Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:27](=[O:28])[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:29]#[N:30])=[CH:23][CH:24]=4)[NH:19][C:18]=3[C:17]([CH3:32])([CH3:31])[C:16]=2[CH:33]=1.[C:34]([O:38][C:39]([N-:41][S:42](N1C=CC(=[N+](C)C)C=C1)(=[O:44])=[O:43])=[O:40])([CH3:37])([CH3:36])[CH3:35].O>N1C=CC=CC=1>[C:34]([O:38][C:39]([NH:41][S:42]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:27](=[O:28])[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:29]#[N:30])=[CH:23][CH:24]=4)[NH:19][C:18]=3[C:17]([CH3:31])([CH3:32])[C:16]=2[CH:33]=1)(=[O:44])=[O:43])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC1(C)c2cc(OCCN)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
Trifluoroacetic acid salt of 8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A8-2, 20 mg, 0.044 mmol) was dissolved in pyridine (0.5 mL), added with N-(tert-butoxycarbonyl)-N-[4-(dimethyl azaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (13.5 mg, 1 eq.), and then stirred at room temperature for 14 hr. The reaction solution was added to water, and then extracted with ethyl acetate. After washing with saturated brine, the organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were separated by silica gel preparative TLC (ethyl acetate) to obtain the title compound (16.1 mg, 68%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1)=[CH:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:8]=1>[Rh].C(O)C>[F:32][C:2]([F:1])([F:31])[CH:3]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:8]=1
Reactant: CCOc1ccc(C(=COCc2ccc(F)c(Oc3ccc(Cl)cc3)c2)C(F)(F)F)cc1
Agent: [Rh]
Solvent: CCO
Product: CCOc1ccc(C(COCc2ccc(F)c(Oc3ccc(Cl)cc3)c2)C(F)(F)F)cc1

Procedure:
A mixture of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-[3-(4-chlorophenoxy)-4-fluorobenzyloxy]prop-2-ene (6 g), rhodium on alumina (0.45 g - commercially available from the Aldrich Chemical Company Ltd, The old Brickyard, New Road, Gillingham, Dorset, England) and ethanol (130 cm3) was stirred under hydrogen at a pressure of 3.2 atmospheres for 8 hours. The catalyst was removed by filtration and the solvent evaporated under reduced pressure. The residual oil was purified by column chromatography on a silica gel support, eluted with n-hexane containing 30% by volume dichloromethane, to give (RS)-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-[3-(4-chlorophenoxy)-4-fluorobenzyloxy]propane.
Reaction SMILES: [C:1](=O)([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[C:15]([F:17])[C:14]([C:18]2[CH:23]=[N:22][C:21]([NH2:24])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC>CO>[CH2:1]([S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([C:18]2[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)=[C:15]([F:17])[CH:16]=1)[CH3:2]
Reactant: CC(=O)SCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCBr
Solvent: CO
Product: CCSCc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.7 %

Procedure:
To a solution of S-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methyl ethanethioate (100 mg, 0.280 mmol) in CH3OH (30 mL) were added Ph3P (150 mg, 0.560 mmol), K2CO3 (78 mg, 0.56 mmol), and bromoethane [drop-wise addition (60 mg, 0.56 mmol)] at rt. The reaction mixture was stirred at rt for 16 h, before removing the solvent in vacuo. The crude product was purified first by preparative-TLC followed by HPLC to give the title compound (70 mg HCOOH salt, 73%).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21

Procedure:
To 1-hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (2.37 grams) in 5 milliliters of pyridine was added octanoyl chloride (1.63 grams). The addition was carried out portionwise with stirring and resulted in the precipitation of a white solid. The reaction mixture was set on a steam bath for twenty minutes, then poured over ice cold aqueous HCl. An oil separated and subsequently crystallized on vigorous stirring. This precipitate was removed by filtration, dissolved in ether, dried over magnesium sulfate, filtered, and ether removed by evaporation under vacuum. The substance was purified by distillation, m.p., 33.5°-35.5° C.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[F:7][C:8]([F:36])([F:35])[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=1)[CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]([F:36])([F:35])[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=1)[CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:4][CH:2]([CH3:3])[CH3:1])[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])[CH:16]=1
Reactant: CC(C)O
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of propan-2-ol (2 mL) in N,N-dimethylformamide (5 mL), sodium hydride (72 mg, 3.00 mmol, 5.00 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (250 mg, 0.58 mmol, 1.00 equiv, 98%). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate and washed with 3×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 280 mg (99%) of product as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:19][C:18](=O)[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:18]2[CH2:17][O:16][CH2:19]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1COC1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1COC1
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 4-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol) and oxetan-3-one (56 mg, 0.78 mmol) in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (264 mg, 1.24 mmol). The resulting mixture was stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting oil was purified by column chromatography (Si—PCC, MeOH/DCM, 0-20%) affording 4-(Methyl(oxetan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester as an oil (40 mg, 16%). 1H NMR (CDCl3, 300 MHz): δ 4.66 (t, J=6.6 Hz, 2H); 4.61 (t, J=6.6 Hz, 2H); 4.16 (s, 2H); 3.95 (p, J=6.6 Hz, 1H); 2.63 (t, J=12.5 Hz, 2H); 2.39 (tt, J=11.7, 3.7 Hz, 1H); 2.20 (s, 3H); 1.60 (d, J=12.5 Hz, 2H); 1.46 (s, 9H); 1.44-1.28 (m, 2H).
Reaction SMILES: [CH:1]1(/[C:7](/[CH2:11][CH3:12])=[CH:8]/[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH:1]1(/[C:7](/[CH2:11][CH3:12])=[CH:8]/[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC/C(=C\CO)C1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC/C(=C\C=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a solution of (E)-3-cyclohexylpent-2-enol (1.50 g, 8.91 mmol) in dichloromethane (45 mL), cooled to 0° C., was added Dess-Martin periodinane (9.7 g, 22.9 mmol). The resulting suspension was warmed to room temperature and stirred for approximately 2 h until the reaction was judged to be complete by TLC. The reaction was poured into 100 mL of saturated aqueous NaHCO3 containing Na2S2O3 (3 g). This mixture was stirred vigorously until both layers became clear. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5% Et2O/pentane) to afford the title compound (1 g, 68% yield) as a colorless oil that was a 3:1 mixture of E:Z isomers. Major isomer: IR (film) 2927, 2746, 1668, 1622, 1450, 1189, 1124, 860 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.04 (d, 1H, J=8.24 Hz, CHO), 5.83 (d, 1H, J=8.24 Hz, C═CH), 2.61 (q, 2H, J=7.4 Hz, CH2CH3), 2.07 (tt, 1H, J=2.6, 11.0 Hz, CH2CHCH2), 1.88-1.71 (m, 5H), 1.41-1.15 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 191.8, 175.2, 124.9, 46.2, 31.9, 26.5, 26.3, 26.0, 25.9, 24.2, 15.4; HRMS (EI+) exact mass calculated for [M]+ (C11H18O) requires m/z 166.1358, found m/z 166.1355.
Reaction SMILES: [C:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:3])[CH3:2].Br[CH2:10][CH2:11][O:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.[I-:24].[Na+]>C(#N)C>[I-:24].[C:1]([N+:4]1[CH:8]=[CH:7][N:6]([CH2:10][CH2:11][O:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCCBr)cc1
Reactant: CC(=O)n1ccnc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OCCn2cc[n+](C(C)=O)c2)cc1
Temperature: 100 °C
Yield: 72.1 %

Procedure:
2.2 g of 1-acetylimidazole, 5.5 g of ethyl 4-(2-bromoethoxy)benzoate, and 3.0 g of sodium iodide were added to 10 ml of dry acetonitrile, and the mixture was heated in a sealed tube under nitrogen atmosphere at 100° C. for 6 hours. After the reaction mixture was cooled, the insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was triturated with an adequate amount of dry diethyl ether and the r resulting powder was collected by filtration and dried to obtain 6.2 g of 1-acetyl-3-[2-(4-ethoxycarbonylphenoxy)-ethyl]imidazolium iodide (72% yield). Colorless hygroscopic amorphous.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:32])[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[C:28]([F:31])([F:30])[F:29])[CH2:16][CH2:15]3)=[N:10][N:9]2[CH:33]=1)=O)C.[CH2:34]([NH2:39])[CH2:35][CH:36]([CH3:38])[CH3:37].[C-]#N.[Na+]>>[CH3:37][CH:36]([CH3:38])[CH2:35][CH2:34][NH:39][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:32])[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[C:28]([F:31])([F:30])[F:29])[CH2:18][CH2:19]3)=[N:10][N:9]2[CH:33]=1)=[O:3]
Reactant: CC(C)CCN
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Agent: [C-]#N
Agent: [Na+]
Product: CC(C)CCNC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (0.100 g, 0.215 mmol), isoamylamine (1 mL), and sodium cyanide (0.020 g, 0.408 mmol) was stirred at room temperature over night. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4, concentrated. The residue was purified by column chromatography. The title compound was obtained as a white solid in 85% yield (0.092 g). 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.74-7.7 (m, 1H), 7.65 (d, J=9.9 Hz, 1H), 7.21-7.16 (m, 1H), 6.86 (d, J=9.9 Hz, 1H), 4.02-3.92 (m, 1H), 3.89-3.79 (m, 1H), 3.62-3.54 (m, 2H), 3.49-3.39 (m, 4H), 3.35-3.28 (m, 2H), 1.74-1.6 (m, 1H), 1.53-1.44 (m, 2H), 0.91 (d, J=6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.5, 162.4, 154.7, 138.4, 137.0, 136.9, 135.6, 129.7, 129.6, 129.5, 126.4, 125.1, 123.3, 122.9, 122.4, 121.4, 118.1, 116.8, 116.5, 114.9, 114.6, 111.8, 46.2, 46.1, 45.6, 41.2, 38.5, 37.3, 25.7, 22.4. MS (ES+) m/z 507 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 102.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.284 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 175 mg (86.2% yield) of the titled compound. MS: m/z=603.2 (M+1).
Reaction SMILES: [Si]([O:8][CH:9]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:10][CH2:11][CH:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:13]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:9]([OH:8])[CH2:10][CH2:11][CH:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:13]2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile are dissolved in 65 ml of tetrahydrofuran, 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added, and the mixture is stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution are then added, and the mixture is stirred at reflux temperature for another 3 h. The cooled reaction mixture is concentrated under reduced pressure and the residue is purified chromatographically on silica gel using n-heptane/ethyl acetate 2/1. This gives 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxo-azetidin-1-yl]benzonitrile of molecular weight 430.48 (C26H23FN2O3); MS (ESI): 431.24 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:45]=[CH:44][C:35]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:34][CH:33]=1>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:44][CH:45]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)NCCC(=O)O)cc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)CCNC(=O)c1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 3-(4-amino-benzoylamino)-propionic acid according to the procedure of Example 66. MS (ES) m/z 595.9.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13][OH:14])=[CH:10][CH:9]=[CH:8]2.P(=O)(O)(O)O.O>C(Cl)Cl>[CH2:2]1[C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:13][O:14]1)[CH:6]=[CH:5][CH:4]=2
Reactant: OCc1cccc2cccc(CO)c12
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Product: c1cc2c3c(cccc3c1)COC2
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A 1-L 3-neck flask equipped with an overhead stirrer, a condenser, and a thermocouple was charged with (8-hydroxymethyl-naphthalen-1-yl)-methanol (33.0 g, 0.175 mol), concentrated phosphoric acid (225 mL), and water (5 mL). The reaction mixture was stirred at 140° C. for 3 h, cooled to room temperature, diluted with CH2Cl2 (800 mL) and transferred to a 2-L separatory funnel. After washing the organic layer with water and saturated NaHCO3 it was dried over MgSO4 and evaporated to yield 1H,3H-Benzo[de]isochromene as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:17][CH2:18]2)[CH2:9][CH2:8]1
Reactant: N[C@H]1CC[C@H](N2CCN(c3ccccn3)CC2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](N2CCN(c3ccccn3)CC2)CC1)c1ccccc1

Procedure:
To a solution of 5.8 g trans-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexylamine (Example 31a) in 100 mL of dichloromethane is added 4 mL of triethylamine and 2.84 mL of benzoyl chloride. The reaction mixture is refluxed under nitrogen for 1 hour. Saturated sodium bicarbonate solution is added. Some of the product comes out of solution at this point and is isolated by filtration. The organic layer is dried and evaporated to give 5.2 g of trans-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide; mp 241-244° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24]C(=O)C(F)(F)F)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].C([O-])(O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:24])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.2 %

Procedure:
To the solution of N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (0.40 g) in THF (27 mL) and water (3 mL) was added 5% LiOH solution (2.3 mL). The reaction was kept stirring at rt for 15 h and was worked up with sat. NaHCO3 solution (20 mL) and extracted with EtOAc (2×20 mL). The organic phase was dried (Na2SO4) and concentrated to afford the crude 3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]aniline (0.30 g, 95% yield) as yellow solid. ES-LC/MS (M+H)+=340.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[OH:13])([O-:3])=[O:2].[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=3[OH:13])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1)c1cccc([N+](=O)[O-])c1O
Temperature: 50 °C
Yield: 40.9 %

Procedure:
A mixture of 1.7 g (9 mmol) of 3-nitrosalicylic acid and 2.7 g (9 mmol) of 4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenylamine in 20 ml of toluene is heated with stirring to 50° C. 0.5 g of phosphorus trichloride is added, and the mixture is heated at the boil under reflux for a further 4 hours. After cooling, the mixture is concentrated and the residue is extracted with dichloromethane. The organic phase is washed repeatedly with water and dried over sodium sulphate. The solvent is distilled off, giving 1.7 g (41% of theory) of N-[4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenyl]-2-hydroxy-3-nitrobenzamide.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH2:15][O:16][C:17]3[C:22]([C:23]=2Cl)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1>C(N(CC)CC)C>[F:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15]2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(F)c(NCC3=C(Cl)c4ccccc4OC3)cc2o1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(F)c(NCC3COc4ccccc4C3)cc2o1

Procedure:
In a manner similar to Example 34, starting with 5-fluoro-6-[(4-chloro-2H-chromene-3-yl)methylamino]benzoxazolin-2-one and hydrogenating it in the presence of triethylamine, the title compound was prepared: m.p. 223°-224° C.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[C:31]1([S:37]([C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[C:20]1[CH3:29]
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
A mixture of triethylsilane (0.71 g), trifluoroacetic acid (0.53 g) and 1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.091 g), 2-benzenesulfonylbenzaldehyde (0.12 g) and 1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred at −10° C. for 15 minutes and then at room temperature for 2 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 to 0:1 by volume) to afford the title compound as a colourless gum (0.17 g).