Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[C:29]=2[CH3:30])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>[Pd].CO.O1CCCC1>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[C:29]=2[CH3:30])=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: Cc1ccn2c(C)c(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1

Procedure:
10% Palladium on carbon (10 g) was added to a mixture of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-3,7-dimethylimidazo[1,2-a]pyridine (27.3 g) in methanol (200 ml) and tetrahydrofuran (200 ml) and the mixture was stirred at ambient temperature under atmospheric pressure of hydrogen gas. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with ethyl acetate and the precipitate was collected by filtration to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (13.8 ).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:18]([CH3:30])[CH2:19][C:20]2[N:21]([CH3:29])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:17])=[CH:10][CH:9]=1.[NH3:31]>>[CH3:30][N:18]([CH2:19][C:20]1[N:21]([CH3:29])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16](/[CH:15]=[CH:14]/[C:11]1[CH:10]=[CH:9][C:8]([NH:3][C:4](=[O:7])[CH2:5][CH2:6][C:2]([NH2:31])=[O:1])=[N:13][CH:12]=1)=[O:17]
Reactant: N
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)CCC2=O)nc1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(NC(=O)CCC(N)=O)nc1
Temperature: 60 °C
Yield: 51.7 %

Procedure:
A mixture of (E)-3-[6-(2,5-dioxo-pyrrolidin-1-yl)pyridin-3-yl]-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (260 mg, 0.645 mmol) and ammonia (12 mL of 0.5M solution in 1,4-dioxane, 6.0 mmol) in a sealed tube was heated to 60° C. overnight. After cooling to ambient temperature, the resulting white precipitate was collected by filtration. The resulting solid was triturated with MeOH, washed with Et2O, and dried under high vacuum at 50° C. for 2 d to give the title compound (140 mg, 52%) as a white solid and as a mixture of amide rotamers: mp 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.67-10.63 (m, 1H), 8.62-8.58 (m, 1H), 8.21-8.07 (m, 2H), 7.60-7.25 (m, 5H), 7.12 (dd, J=7.7, 7.4 Hz, 1H), 7.00 (dd, J=7.3, 6.9 Hz, 1H), 6.77 (br s, 1H), 6.42-6.17 (m, 1H), 5.05-4.85 (m, 2H), 3.72-3.68 (m, 3H), 3.12-2.99 (m, 3H), 2.64-2.60 (m, 2H), 2.40-2.36 (m, 2H); MS (ESI) m/e 420 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:4]2[CH:3]=1.[C:21]([Mg]Br)#[CH:22].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:21]#[CH:22])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Cl)cc3c2C=O)cc1
Reactant: C#C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a cold (-78° C.) suspension of 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.90 g, 3.14 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesium bromide (7.5 mL, 0.5 M in tetrahydrofuran, 3.77 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at room temperature for 4 hours. The resultant solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration provided 1-[5-chloro-2-(4methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (1.05 g, 100%) as a white solid. 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.05 (s, 1H), 7.72 (d, 2H), 7.05 (d, 2H), 6.80 (dd, 1H), 5.78 (s, 1H), 3.91 (s, 3H), 2.74 (s, 1H), 2.53 (s, 1H); MS m/z 313 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][CH2:9][C:10]2([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]([BH3-])#N.[Na+].C=O>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH2:9][C:10]2([N:16]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH3:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(CCNC2(COC(c3ccccc3)c3ccccc3)CCCCC2)cc1
Agent: C=O
Agent: [Na+]
Product: COc1ccc(CCN(C)C2(COC(c3ccccc3)c3ccccc3)CCCCC2)cc1

Procedure:
The title compound was prepared as described in Example 5, Method A, using 1-diphenylmethoxymethyl-1-(4-methoxyphenethylamino)cyclohexane (see Example 4) and sodium cyanoborohydride/formaldehyde. The title compound was obtained as a colourless oil (0.58 g, 66%), which was characterised from its 1H-n.m.r. spectrum.
Reaction SMILES: [C:1]([OH:17])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48](=[NH:50])[NH2:49])[CH:44]=2)[CH:39]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:17][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:48](=[NH:49])[NH2:50])[CH:44]=2)[CH:39]=1)(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCC(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a solution of 4.3 g of n-pentadecanoic acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with ethyl ether, then with acetone, dissolved in a methanol-dimethylformamide mixture, freed from the insolubles by filtration, and concentrated under reduced pressure. The crystals formed upon addition of ethyl ether were recrystallized from methanol to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl pentadecanoate methanesulfonate.
Reaction SMILES: [CH3:1][Sn](C)(C)C.[OH:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[C:10](Br)=[CH:9][N:8]=1>>[OH:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:1])=[CH:9][N:8]=1
Reactant: Nc1cccc2c(O)ncc(Br)c12
Reactant: C[Sn](C)(C)C
Product: Cc1cnc(O)c2cccc(N)c12

Procedure:
According to the method of Example 106, Step A, a methylation reaction with tetramethyltin was performed by using Intermediate 138 to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[C:41]([O:49][CH3:50])=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:39][C:40]1[C:41]([O:49][CH3:50])=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: COc1c(F)cccc1B(O)O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1c(F)cccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 72.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (3-fluoro-2-methoxyphenyl)boronic acid (69 mg, 0.4 mmol), sodium carbonate (43 mg, 0.4 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-ethyl acetate) to give 79 mg (73% yield) of the title compound. Purity 100%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:20].S([O-])([O-])(=O)=S.[Na+].[Na+]>>[Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([C:8]([OH:20])([OH:13])[C:9]([F:10])([F:11])[F:12])=[N:6][CH:7]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cc1cc(C(O)C(F)(F)F)ncc1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(O)(O)C(F)(F)F)ncc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(5-bromo-4-methylpyridin-2-yl)-2,2,2-trifluoro-ethanol (345 mg; 1.2775 mmol) in dichloromethane (10 mL; 156.0 mmol) was added Dess-Martin periodinane (0.7313 g; 1.672 mmol). The reaction mixture was stirred at room temperature for 5 hours. 20 mL of a 10% aqueous solution of sodium thiosulfate was added and the reaction stirred for an additional 10 minutes. The reaction mixture was washed with 2 M aqueous sodium carbonate, dried over MgSO4, filtered, and concentrated. The crude product was carried forward without purification. LCMS (ESI): M+H=286.0; 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.72 (s, 1H), 7.59 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:20](=[O:21])[O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
A solution of 4-(2-methoxyethoxy)aniline (0.397 g, 2.37 mmol) and pyridine (1 mL, 12.4 mmol) in DCM (3 mL) in was treated with 4-nitrophenyl chloroformate (Aldrich) (0.505 g, 2.51 mmol) added in portions (exothermic!). The pale yellow solution was stirred at RT for 5 h. The reaction mixture was partitioned between 0.5N HCl (20 mL) and DCM (30 mL). The organic phase was washed with 0.5N HCl (30 mL), saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saturated aqueous sodium chloride (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (50 g, eluent: EtOAc in hexanes 10%-50%) to give 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.57 g, 72% yield) as an off—white solid. 1H NMR (400 MHz, CDCl3) δ 8.25-8.32 (m, 2H); 7.32-7.43 (m, 4H); 6.87-6.97 (m, 3H); 4.09-4.15 (m, 2H); 3.72-3.79 (m, 2H); 3.46 (s, 3H). m/z (ESI, +ve ion) 333.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]([F:17])([F:16])[F:18])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2ccc(C(F)(F)F)cc2n1
Product: CC(C#N)(Cn1nc2ccc(C(F)(F)F)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5-trifluoromethyl-2H-benzotriazol-2-yl)-propionitrile, described in Example 11, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.16 g, 61%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=474. 1H NMR: (400 MHz, CHLOROFORM-d): 1.88 (s, 3H), 5.39 (dd, J=112.8, 13.7 Hz, 2H), 7.38 (br s, 1H), 7.65 (d, J=9.1 Hz, 1H), 7.75-7.88 (m, 4H), 8.02 (d, J=9.0 Hz, 1H) and 8.25 (br s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −63.01 (s, 3F) and −42.23 (s, 3F).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[C:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH:9]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[C:8]1[CH2:15][CH2:14][CH:11]([CH:12]=[O:13])[CH2:10][CH:9]=1
Reactant: CC1=CCC(C2=CCC3(CC2)CO3)C1(C)C
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1=CCC(C2=CCC(C=O)CC2)C1(C)C
Reaction time: 2 h

Procedure:
6-(2,2,3-Trimethyl-cyclopent-3-enyl)-1-oxa-spiro[2.5]oct-5-ene (XIV, 2.72 g, 12.5 mmol,), dissolved in toluene (5 ml), are added dropwise to a solution of BF3.OEt2 (1.7 ml) in toluene (20 ml). After 2 hours, the reaction solution is poured onto ice (10 ml), then the phases are separated and the organic phase is washed once with saturated NaCl solution. The organic phase is then dried over Na2SO4, filtered off and concentrated in a rotary evaporator. 2.07 g of crude product having a purity of 83% are obtained, which is used in the next step without being purified further.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[C:20]2=[N:21][S:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].O[Li].O.Cl>C1COCC1.O>[N:23]1[S:22][N:21]=[C:20]2[C:15]([S:12]([NH:11][C:5]3[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=3[C:3]([OH:24])=[O:2])(=[O:13])=[O:14])=[CH:16][CH:17]=[CH:18][C:19]=12
Reactant: COC(=O)c1ccc(C)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(NS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A solution of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methylbenzoic acid methyl ester (1.22 g, 3.36 mmol) in 3:1 THF/water (10 mL) was treated with LiOH.H2O (1.41 g, 33.6 mmol) and was stirred at rt for 16 h. The mixture was acidified with 1 N HCl, and the resulting precipitate was collected by filtration, washing with water. Drying in air provided the title acid as a tan solid (0.89 g, 2.5 mmol, 74%). 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.84 (d, J=8.1, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.56 (br s, 1H), 6.83 (br d, J=8.4, 1H), 2.32 (s, 3H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16]/[C:17](/[C:27]([F:30])([F:29])[F:28])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([OH:24])=[O:23])[C:20]1([CH3:26])[CH3:25].[CH2:31]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[F:46])[CH2:41]O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:16]/[C:17](/[C:27]([F:28])([F:29])[F:30])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([O:24][CH2:41][C:40]2[CH:43]=[CH:44][C:45]([F:46])=[C:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:39]=2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: OCc1ccc(F)c(Cc2ccccc2)c1
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1ccc(F)c(Cc2ccccc2)c1
Yield: 36.5 %

Procedure:
A solution of dicyclohexylcarbodiimide (0.4 g) in dichloromethane (10 cm3) was added to a stirred mixture of (1RS, cis)-3-(Z-2-chloro,3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (0.54 g), 3-benzyl-4-fluorobenzyl alcohol (0.43 g), 4-dimethylaminopyridine (0.02 g) and dry dichloromethane (5 cm3), and the resultant mixture stirred at the ambient temperature (ca. 20° C.) for 18 hours. The reaction mixture was then heated to the reflux temperature for 3 hours, and subsequently cooled again. The precipitate which formed was removed by filtration, and the filtrate concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by column chromatography using a silica column eluted with a mixture of ethyl acetate (1 part by volume) and petroleum ether (boiling range 60°-80° C., 19 parts by volume), to yield 3-benzyl-4-fluorobenzyl (1RS, cis)-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylate (0.32 g).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([S:34]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][N:8]3[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[C:6]([CH3:19])=[N:7]3)=[CH:13][CH:14]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NS(=O)(=O)c3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sulfonamide formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 54 mg, 0.20 mmol) in dichloromethane (1 mL) was added triethylamine (72 μL, 0.51 mmol) and phenylsulfonyl chloride (36 μL, 0.25 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved in methanol (0.5 mL) and treated with aqueous LiOH solution (1 M, 0.4 mL). After 1.5 h, the mixture was neutralized and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% trifluoroacetic acid).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[C:20]=3[CH3:29])/[CH3:18])/[C:9]2=[O:30])=[CH:4][CH:3]=1.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>ClCCl>[C:31]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[C:20]=3[CH3:29])/[CH3:18])/[C:9]2=[O:30])=[CH:4][CH:3]=1)(=[O:34])[CH:32]=[CH2:33]
Reactant: C=CC(=O)Cl
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1c(C)n(C)c2ccccc12
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3c(C)n(C)c4ccccc34)C2=O)cc1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution obtained by dissolving 1.2 g of N-(4-hydroxyphenyl)-2-[(E)-1-(1,2-dimethyl-3-indolyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 16 in 25 ml of dichloromethane, followed by dropwise addition of 0.36 ml of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, followed by removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(1,2-dimethyl-3-indolyl)ethylidene]-3-isopropylidenesuccinimide in yield of 88.5%.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:31]([O:30][C:28]([C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:23]1)=[O:29])[CH3:32]
Reactant: ClCCOCCN1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of sodium hydride (0.40 g, 0.010 mol, 60% oil dispersion) and 10,11-dihydro-5H-dibenz[b,f]azepine (1.95 g, 0.010 mol) in dry dibutylether (30 ml) was heated at reflux temperature for 3.5 h under an atmosphere of nitrogen. The reaction mixture was cooled to 100° C. and bis-2-chloro-ethyl ether (4.7 ml) was added and the mixture was heated at reflux temperature for 16 h. The reaction mixture was cooled and water (50 ml) was added. The mixture was extracted with toluene (100 ml). The organic extract was dried over sodium sulphate and the solvent evaporated in vacuo to give 2.8 g of an oily residue containing 2-chloro-1-(2-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)ethoxy)ethane. To this oil was added ethyl (R)-3-piperidinecarboxylate (3.0 g, 0.019 mol) and the mixture was heated at 150° C. for 1.5 h. The reaction mixture was allowed to cool to 80° C. and toluene (100 ml) was added. The mixture was then allowed to cool to room temperature and a solution of potassium carbonate (1.4 g) in water (100 ml) was added. The phases were separated and the organic phase was washed successively with water, an aqueous sodium acetate solution (pH 5) and an aqueous citric acid solution (pH 5). The organic phase was then extracted with a 5% aqueous citric acid solution (50 ml). The acidic (pH 1) aqueous extract was washed with toluene (2×50 ml) and then a 4 N sodium hydroxide solution was added until pH 6-7. The aqueous mixture was extracted with toluene and the organic extract was treated with charcoal and dried over sodium sulphate. The solvent was evaporated in vacuo to give 2.1 g (50%) of (R)-N-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.20 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.C([O-])(O)=O.[Na+]>[O:1]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2c(-c3ccccc3)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(-c3ccccc3)ccnc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 7-hydroxy-4-phenylquinoline (366 mg), tert-butyldimethylsilyl chloride (200 mg) and imidazole (282 mg) in DMF (2 mL) was stirred at r.t. for 17 hr and then diluted with 5% aq. NaHCO3 (20 mL). The mixture was extracted with EtOAc (3×) and the combined organics were washed with H2O (3×), brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; EtOAc/hexane (15:85)) provided the title compound as a solid.