Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([O:62][C:63]4[N:68]=[CH:67][C:66](O)=[CH:65][CH:64]=4)[CH:60]=3)[N:55]=[CH:54][N:53]=2)=[N:47]1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([O:62][C:63]4[N:68]=[CH:67][C:66]([O:1][CH2:2][CH:3]5[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]5)=[CH:65][CH:64]=4)[CH:60]=3)[N:55]=[CH:54][N:53]=2)=[N:47]1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCC5CN(C(=O)OC(C)(C)C)C5)cn4)cc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (110 mg, 0.60 mmol), triphenyl phosphine (160 mg, 0.60 mmol) and diethyl azodicarboxylate (0.095 mmol, 0.60 mmol) were added to a tetrahydrofuran solution (3 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (100 mg, 0.30 mmol) obtained in Example 6-3), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain tert-butyl 3-({[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}methyl)azetidine-1-carboxylate (136 mg, yield: 90%) as a pale yellow amorphous solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17]
Reactant: COCCN
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 77.7 %

Procedure:
While cooling with ice, 17.2 g (0.05 mole) of α-[4-(p-trifluoromethylphenoxy)-phenoxy]-propionyl chloride are added dropwise to a mixture of 4.1 g (0.055 mole) of 2-methoxyethylamine, 7.5 ml (0.055 mole) of triethylamine and 50 ml of methylene chloride, and the temperature is allowed to rise to 20° C. The reaction mixture is stirred for 2 hours, then concentrated. The residue is filtered in ether over a small column of silica gel. Concentration of the filtrate affords 14.9 g (77.6%) of α-[4-(p-trifluoromethylphenoxy)-phenoxy]-propionic acid (2-methoxy)-ethylamide with a melting point of 73°-75° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.N1C=CC=CC=1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccnc1C1CCC2(CC1)OCCO2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccnc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyridin-3-ylamine (0.141 g, 0.603 mmol, prepared as described in Example 3: Steps A-B from 3-amino-2-bromopyridine) was dissolved in anhydrous dichloromethane (10 mL) under Ar, treated with methanesulfonyl chloride (0.155 mL, 1.48 mmol), a few drops of anhydrous pyridine, and stirred at ambient temperature for 24 h. The reaction was quenched with saturated aqueous NaHCO3, the aqueous layer extracted thrice with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a very hygroscopic yellow solid. ESI-MS (m/z): Calcd. For C14H20N2O4S: 312. found: 313 (M+H)
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:28][CH2:29][N:30]1[C:34]2=[N:35][CH:36]=[CH:37][C:38](Cl)=[C:33]2[CH:32]=[N:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1.O>[CH2:21]([O:28][CH2:29][N:30]1[C:34]2=[N:35][CH:36]=[CH:37][C:38]([O:8][C:3]3[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=3)=[C:33]2[CH:32]=[N:31]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccnc2c1cnn2COCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccnc3c2cnn3COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
P-Aminophenol (800 mg, 7.33 mmol) and potassium t-butoxide (820 mg, 7.31 mmol) were dissolved in NMP (10 mL), and potassium carbonate (510 mg, 3.69 mmol) was added thereto. The resulting mixture was stirred at room temperature for 1 hour, and 1-benzyloxymethyl-4-chloro-1H-pyrazolo[3,4-b]pyridine (860 mg, 5.62 mmol) was added thereto. The resulting mixture was stirred at 80° C. for 0.5 hours. The reaction container was cooled, and the content was diluted with water (100 mL) and extracted with ethyl acetate (100 mL) three times. The combined organic layer was washed with saturated brine (50 mL) twice, dried, and concentrated. The residue was purified by silica-gel column chromatography (Fuji Silysia, BW300, 30 g, n-hexane:EtOAc=1:1) to give 4-(1-benzyloxymethyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline as a light-yellow syrup (1105 mg, yield: quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][OH:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:33][C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][O:15][CH2:33][C:34]3[CH:35]=[C:36]([C:44]([F:46])([F:47])[F:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=3)([CH2:11]2)[CH:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cc(CI)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC2C[C@@]2(CO)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC2(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
To Intermediate 19, one enantiomer being (1S,2S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.40 g, 1.4 mmol) in THF (10 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5M/toluene, 4.1 mL, 2.1 mmol) dropwise and the mixture was stirred for an additional 5 minutes. 1-Iodomethyl-3,5-bis-trifluoromethyl-benzene (0.69 g, 1.9 mmol) in THF (4 mL) was added and the reaction stirred at −78° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. Water was added cautiously and the solvent removed at reduced pressure. The residue was partitioned between H2O and EtOAc, the organics were washed with brine and dried over calcium sulfate, filtered and concentrated to an oil. The crude product was purified by flash chromatography by elution with a gradient of hexanes to 20% EtOAc/Hexanes to give the title compound (0.52 g, 73% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:22]([O:24]C(C)(C)C)=[O:23])([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([CH:11]([CH3:38])[CH2:12][P:13]([CH2:20][CH:21]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:22]([OH:24])=[O:23])([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CP(=O)(CC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CP(=O)(O)CC(CCC(=O)O)C(=O)O)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a solution of di-tert-butyl 2-[[[2-(benzylcarboxy)propyl]tert-butoxyphosphinyl]methyl]pentane-1,5-dioate (1.6 g, 2.89 mmol) in dichloromethane (10 ml) under nitrogen was added trifluoroacetic acid (10 ml). The reaction mixture was stirred for two hours and then concentrated under reduced pressure. Additional dichloromethane was added to the reaction residue and removed under reduced pressure. The product was dissolved in ethyl acetate and washed with water, then the organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure leaving a clear oil (800 mg, 72%). 1H NMR (D2O): δ1.2 (m, 3H), 1.6-1.8 (m, 4H), 2.1 (m, 2H), 2.2 (m, 2H), 2.6 (m, 1H), 2.8 (m, 1H), 5.0 (m, 2H), 7.3 (m, 5H). Analysis calculated for C17H23PO8 1.0H2O: C, 50.50; H, 6.23. Found: C, 50.52; H, 5.92.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH:21]([CH3:23])[CH3:22])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4fluorophenyl)-5-(3-methyl-1-butenyl)pyridine (Example 27) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.14 (m, 4 H) 4.33 (d, J=5.5 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.22 (sept, J=6.6 Hz, 1 H), 2.27 (m, 2 H), 1.35 (m, 1 H), 1.33 (d, J=7 Hz, 6 H), 1.30 (d, J=7 Hz, 6 H), 1.17 (m, 3 H), 0.70 (d, J=6.6 Hz, 6 H). FAB-MS: calculated for (C23H32FNO) 357, found 358 (M+H). Anal. Calcd for C23H32FNO: C, 77.27; H, 9.02; N, 3.92. Found: C, 77.34; H, 9.15; N, 3.69. mp 43-45° C. Rf=0.2 (20% ethyl acetate/hexane).
Reaction SMILES: Br.C[O:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1.C([O-])(O)=O.[Na+]>Br.O>[S:10]1[C:6]2[CH:5]=[C:4]([OH:3])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9]1
Reactant: COc1ccc2ncsc2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2ncsc2c1
Yield: 57 %

Procedure:
6-methoxybenzo[d]thiazole hydrobromide (1.00 g, 4.06 mmol) was dissolved in aqueous hydrobromide (10 mL of 48% solution). After heating to reflux for 10 hours, the mixture was cooled in an ice bath and diluted with water (50 mL). After adjusting the pH to 8 with the slow addition of solid NaHCO3, the mixture was filtered, washing the solid with water and air-drying to provide the product (0.35 g, 57%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].[Li]CCCC.[CH2:23]=[O:24]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:23][OH:24]
Reactant: C=O
Reactant: C#CCCCc1nc(-c2ccccc2)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCCC#CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Alkyne 1-7 (1.44 g, 6.4 mmol) was dissolved in THF (100 mL) at −78° C. under N2 atmosphere. nBuLi (5.6 mL, 9.0 mmol) was then added and the reaction stirred at −78° C. for 1 hour. Paraformaldehyde (320 mg, 9.6 mmol) was then added in one portion and the reaction stirred while allowing equilibration to 23° C. over 16 hours. Reaction was washed with dilute aqueous HCl, water, brine, and dried over MgSO4. After removing solvent in vacuo chromatography of the residue with 25% EtOAc/Hexanes gave 1.5 g of the product 1-8 as a clear yellowish oil (92%). NMR CDCl3 (δ): 7.97 (@H, m); 7.43 (3H, m); 4.25 (2H, t, J=2.2, 4.4 Hz); 2.60 (2H, t, J=7.3, 14.6 Hz); 2.33 (3H, s); 2.27 (2H, m); 1.89 (2H, m). M+1=256.2.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:48])[CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([NH:21][C@H:22]([B:35]2[O:43]C3C(C)(C4CC(C3)C4(C)C)[O:36]2)[CH2:23][C:24]2[C:25](OC)=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([OH:29])=[O:28])=[O:20])[CH2:14][CH2:13]1)=O)(C)(C)C.Cl>>[NH2:8][C@@H:9]([CH3:48])[CH2:10][NH:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]([NH:21][C@H:22]2[CH2:23][C:24]3[CH:32]=[CH:31][CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]=3[O:36][B:35]2[OH:43])=[O:20])[CH2:16][CH2:17]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](NC[C@H](C)NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: Cl
Product: C[C@H](N)CN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
To 3-((2R)-2-(2-(trans-4-((S)-2-(tert-butoxycarbonylamino)propylamino) cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid from Step 2 in a flask was added 3N aqueous HCl and the reaction mixture was stirred at refluxing for 1 hr. The product was purified using reverse phase HPLC and dried using lyophilization. ESI-MS m/z 409 (MH)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].[CH:12]([O-])([O-])[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:12][O:13][CH2:14][CH3:15])[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: CCOC([O-])[O-]
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: CC(=O)OC(C)=O
Product: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Yield: 62.5 %

Procedure:
A mixture of 36 g (0.189 mole) of 3-carboxymethylrhodanine, 33.6 g (0.225 mole) of ethyl orthoformate and 225 ml of acetic anhydride was subjected to reactiqn under reflux for about 1 to 2 hours and then the reaction mixture was concentrated. A precipitate was formed by the addition of a small amount of chloroform to the residue. The precipitate was separated and recrystallized from ethyl acetate to give 29.2 g of 3-carboxymethyl-5-ethoxymethylidenerhodanine in the form of brownish white crystal (yield: 62.5 %).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([C:11]([C:13]2[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=2)=[CH2:12])[N:8]=[CH:7]1)(=O)=O.[H][H]>CCO.[Pd]>[O:17]1[C:16]2[CH:21]=[CH:22][C:13]([CH:11]([C:9]3[N:8]=[CH:7][NH:6][CH:10]=3)[CH3:12])=[CH:14][C:15]=2[O:20][CH2:19][CH2:18]1
Reactant: [H][H]
Reactant: C=C(c1ccc2c(c1)OCCO2)c1cn(S(=O)(=O)N(C)C)cn1
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccc2c(c1)OCCO2)c1c[nH]cn1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
4-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-imidazole-1-sulfonic acid dimethylamide (Intermediate-J1) (0.25 g, 0.75 mmol) in EtOH (10 mL) was reduced with 10% Pd/C catalyst (25 mg) under 40 psi of hydrogen at rt for 2.5 h. The mixture was filtered through Celite. The solution was concentrated and the residue was dissolved in 1.5 M HCl (10 mL) and heated to reflux for 3 h. The mixture was cooled to rt and basified with sat solution of NaHCO3. The mixture was extracted with ethyl acetate (2×) and the organic solution was dried over Na2SO4, filtered and evaporated to give 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-imidazole (Intermediate-J2) as a tan solid 0.14 g (87%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([OH:23])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[OH:23])[CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccc(C(O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(O)Cc2ccnc(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To the solution of [4-(2-hydroxy-2-p-tolyl-ethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (80 mg, 0.24 mmol) in DCM (2 mL) is added trifluoroacetic acid (0.5 mL). The mixture is stirred for 30 min at room temperature. Then saturated NaHCO3 aquaous solution (10 mL) is added slowly and the resulting mixture is extracted with DCM (2×10 mL). All the organic layers are combined and concentrated. The crude is purified by silica flash column chromatography eluting with EtOAc in Heptane (gradient from 0% to 100%) to give 40 mg of the desired product.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[C:18]=1[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([Cl:1])[C:13]2[O:17][CH2:16][CH2:15][C:14]=2[C:18]=1[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)NCCCc1c(Cl)ccc2c1CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NCCCc1c(Cl)cc(Cl)c2c1CCO2
Reaction time: 64 h
Yield: 42.7 %

Procedure:
N-Chlorosuccinimide (173 mg) was added to a solution of N-[3-(5-chloro-2,3-dihydro-benzofuran-4-yl)-propyl]-acetamide (0.2 g) in glacial acetic acid (5 ml) at room temperature under nitrogen and the mixture stirred for 64 h. The solution was adusted to pH 9 with sodium carbonate (2N; 10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with brine (20 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by HPLC, eluting with 50% acetonitrile/water+0.1% TFA gave the title compound as a colourless gum (97 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26]([C:28]1[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[N:29]=[N:30][C:31]([O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:32][CH:33]=1)=[O:27]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Reactant: COC(=O)c1ccc(Cl)nn1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)nn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (obtained in Example 93, step 6) by alkylation with methyl-6-chloropyridazine-3-carboxylate [CAS Reg. No. 65202-50-8]. MS (m/e)=482.0 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C1O[C:14]([CH2:16][CH2:17][NH2:18])([CH3:15])[O:13]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:15][C:14](=[O:13])[CH2:16][CH2:17][NH:18]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(F)ccc1C=O
Reactant: CC1(CCN)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1C1CC(=O)CCN1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
4-Fluoro-2-methyl-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluenesulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Product: COC(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 97.5 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and methyl chloroformate. Yield 97.5%
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.CO>O1CCCC1>[NH2:7][CH2:6][C:5]1[C:4]([Cl:11])=[CH:3][C:2]([NH2:1])=[C:9]([I:10])[CH:8]=1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc(I)c(N)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A dried 25 ml of two-neck round bottom flask was filled with argon gas. The solution of 4-amino-2-chloro-5-iodo-benzonitrile (63.8 mg, 0.23 mmol) in tetrahydrofuran was put into the flask and cooled to 0° C. To the solution was added Borane-THF complex (2 eq, 0.46 mmol, 0.4 ml) slowly. The temperature of the mixture was raised and heated to reflux for 12 hours. After confirming the completion of the reaction with TLC, to the solution was added methanol slowly (generation of bubbles) and stirred for 2 hours. The methanol was removed under reduced pressure and the residue was extracted with ethylacetate. The ethylacetate layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a yellow syrup (46.5 mg, 71.85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30]C1C=C(C(=O)CC2C=CN=CC=2)C=CC=1OCC1C=CC2C(=CC=CC=2)N=1>>[F:30][C:14]1[CH:13]=[C:12]([C:8]2[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:11][NH:10][N:9]=2)[CH:29]=[CH:28][C:15]=1[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Product: Fc1cc(-c2n[nH]cc2-c2ccncc2)ccc1OCc1ccc2ccccc2n1

Procedure:
Following the procedure for the preparation of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline but substituting 1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (bs, 2H), 8.19 (d, J=8.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.71 (m, 4H), 7.54 (t, J=7.1 Hz, 1H), 7.18 (m, 3H), 7.07 (m, 2H), 5.42 (s, 2H); MS: (M+H m/z=397.0).