixture was stirred for 16 hours at 110° C., cooled and then evaporated down under reduced pressure. The residue was partitioned between 100 ml of water and 1 liter of methylene chloride, and 20 ml of 50% strength sodium hydroxide solution were added, while cooling with ice. The organic layer was separated off, washed with three times 50 ml of water, dried, and evaporated down under reduced pressure. The solid, colorless residue was left to stand with 15 ml of ether at +5° C. for 1 hour, after which it was filtered off under suction and washed with 20 ml of cold n-pentane. 13.2 g (70.4% of theory) of N-[2-(7-chlorodibenzofuran-3-yloxy)-ethyl]-imidazole of melting point 150°-151° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:4]=1/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])#[N:2].[OH-].[Na+].O.Cl>C(O)C.O1CCCC1>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:4]=1/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])#[N:2]
Reactant: CCOC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1C1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C3CCc4ccccc43)c2n1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 88.6 %

Procedure:
Ethyl (2E)-3-[3-cyano-1-(indan-1-yl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]acrylate (5.54 g) was dissolved in ethanol-tetrahydrofuran (1 : 1, v/v) (60 ml) and a 2 N aqueous sodium hydroxide solution (14.4 ml) was added thereto at 50° C. After agitating the mixture at 50° C. for 40 minutes, the reaction solution was poured into water (300 ml), and concentrated hydrochloric acid was added thereto to adjust the pH to 3 to 4. The resultant mixture was extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). After the organic layer was washed with water and dried (over anhydrous magnesium sulfate), the solvent was distilled off under reduced pressure and the crystal was collected by filtration to give (2E)-3-[3-cyano-1-(indan-1-yl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]acrylic acid (4.55 g, 89%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.ClCCl.[NH2:13][C:14]1[C:19]([OH:20])=[C:18]([F:21])[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]=1[C:29]#[N:30].[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=O)([O-:33])=[O:32]>O>[F:21][C:18]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]([C:29]#[N:30])=[C:14]2[C:19]=1[O:20][C:36]([C:35]1[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=1[N+:31]([O-:33])=[O:32])=[N:13]2
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3[N+](=O)[O-])nc2c1C#N
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Diisopropylethylamine (523 μl, 3 mmol) was added to a dichloromethane (10 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methyl-biphenyl-3-carbonitrile (I-41) (485 mg, 2.0 mmol), and after cooling with ice, 2-nitrobenzoyl chloride (408 mg, 2.2 mmol) was added, followed by stirring at the same temperature for 1 hour. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. In xylene (30 ml) in the presence of a catalytic amount of p-tosylic acid, the resulting residue was heated under reflux for 16 hours with a Dean-Stark device. After cooling, the solvent was evaporated away, and the resulting residue was dissolved in chloroform, washed with saturated sodium bicarbonate water, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography. Elution with chloroform gave the entitled compound (576 mg, 77%) as a colorless solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>C(N(CC)CC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: C#CC(=O)OCC
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C#Cc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a mixture of 1,4-diiodobenzene (1.0 g, 3.03 mmol), Pd(PPh3)2Cl2 (580 mg, 0.606 mmol) and CuI (115 mg, 0.606 mmol) in triethylamine (20 mL), ethyl propiolate (590 mg, 6.06 mmol) was added under N2. The resulting mixture was stirred at 80° C. for 16 h under N2. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound (360 mg, 30%). 1H NMR (DMSO-d6, 400 MHz): δ 7.86 (d, 2H), 7.45 (d, 2H), 4.24 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[OH:10])[CH:5]=O.[CH3:12][O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:15])[CH:16]=[CH:5][C:4]1[CH:3]=[C:2]([I:1])[C:9]([OH:10])=[C:8]([I:11])[CH:7]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(I)c(O)c(I)c1
Solvent: c1ccccc1
Product: COC(=O)C=Cc1cc(I)c(O)c(I)c1
Temperature: 25 °C

Procedure:
A 50 mL round bottomed flask equipped with a Teflon coated magnetic stirring bar, a reflux condenser and a rubber septum was charged with 3,5-diiodo-4-hydroxybenzaldehyde (1 g, 2.68 mmol), methyl (triphenylphosphoranylidene) acetate (1.79 g, 5.36 mmol) and benzene (30 mL). The reaction mixture was heated to a gentle reflux for 24 h. The reaction mixture was cooled to ambient temperature and concentrated to dryness. The title compound obtained was a white solid (891 mg, 78%) after the crude material was subjected to flash chromatography (SiO2, using 20% EtOAc/Hex as the eluent).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3([CH:31]([CH:33]4SCCCS4)[OH:32])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=[O:3])[CH3:2].C1C(=O)N(Br)C(=[O:46])C1>C(#N)C.O>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:40])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:39])[CH2:12][CH2:13][C@@:14]3([CH:31]([OH:32])[CH:33]=[O:46])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)C5SCCCS5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Solvent: O
Solvent: CC#N
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C(O)C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a solution of 103 (1.2 g, 1.945 mmol) in acetonitrile (20 ml) and water (5.00 ml) stirred in air at rt was added NBS (1.385 g, 7.78 mmol) in one charge. The reaction mixture was stirred at rt for 0.5 h, then quenched with Na2SO3 (solid), concentrated and the residue was extracted with EtOAc. The organic phase was washed with water and saturated brine, dried over sodium sulphate and concentrated in vacuo to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-hydroxy-2-oxoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (104) (1.09 g, 1.083 mmol, 55.7% yield) as a light yellow solid which was used without further purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:16]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[N:19][N:18]=[N:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:39]([O:47][C@@H:48]1[CH2:56][C@@H:51]2[O:52][C:53](=[O:55])[CH2:54][C@@H:50]2[C@H:49]1/[CH:57]=[CH:58]/[C@@H:59]([O:66][Si:67]([C:80]([CH3:83])([CH3:82])[CH3:81])([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[CH:60]([CH3:65])[CH2:61][CH2:62][CH2:63][CH3:64])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:39]([O:47][C@@H:48]1[CH2:56][C@@H:51]2[O:52][C:53]([CH:24]([CH2:23][CH2:22][CH2:21][C:20]3[N:16]([C:15]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:17]=[N:18][N:19]=3)[C:25]#[N:26])([OH:55])[CH2:54][C@@H:50]2[C@H:49]1/[CH:57]=[CH:58]/[C@@H:59]([O:66][Si:67]([C:80]([CH3:82])([CH3:81])[CH3:83])([C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[CH:60]([CH3:65])[CH2:61][CH2:62][CH2:63][CH3:64])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: N#CCCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(C)[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC(C)[C@@H](/C=C/[C@@H]1[C@H]2CC(O)(C(C#N)CCCc3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2C[C@H]1OC(=O)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of lithium diisopropylamide (13.4 mL, 26.8 mmol, 2M solution) in THF (170 mL) was cooled to −78° C. as a solution of 1-(triphenylmethyl)-1H-tetrazole-5-pentanenitrile (10.55 g, 26.8 mmol) in THF (30 mL) was added slowly. The reaction was allowed to warm to ambient temperature 30 min, before cooling to −78° C. The reaction was stirred as a solution of (3aR,4R,5R,6aS)-5-(benzoyloxy)-4-[(1E,3S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-one (3.3 g, 5.4 mmol) in THF (50 mL) was added slowly. The reaction was warmed to room temperature and stirred for 16 h. The reaction was treated with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried and concentrated. Purification by normal phase chromatography eluting with a gradient of ethyl acetate in hexane afforded α-[(3aR,4R,5R,6aS)-5-(benzoyloxy)-4-[(1E,3S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-1-octenyl]hexahydro-2-hydroxy-2H-cyclopenta[b]furan-2-yl]-1-(triphenylmethyl)-1H-tetrazole-5-pentanenitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>C1COCC1>[CH3:32][N:33]([CH3:37])[C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:35]
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2

Procedure:
1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) was dissolved in THF (50 ml) and triethylamine (2 g) was added. At 5° C. dimethylcarbamoylchloride (1 g) in THF (15 ml) was added dropwise. After completed addition the mixture was refluxed for 1.5 hours. THF was evaporated. Water was added and extraction with dichloromethane (2×50 ml) and work-up as above of the combined organic phases yielded crude title product, which was purified by column chromatography on silica gel (eluted with 4% triethylamine in a 1:1 mixture of ethyl acetate and heptane). The pure title compound 6a crystallized from diethyl ether. Yield: 1.4 g, mp: 141-144° C. 1H NMR (CDCl3): δ 1.65-2.55 (m, 10 H); 2.70 (dd, 1 H); 2.70-2.95 (m, 2 H); 2.95-3.05 (m, 1 H); 3.05 (s, 6 H); 3.15 (broad d, 1 H); 3.35 (qui, 1 H); 6.25 (s, 1 H); 6.95-7.25 (m, 6 H); 7.45 (s, 1 H)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH3:33])=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=3)[CH:21]=[C:20]([CH2:34][O:35]C(=O)C)[C:19]=2[CH2:39][O:40]C(=O)C)[CH:15]=[CH:14][N:13]=1.C[O-].[Na+].C(O)(=O)C>CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH3:33])=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=3)[CH:21]=[C:20]([CH2:34][OH:35])[C:19]=2[CH2:39][OH:40])[CH:15]=[CH:14][N:13]=1
Reactant: CCOc1cc2cc(COC(C)=O)c(COC(C)=O)c(-c3ccnc(-n4ccc5ccccc5c4=O)c3)c2cc1OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc2cc(CO)c(CO)c(-c3ccnc(-n4ccc5ccccc5c4=O)c3)c2cc1OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.4 %

Procedure:
To a solution of 1-[2-(1-oxo-1,2-dihydroisoquinolin-2-yl)-4-pyridyl]-2,3-bis(acetoxymethyl)-6,7-diethoxynaphthalene (1.84 g) in methanol (50 ml) is added sodium methoxide (0.52 g) under ice-cooling. The mixture is stirred at room temperature for 2.5 hours. To the mixture is added sodium methoxide (0.17 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. Acetic acid (0.74 ml) is added to the reaction mixture under ice-cooling, and the mixture is concentrated under reduced pressure to remove the solvent. To the residue are added methylene chloride and an aqueous sodium hydrogen carbonate solution, and the methylene chloride layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:ethanol=25:1) to give 1-[2-(1-oxo-1,2-dihydroisoquinolin-2-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-diethoxynaphthalene (0.95 g) which is listed in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH2:8][NH2:9])[CH:7]=1.C([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])(OC(C)(C)C)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH:7]=1)[CH2:8][NH:9][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][NH:22]1
Reactant: NCc1cc(F)ccc1-n1cnnn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: O=C(NCc1cc(F)ccc1-n1cnnn1)[C@@H]1CCCN1

Procedure:
The title compound was prepared essentially according to the procedures described in Example 26, Step B, starting from 1-[5-fluoro-2-(1H-tetraazol-1-yl)phenyl]methanamine and Boc-L-proline.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(O)ccc(C(=O)NC)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 10 (200 mg, 0.96 mmol), the compound of Example 23 (400 mg, 0.96 mmol) and potassium carbonate (264 mg, 1.92 mmol) were added to about 20 ml of DMF. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. Chromatography of the crude material on silica gel with 30% ethyl acetate/hexane as eluant followed by rechromatography using the same solvent system gave the product.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1)=[O:17]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Temperature: 150 °C

Procedure:
A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-chlorobenzamide hydrochloride (Intermediate 19; 100 mg, 0.36 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 79 mg, 0.44 mmol) and DIPEA (190 μl, 1.09 mmol) in dry DMSO (1.2 ml) was sealed and heated at 150° C. for 17 hours. The reaction mixture was filtered through cotton wool and purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([NH2:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CCc1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.08 g), triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethyl chlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (20 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-(5-phenyl-4-isoxazolyl)propionamide (0.82 g, yield 78%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 151–152° C.