Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]4([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:44][CH2:43]4)=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:55])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]4([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:43][CH2:44]4)=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:55]=[O:16])=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Temperature: 76 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
AIBN (6.5 mg, 0.040 mmol) was added to a stirring solution of NBS (26 mg, 0.15 mmol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (61 mg, 0.13 mmol) in CCl4 (20 ml). The mixture was heated to 76° C. and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (18.5 mg, 0.158 mmol) and subjected to MW irradiation (150° C.) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2× followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (34 mg, 0.071 mmol, 54% yield) consistent by LCMS. LC-MS retention time: 1.64 min; m/z (MH+): 477. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:26]2[CH2:27][CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: c1ccc2c(c1)CCNC2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCc4ccccc4C3)CC2C)cc1OC
Yield: 38.9 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 1,2,3,4-tetrahydroisoquinoline (487 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (210 mg, yield: 39%) as a white crystal. (cis:trans=1:1)
Reaction SMILES: [F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][C:5]1([CH2:49][O:50][CH3:51])[CH2:10][CH2:9][CH2:8][N:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][C:5]1([CH2:49][O:50][CH3:51])[CH2:10][CH2:9][CH2:8][N:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1
Reactant: COCC1(Cc2ccccc2F)CCCN(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COCC1(Cc2ccccc2F)CCCN(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1
Reaction time: 0.25 h

Procedure:
In a flask, N-(3-(2-fluorobenzyl)-3-(methoxymethyl)piperidin-1-yl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (crude, from previous step) was reacted with trifluoroacetic acid (3 mL) for 1 hour. After reaction completion triethylsilane (0.1 mL) was added, and the reaction was stirred for an additional 15 minutes. The reaction was concentrated and rinsed with diethyl ether. The resulting remaining precipitate was dried and further purified using HPLC to give the titled compound. LC-MS: 488.24 [M+H]. LC/MS RT=2.49 min.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH3:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Br:13]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:13][C:6]12[CH2:11][C:2]3([CH3:1])[CH2:9][CH:8]([CH2:10][C:4]([CH3:12])([CH2:3]3)[CH2:5]1)[CH2:7]2
Reactant: BrBr
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reaction time: 4 h
Yield: 83 %

Procedure:
Mix 0.5 mol of 1,3-dimethyl adamantane with a ten times excess of bromine (5 mol). Slowly heat and stir for 4 hrs under reflux. Subsequently, allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until discoloration of the aqueous solution. Then extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]4[C:28]([CH3:39])=[N:29][CH:30]=[C:31]([C:37]=4[CH3:38])[C:32]([O:34]CC)=[O:33])[C:23]([Br:40])=[CH:22][N:21]=3)[S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]4[C:28]([CH3:39])=[N:29][CH:30]=[C:31]([C:37]=4[CH3:38])[C:32]([OH:34])=[O:33])[C:23]([Br:40])=[CH:22][N:21]=3)[S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(C)c(Oc2cc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)ns3)ncc2Br)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C(=O)O)c(C)c1Oc1cc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)ncc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
Ethyl 5-(2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-bromopyridin-4-yloxy)-4,6-dimethylnicotinate (prepared according to Example 7; 0.050 g, 0.08 mmol) was dissolved in EtOH (2 mL). NaOH (1N in H2O, 0.28 ml, 0.28 mmol) was added. The reaction stirred at 60° C. for 1 hour. The solution was cooled and concentrated. The material was acidified with saturated NH4Cl solution and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated to give 5-(2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-bromopyridin-4-yloxy)-4,6-dimethylnicotinic acid (0.012 g, 25% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 1.52-1.55 (m 2H), 1.89-1.93 (m, 2H), 2.34 (s, 6H), 2.84-2.93 (m, 3H), 3.90-3.94 (m, 2H), 6.20 (s, 1H), 8.62 (s, 1H), 8.89 (s, 1H), 11.69 (s, 1H), 13.09 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:27])[CH3:26])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 5.0 g (24.1 mmol) of 1-(4-nitro-phenyl)-piperazine in 100 mL of dichloromethane was added 5.04 mL (28.9 mmol) of diisopropyl-ethylamine. The solution is cooled in an ice-bath, treated with 1.89 mL (26.5 mmol) of acetyl chloride, and stirred at room temperature overnight. The reaction is washed successively with water, 0.5 M HCl, saturated sodium hydrogen carbonate, and brine, and dried over magnesium sulfate, and concentrated to give 5.91 g (98.5%) of the product as a solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH2:9]1)C1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23]>ClC(Cl)C>[CH2:9]1[C:10]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:11]=2[CH2:12][CH2:13][N:8]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cl
Reactant: c1ccc(CN2CCc3c(oc4ccccc34)C2)cc1
Solvent: CC(Cl)Cl
Product: COC(=O)N1CCc2c(oc3ccccc23)C1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 2-benzyl-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine (0.2 g, 0.75 mmol) and methyl chloroformate (0.358 g, 3.787 mmol) in dichloroethane (15 mL) was refluxed for 1 h. The reaction mixture was cooled to room temperature and washed with saturated NaHCO3 (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to furnish methyl 3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (0.150 g, 85.7%). 1H NMR (200 MHz, CDCl3): δ 2.70-2.76 (m, 2H), 3.80 (s, 5H), 4.72 (m, 2H), 7.22 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(4′-Bromobiphenyl-4-yl)methanol (0.70 g, 2.7 mmol) and imidazole (0.54 g, 8.0 mmol) were dissolved in tetrahydrofuran (20 mL), and tert-butyldimethylchlorosilane (1.2 g, 8.0 mmol) was added under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, and subsequently washed sequentially with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.90 (hexane/ethyl acetate=9/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.92 g, 2.4 mmol) as a white solid (yield 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][OH:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2cc(-c3ccccc3)nc2CO[Si](C)(C)C(C)(C)C)cc1
Yield: 90 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-hydroxymethyl-4-phenylimidazole (1.68 g, 5.71 mmol) in CH2Cl2 (35 mL) with N,N-diisopropylethylamine (3.2 mL, 18.4 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.46 g, 9.69 mmol) at room temperature for 60 hours. Quench with H2O (40 mL), extract with CH2Cl2 (100 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 20:1→9:1) to provide 2.09 g (90% yield). MS (ES+): m/z=409 (M+H)+
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:27][O:28]C(=O)C)([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:32]1[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:27][OH:28])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@@H:6]([N:32]2[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1

Procedure:
To a stirred solution of nucleoside 40 (2.0 g, 3.7 mmol) in methanol (25 cm3) was added sodium methoxide (0.864 g, 95%, 16.0 mmol). The reaction mixture was stirred at room temperature for 10 min and neutralised with 20% aqueous hydrochloric acid. The solvent was partly evaporated and the residue was extracted with ethyl acetate (3×50 cm3). The combined organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×20 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v) as eluent to give 41 as a white solid material (1.58 g, 95%). δH (CDCl3) 9.95 (1H, br s, NH), 7.69 (d, J 8.1, 6-H), 7.35-7.17 (10H, m, Bn), 6.02 (1H, d, J 2.3, 1′-H), 5.26 (1H, d, J 8.1, 5-H), 4.80 (1H, d, J 11.7, Bn), 4.47 (1H, d, J 11.7, Bn), 4.45-4.24 (4H, m, Bn, 2′-H, 3′-H), 3.81 (1 H, d, J 11.9, 1″-Ha), 3.69 (2H, br s, 2′-OH, 1″-OH), 3.67 (2H, m, 5′-Ha, 1″-Hb), 3.48 (1H, d, J 10.3, 5′-Hb). δC (CDCl3) 163.78 (C-4), 150.94 (C-2), 140.61 (C-6), 137.33, 137.22, 128.59, 128.18, 128.01 (Bn), 102.16 (C-5), 91.46, 88.36 (C-1′, C-4′), 76.73, 74.66, 73.71, 73.29, 70.81, 62.81 (C-2′, C-3′, C-5′, C-1″, Bn). FAB-MS m/z 455 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Cl)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[CH3:37])[CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([C:32]4[S:33][CH:34]=[CH:35][C:36]=4[CH3:37])[CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1sccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1ccsc1C(CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Benzyl chloride 2.3 (113 mg, 0.434 mmol) and phenol 54.1 (100 mg, 0.362 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50° C. for 16 h, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% to 60% ethyl acetate in hexanes). Eluant containing desired compound was concentrated and dissolved in a THF/MeOH/2N LiOH(aq) (1:1:1) solution (2 mL). The mixture was stirred at room temperature for 90 min., the solution was poured into 0.65 N HCl(aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 154 mg (0.311 mmol) of carboxylic acid 54 was obtained. 1H NMR (400 MHz) (CDCl3) δ 7.43-7.70 (m, 8H), 7.21 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=5.0 Hz), 6.92 (d, 2H, J=8.6 Hz), 6.76 (d, 1H, 5.0 Hz), 5.09 (s, 2H), 4.74 (t, 1H, J=7.8 Hz), 3.05 (d, 2H, J=7.8 Hz), 2.15 (s, 3H).
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Using General Procedure I; a solution of ethyl [4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1cccc(Cl)c1
Product: COc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1c(F)cnn1C
Yield: 27 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-chlorophenylisocyanate, in a similar manner as described in Example 1.68. An additional purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) was necessary, providing a 10 mg (27% yield) of Compound 83: LCMS m/z (%)=377 (M+H37Cl, 25), 375 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.28 (s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 7.64 (dd, J1=8.8 Hz, J2=2.8 Hz 1H), 7.48 (d, J=2.8 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.34 (dd, J1=9.2 Hz, J2=0.8 Hz, 1H), 7.26 (dd, J1=8.2, J2=8.2 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.00 (dd, J1=8.8 Hz, J2=0.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.35 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: C([N:6]1[CH2:27][CH2:26][C:9]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)(OCC)=O.[OH-].[K+]>C(O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9]3[CH2:26][CH2:27][NH:6][CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CCCCCCCCn1c2c(c3cc(F)ccc31)CN(C(=O)OCC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCn1c2c(c3cc(F)ccc31)CNCC2
Yield: 67.3 %

Procedure:
To the solution of 2-carbethoxy-8-fluoro-5-n-octyl-1,2,3,4-tetrahydropyrido[4,3-b]indole (4a) in ethanol was added the aqueous solution of potassium hydroxide. The mixture was refluxed for 16 h. The reaction mixture was concentrated to remove ethanol and extracted with DCM for three times (15 mL×3). The DCM layer was washed with brine, dried with Na2SO4, filtered and concentrated to give brow residue. This residue was purified by silica gel column chromatography to give yellow oil. Yield: 67.3%. 1H NMR (300 Hz, CDCl3) δ 7.19-7.15 (m, 1H), 7.06-7.02 (m, 1H), 6.91-6.85 (m, 1H), 4.04 (br, 2H), 3.96 (q, 2H, J=7.35 Hz), 3.27 (br, 2H), 2.76 (br, 2H), 1.72-1.68 (m, 2H), 1.29-1.25 (m, 10H), 0.87 (t, 3H, J=6.4 Hz). 13C NMR (75 Hz, CDCl3) δ 159.06, 155.97, 135.02, 132.51, 125.65, 125.52, 109.49, 109.36, 108.86, 108.52, 102.86, 102.55, 43.11, 31.74, 30.31, 29.27, 29.13, 27.03, 22.56, 14.03. MS (ESI) [M+H]+ 303.2
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.I[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Ic1cccnc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccnc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 34, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-iodopyridine. The title compound was obtained in 82% yield as light brown foam. MS (m/e): 483.3 (MH+, 100%).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:12]Br>O>[Br:12][CH:4]([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: O
Product: CCOC(=O)C(Br)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a 0° C. solution of ethyl 4-methyl-3-oxopentanoate (5.0 mL, 31 mmol) in water (20 mL) was added bromine (16 mL, 31.3 mmol) via syringe pump (0.5 hour). The mixture was stirred at 0° C. for 0.5 hour. The solution was extracted with EtOAc (3×20 mL). The organic extracts were combined, extracted with brine (2×60 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 2-bromo-4-methyl-3-oxopentanoate (6.0 g, 82% yield). The product was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].C(N(CC)CC)C.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[Si:14]([O:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1C=CCO1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccco1

Procedure:
To a freshly distilled solution of 2(5H)-furanone (2.86 g, 34 mmol) in dichloromethane (20 ml), distilled triethylamine (6.6 ml. 47.4 mmol) is added under argon at 0° C. and then rapidly followed by tert-butyldimehylsilyltrifluoromethane sulfonate (8.6 ml, 37.3 mmol) The reaction mixture is allowed to return to room temperature and the stirring is maintained for two hours. The solvent is then removed under reduced pressure and the oily residue is purified by flash chromatography on silica gel (ethyl acetate-heptane, 1:9) in order to thus obtain compound 10 (Z=O) in the form of a slightly colored oil (5.3 g, 79%). The spectroscopic data for this compound (1H and 13C NMR) are identical to those described in the literature (G. Rassu, Z. Zanardi, L. Battistini, E. Gaetani, G. Casiraghi, J. Med. Chem ., 1997, 40, 168).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CN1C(=O)CCC1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc2sc(Br)nc2c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc2sc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-bromo-5-methoxybenzthiazole (1 eq), 4-Bromoaniline (2 eq) and disopropylethylamine was subjected to microwave in NMP at 220° C. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product. MS: MH+=335