Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:5][N:4]=1.Cl.N1C=CC=CC=1>ClCCl>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[N:4][CH:5]=2)=[N:11][CH:12]=1
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Temperature: 200 °C
Yield: 67.6 %

Procedure:
A mixture of 2-methoxy-5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridine (0.28 g, 1.04 mmol) and pyridine hydrochloride (1.00 g, 8.65 mmol) was heated in a kugelrohr oven at 200° C. for 10 minutes. After cooling to room temperature, the reaction mixture is dissolved in dichloromethane and extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound (180 mg, 68% yield) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH:17]([CH3:19])[CH3:18])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:4].Cl[C:21]1[S:25][N:24]=[C:23]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[N:22]=1>CS(C)=O.C(N(CC)CC)C.[Cl-].[Na+].O>[O:12]1[C:11]2[CH:15]=[CH:16][C:8]([CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@H:2]([NH:1][C:21]3[S:25][N:24]=[C:23]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:22]=3)[CH:17]([CH3:19])[CH3:18])=[CH:9][C:10]=2[O:14][CH2:13]1
Reactant: Clc1nc(-n2ccnc2)ns1
Reactant: CC(C)C(N)C(=O)NCCc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[C@@H](Nc1nc(-n2ccnc2)ns1)C(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.7 %

Procedure:
2-Amino-N-(2-benzo[1,3]dioxol-5-yl-ethyl)-3-methyl-butyramide (135 mg, 0.51 mmol) was dissolved in DMSO (2 mL) and triethylamine (150 μL). Next, the 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole (95.1 mg, 0.51 mmol) was added to the reaction vessel and it was stirred at room temperature for 16 hours. After this period, a portion of brine (50 mL) was added and the mixture was transferred to a separatory funnel and extracted with ethyl acetate (75 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude material was purified by Flash Chromatography (0-50% ACN/DCM gradient) to afford 20.4 mg of pure product, N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-ylamino)-3-methyl-butyramide. [M+H]+ 414.84; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.71 (s, 1H), 6.99 (s, 1H), 6.62-6.52 (m, 3H), 5.82-5.80 (m, 2H), 4.0 (Br s, 1H), 3.64-3.47 (m, 3H), 2.76-2.72 (m, 2H), 2.30-2.29 (m, 1H), 1.03-1.01 (m, 6H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[OH:14][C@H:15]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl.O>[CH3:10][O:11][CH2:12][O:14][C@H:15]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COCCl
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCO[C@H](Cc1ccc(N2CCOCC2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Diisopropylethylamine (1.15 ml) and chloromethyl methyl ether (0.5 ml) were added to a solution of benzyl (R)-2-hydroxyl-3-(4-morpholinophenyl)propionate (1.5 g) in dichloromethane (15 ml) under ice-cooling and the mixture was stirred at room temperature for 19 hours. This reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (20 ml×3). The organic layer was washed serially with 5% sodium hydrogencarbonate solution (20 ml), water (20 ml) and saturated aqueous solution of sodium chloride (20 ml) in the order mentioned and dehydrated over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography, elution being carried out with hexane-ethyl acetate (1:2, v/v). From the fraction containing the objective compound, the solvent was distilled off under reduced pressure to provide 1.73 g of benzyl (R)-2-methoxymethoxy-3-(4-morpholinophenyl)propionate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[H][H]>C1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: [H][H]
Reactant: CCN(c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])C1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCN(c1ccc(C(=O)c2ccccc2)cc1N)C1CCCCC1

Procedure:
7.1 g. of 3-nitro-4-(N-ethyl-N-cyclohexylamino)-benzophenone are dissolved in a 1:1 mixture of benzene and ethyl acetate, and 0.7 g. of palladiumized carbon are added to the mixture. The mixture is hydrogenated at room temperature and 3 atm. hydrogen pressure until the uptake of the calculated amount of hydrogen (this requires about one hour). Thereafter the catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. 6.35 g. of crude product are obtained. After recrystallization from isopropanol, 5.8 g. of pure 3-amino-4-(N-ethyl-N-cyclohexylamino)-benzophenone, melting at 106.5°-107.5° C are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[N:11][N:10]=[C:9]1[CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[C:12]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]2)=[N:11][N:10]=[C:9]1[CH2:25][N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCc1nnc(C2CCN(c3ccccn3)CC2)n1Cc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCN(C)Cc1nnc(C2CCN(c3ccccn3)CC2)n1Cc1ccccc1

Procedure:
The amine from example 43 (50 mg, 0.12 mmol), formaldehyde (37% aq, 40 μl, 0.49 mmol) and sodium triacetoxyborohydride (51 mg, 0.24 mmol) in dichloromethane (1 ml) was stirred vigorously at room temperature for 21 hours. The reaction mixture was partitioned between dichloromethane and aqueous sodium carbonate solution, and the layers separated. The organic phase was dried (MgSO4), evaporated under reduced pressure, and the product triturated from ether to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]=[O:11].C([O-])(=O)C.[K+].Br[C:18]1[CH:34]=[CH:33][C:21]([C:22]([C@@H:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([O:31][CH3:32])=[O:30])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][CH:25]3[C:29]([O:31][CH3:32])=[O:30])=[O:23])=[CH:33][CH:34]=2)[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]=[O:11]
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: O=CNc1ccc(I)cc1F
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)C1CCCC1C(=O)c1ccc(-c2ccc(NC=O)c(F)c2)cc1
Temperature: 80 °C
Yield: 169.4 %

Procedure:
To a suspension of 2-fluoro-4-iodophenylformamide (5.11 g, 19.28 mmol) bis(pinacolato)diboron (4.89 g, 19.28 mmol), potassium acetate (5.67 g, 57.84 mmol), and palladium acetate (129 mg, 0.58 mmol) in N,N-dimethylformamide (125 mL) was bubbled through argon for 30 minutes. The reaction mixture was then heated at 80° C. for 3 h. After the mixture was cooled to rt, methyl (R,R)-2-(4-bromobenzoyl)cyclopentanecarboxylate (2.2 g, 7.35 mmol, 97% ee), tetrakis(triphenylphosphine)palladium(0) (668 mg, 0.58 mmol), and cesium carbonate (9.43 g, 28.92 mmol) were added, and the reaction mixture was then heated at 80° C. for 16 h. The mixture was then cooled to rt, quenched with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Solvent was then removed under reduced pressure and the crude product was purified by flash chromatography (Biotage 75) using 1:1 ethylacetate/hexane to afford methyl 2-{[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentanecarboxylate (4.6 g, 65%). LC-MS ret. time 3.15 min, m/z 342.0 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.52–1.94 (m, 1H), 1.92–2.07 (m, 1H), 2.10–2.21 (m, 1H), 3.48 (m, 1H), 3.55 (s, 3H), 4.12 (q, 1H), 7.59 (dd, 1H), 7.62 (dd, 1H), 7.87 (d, 2H), 8.09 (d, 2H), 8.25 (t, 1H), 8.34 (s, 1H), 10.62 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:21]=[C:20]([Si](C)(C)C)[C:11]3[C:12]4[C:13]([NH:19][C:10]=3[C:9]2=[O:26])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=4)=[CH:5][CH:4]=1.[I:29]I>C(O)C.C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[I:29][C:20]1[C:11]2[C:12]3[C:13]([NH:19][C:10]=2[C:9](=[O:26])[N:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=1)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3
Reactant: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reactant: II
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Cn2cc(I)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Reaction time: 0.25 h

Procedure:
In a 2 L round bottom flask, 7-(4-methoxybenzyl)-3-methyl-5-trimethylsilyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (18.6 g, 47.505 mmol) was suspended in ethanol (1 L) and DCM (150 mL), then cooled in an ice bath. To the cooled mixture was added silver tetrafluoroborate (AgBF4, 10.17 g, 52.255 mmol) and after 15 minutes of stirring, iodine (18.08 g, 71.257 mmol) was added. The reaction was stirred at 0° C. for one hour followed by five hours at ambient temperature. The crude yellow solid was collected by filtration, suspended in 10% wt Na2S2O3 (700 mL) and stirred for 1 h. The solid was collected by filtration and again washed with 10% wt Na2S2O3. The product (light yellow solid) was collected by filtration, washed with water and diethyl ether and dried under high vacuum. The material was taken forward without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3 H) 3.81 (s, 3 H) 5.26 (s, 2 H) 6.90 (d, J=8.84 Hz, 2 H) 7.34 (d, J=8.59 Hz, 2 H) 7.44 (s, 1 H) 8.51 (s, 1 H) 8.92 (s, 1 H). ESI-MS: m/z 446.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:19][S:20]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: OCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCc1ccccc1

Procedure:
The 2-benzyloxyethanol (Aldrich, 0.25 g, 1.7 mmol), triethylamine (0.67 mL, 5.0 mmol), and methanesulfonyl chloride (0.19 mL, 2.5 mmol) in 20 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:15])(=[O:14])[NH:6][C:5]=1[C:16]([O:18][CH3:19])=[O:17].S(OC)(O[CH3:24])(=O)=O>CN(C=O)C.O>[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:14])(=[O:15])[N:6]([CH3:24])[C:5]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 30 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a suspension of 3.5 grams (.086 moles) of sodium hydroxide in 68 ml DMF, a solution of 20 grams (.078 moles) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is added in 34 ml DMF over a period of about 5 minutes at about 25° C. 11.9 Grams (.094 moles) of dimethyl sulphate is added over a period of about 30 minutes at a maximum temperature of 30° C. The reaction is stirred for 3 hours at 30° C. and diluted with about 150 ml of water. It is cooled to 15° C., filtered and washed well with water. After drying, there is obtained 20 grams (95%) of product, m.p. 163°-165° C.
Reaction SMILES: C([BH3-])#N.[F:4][C:5]([F:26])([F:25])[C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]=2[CH2:23][NH2:24])[CH:9]=[CH:10][CH:11]=1.O.O=[CH:29][C:30]([OH:32])=[O:31]>ClCCl.CO>[F:26][C:5]([F:4])([F:25])[C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][C:15]=2[CH2:23][NH:24][CH2:29][C:30]([OH:32])=[O:31])[CH:9]=[CH:10][CH:11]=1
Reactant: O=CC(=O)O
Reactant: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(O)CNCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22 %

Procedure:
In a reactor equipped with a filter and an emptying system and placed on a vortex, were introduced 0.33 g (0.656 mmol) of cyanoborohydride resin. The resin was swelled in 3 ml of dichloromethane, the mixture was stirred at r.t. for 10 min and then dichloromethane was removed by filtration. The operation was repeated a second time and then a mixture of 0.2 g of (3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl) methanamine and 0.055 g (0.596 mmol) of 2-oxoacetic acid hydrate solubilised in 3 ml of methanol was added. The mixture was stirred under a slow vortex at r.t. for 24 h. The resin was removed by filtration, washed with 15 ml of methanol, 15 ml of dichloromethane and then again 15 ml of methanol. The obtained filtrate was concentrated in vacuo and the residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol/aqueous ammonia (20% by mass), 80/20/2, v/v/v). 0.049 g (yield=22%) of 2-(((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)amino) acetic acid were obtained as a white solid. LC-MS: m/z=374 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.76 (d, J=6.7 Hz, 1H), 8.13 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.69 (dd, J=8.3, 7.1 Hz, 2H), 7.53-7.42 (m, 1H), 7.16 (td, J=6.8, 1.0 Hz, 1H), 4.17 (s, 2H), 3.31 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[OH:10].Br[CH2:12]Cl.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[O:10][CH2:12][O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: ClCBr
Reactant: COc1cccc(O)c1O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1OCO2
Reaction time: 4 h

Procedure:
A mixture of 3-methoxy-benzene-1,2-diol (1.161 g, 8.28 mmol) in DMF (10 mL) was added to bromo-chloro-methane (611 ul, 1.1 equivalents) and stirred at 90 degrees Celsius for 4 hours. The mixture was poured into water and extracted with dichloromethane. The organic layer was poured thru a phase separator cartridge and concentrated to dryness. The crude product is a yellow liquid. The liquid was purified by column chromatography yielding 1.21 g, (96%). 1H-NMR (DMSO, 500 MHz) 6.7 (t, 1H), 6.63 (d, 1H), 6.58 (d, 1H), 5.97 (s, 2H), 3.83 (s, 3H) HPLC (method A) 2.86 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[C:11]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:36]C1C=CC(C=O)=C(O)C=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].BrCC(C1C=CC(OC)=CC=1)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[C:11]([CH:10]=1)[O:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: C=Cc1ccc(OCc2ccccc2)cc1OCC(=C)c1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: COc1ccc(C(=O)CBr)cc1
Agent: [K+]
Product: C=Cc1ccc(OCc2ccccc2)cc1OCC(=O)c1ccc(OC)cc1
Yield: 74 %

Procedure:
Alternatively, the compound 2 can be obtained by reacting 4-benzyloxy-2-hydroxybenzaldehyde with a mixture of MTPPB and t-BuOK, followed by reaction with 2-bromo-4′-methoxyacetophenone, and the resultant mixture, instead of being subjected to purification to afford compound 2a, was continuously reacted with a mixture of MTPPB and t-BuOK in THF, giving a one pot yield of 74%.
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[C:16]=2[CH3:27])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:35])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:35][CH2:27][C:16]1[C:17]([C:23]([F:24])([F:25])[F:26])=[C:18]([CH:21]=[CH:22][C:15]=1[N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:19]#[N:20]
Reactant: Cc1c(N=C(c2ccccc2)c2ccccc2)ccc(C#N)c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(N=C(c2ccccc2)c2ccccc2)c(CBr)c1C(F)(F)F
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of the benzonitrile (3.53 g, 9.69 mmol) from step D in CCl4 (90 mL) was added NBS (1.98 g, 11.14 mmol) and benzoyl peroxide (70%, 0.352 g, 1.45 mmol). The mixture was heated at reflux for 3 h. After cooling to ambient temperature, the reaction was diluted with CH2Cl2 (100 mL), washed with 1N NaOH (100 mL), brine (100 mL), dried (MgSO4) and concentrated. Purification by SiO2 chromatography (10% EtOAc in hexanes) afforded 3-(bromomethyl)-4-[(diphenylmethylidene)amino]-2-(trifluoromethyl)benzonitrile (4.08 g, 95%) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J=8.3 Hz, 1H), 7.78-7.11 (m, 10H), 6.91 (d, J=8.6 Hz, 1H), 4.78 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>C(#N)C.O.FC(F)(F)C(O)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)(=O)C.C(OCC)(=O)C.O.CO>[F:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][NH:6][C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]=[CH:14][CH:13]=[CH:12]4)=[O:8])[CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: O=C(NCc1cccc(Br)c1)c1ccc2ncccc2c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(-c2cccc(F)c2)c1)c1ccc2ncccc2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 8.3 %

Procedure:
To a mixture of quinoline-6-carboxylic acid 3-bromobenzylamide described in Preparation Example E+-8 (4.0 mg, 0.012 mmol), toluene (1 mL) and methanol (0.25 mL) were added an aqueous solution of 2M sodium carbonate (0.5 mL), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and 3-fluorophenylboronic acid (1.7 mg, 0.012 mmol), and the solution was stirred at 70° C. for 4 hours. After cooling, water, ethyl acetate and acetic acid were added for extraction, the solution was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (0.47 mg, 0.0010 mmol, 8.3%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].C[Si]([C:19]#[CH:20])(C)C.C([O-])([O-])=O.[K+].[K+]>C(N(CC)CC)C.CO.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>[C:19]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])#[CH:20]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of trimethylsilyl acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(2-trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:10][N:11]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:13]/[C:12]/2=[N:20]\[C:21]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=S)[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:39]#[C:40][NH2:41]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([O:4][C:5]1([CH2:10][N:11]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:13]/[C:12]/2=[N:20]\[C:21]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[N:41][C:40]#[N:39])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCCC1
Reactant: N#CN
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCCC1
Yield: 75 %

Procedure:
The product of Example 24D (1.6 g, 3.2 mmol), triethylamine (1.8 mL, 13 mmol), cyanamide (0.40 g, 9.7 mmol) and Hg(OAc)2 (2.0 g, 6.5 mmol) in acetonitrile (20 mL) were processed as described in Example 16E to provide the title compound (1.2 g, 2.4 mmol, 74% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.34-1.40 (m, 9H), 1.65-1.84 (m, 4H), 1.86-2.09 (m, 4H), 2.00-2.02 (m, 3H), 3.91 (s, 3H), 4.72 (s, 2H), 6.70 (s, 1H), 6.94 (d, J=9.1 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.7, 2.8 Hz, 1H); MS (DCI/NH3) m/z 489 (M+H)+. Anal. calculated for C24H29ClN4O3S: C, 58.94; H, 5.98; N, 11.46. Found: C, 58.88; H, 5.86; N, 11.32.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=O.B.C1COCC1>C1COCC1>[CH3:9][N:7]([CH2:5][C:4]1[CH:3]=[C:2]([NH2:1])[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=1)[CH3:8]
Reactant: CN(C)C(=O)c1cc(N)cc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Product: CN(C)Cc1cc(N)cc(C(F)(F)F)c1

Procedure:
3-Amino-N,N-dimethyl-5-trifluoromethyl-benzamide (2.0 g; 8.6 mmol) dissolved in THF (20 ml) is reduced with a 1 M solution of BH3.THF (26 ml) as described in Stage 134.1, yielding the title compound: MS: [M+1]+=219.