Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:4])CC.Cl[C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1.[C-]#N.[Na+]>CN(C)C1C=CN=CC=1.O>[Cl:12][C:11]1[C:6]([C:1]#[N:4])=[N:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=1
Reactant: CCC#N
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 15 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Propionitrile (656 ml), 2,3-dichloro-5-trifluoromethylpyridine (87.5 g) and 4-dimethylaminopyridine (52 g) were heated at reflux for 5 hours under nitrogen. The mixture was cooled and a solution of sodium cyanide (30 g) in water (110 ml) added at 15° C. After stirring at 15° C. for 5 hours the reaction was complete and water (250 ml) added to dissolve the inorganic salts. The organic phase was washed with water followed by extraction with 2N HCl to remove 4-dimethylaminopyridine. Propionitrile was removed by vacuum distillation at 40° C. to give the product, 3-chloro-2-cyano-5-trifluoromethylpyridine in 73 to 84% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>C(Cl)Cl>[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:8])=[O:44]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of 6.9 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 1.5 mL of pyridine and 69 mL of methylene chloride was added dropwise 3.27 g of 3-(chloromethyl)benzoyl chloride, followed by stirring for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, ethanol was added thereto, and the precipitated solid was collected by filtration, thereby obtaining 9.27 g of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([F:21])[CH:12]=2)=[N:4][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:21])[CH:12]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CC3)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(C2CC2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To methyl 4-(3-amino-6-cyclopropylpyrazin-2-yl)-2-fluorobenzoate (250 mg, 0.870 mmol) in THF (6 mL) and MeOH (3 mL) was added 1M LiOH (1.740 mL, 1.740 mmol). The reaction mixture was stirred at room temperature for 2 h. The pH of reaction mixtures was adjusted to ˜4 by aqueous. 2N HCl. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated to yield 4-(3-amino-6-cyclopropylpyrazin-2-yl)-2-fluorobenzoic acid (230 mg, 97%) as a light yellow solid. LCMS (m/z): 274.2 (MH+), 0.621 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12]COC)#[C:2][CH2:3][CH3:4]>Cl.CC(C)=O.CCOCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])#[C:2][CH2:3][CH3:4]
Reactant: CCC#Cc1ccc(F)cc1OCOC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCC#Cc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
1-But-1-ynyl-4-fluoro-2-methoxymethoxy-benzene (6.1 g, 29 mmol) is dissolved in 250 mL of a 10% solution of concentrated HCl in acetone. The solution is stirred at room temperature for 5 h. The reaction is diluted with ether and washed with saturated aqueous NaHCO3 and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 5% AcOEt/hexane) to yield 3.52 g (73%) of the title compound as an orange oil. GCMS m/e 164[M]+.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:22])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1.CCCCCC>CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]([NH:5][C:6](=[O:22])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCCN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1C(=O)NC(C)(C)C
Temperature: 25 °C

Procedure:
N-tert-Butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide can be then produced by dissolving N-tert-Butyl-6-chloro-4-(4-fluoro-2-methyl-phenyl)-nicotinamide in dimethylsulfoxide and potassium carbonate, followed by the addition of thiomorpholine. The resulting suspension is stirred, cooled to room temperature, and partitioned between ethyl acetate and half-saturated aqueous sodium chloride solution. The phases are then separated and the organic phase washed with half-saturated aqueous sodium chloride. The aqueous phases are then extracted with ethyl acetate. The combined organic extracts are dried and concentrated in a rotary evaporator to produce a yellow oil. This oil is heated with the dropwise addition of n-hexane to obtain a refluxing suspension, which can be cooled to room temperature and further stirred at 0° C. for about one hour. The precipitate is filtered off, washed with cold n-hexane:ethyl acetate 9:1, and dried in a vacuum oven to yield N-tert-butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide as a light beige powder.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: CC1CCNC(=O)c2cc3cc(F)cc(Br)c3n21
Reactant: OB(O)c1ccccc1
Product: CC1CCNC(=O)c2cc3cc(F)cc(-c4ccccc4)c3n21

Procedure:
The title compound, grey solid (67 mg, 87%), MS (ISP) m/z=309.4 [(M+H)+], mp 232.5° C., was prepared in accordance with the general method of example 1 from (RS)-7-bromo-9-fluoro-5-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 3) (77.8 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Ic1n[nH]c2ncccc12
Reactant: Fc1ccc(CBr)c(F)c1
Product: Fc1ccc(Cn2nc(I)c3cccnc32)c(F)c1
Temperature: 0 °C

Procedure:
Analogously to the synthesis of Example 7A, 54.00 g (215.98 mmol) of 3-iodo-1H-pyrazolo[3,4-b]pyridine (synthesis described in WO 2006/130673, Example 4) were reacted with 50.18 g (237.578) of 2,4-difluorobenzyl bromide. Ice-water was added to the crude product, the mixture was filtered off with suction and the precipitate was washed with isopropanol and pentane and then dried under high vacuum. This gave 76.7 g of the title compound (89% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][N:13]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:14][N:13]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)c1ccc(Br)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2F)nc1
Temperature: 90 °C
Yield: 42.2 %

Procedure:
To a round-bottom flask was added 2-fluoro phenylboronic acid (271 mg, 1.94 mmol), palladium tetrakis(triphenylphosphine) (22.4 mg, 0.0194 mmol)) and tert-butyl 6-bromonicotinate (500 mg, 1.94 mmol) and the mixture was evacuated 3× with N2. The solids were dissolved in 25 mL of DMF, followed by addition of 2.9 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. The mixture was cooled to room temperature and then poured into a seperatory funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO4, filtered and concentrated to afford an orange oil. The crude mixture was purified by chromatography (silica, 10% EtOAc:Heptane) to afford the desired product (224 mg, 40%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.16 (1H, d, J=2.2 Hz), 8.34 (1H, dd, J=8.3, 2.3 Hz), 7.90-8.05 (2H, m), 7.50-7.62 (1H, m), 7.33-7.44 (2H, m) 1.59 (9 H, s).
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.[OH:9][C:10]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:11]=1C#N.Cl>O.C1COCC1>[OH:9][C:10]1[C:17]([CH:18]([CH3:19])[CH3:20])=[CH:16][C:15]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:11]=1[C:7](=[O:6])[CH3:8]
Reactant: CC(C)c1cc(C#N)c(O)c(C(C)C)c1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(C)C)cc(C(C)C)c1O
Yield: 12.6 %

Procedure:
To dry THF (10 mL) there was added 3.0 M solution of methylmagnesium bromide in diethylether (Aldrich) (10.9 mL; 32.8 mmole) and then a previously prepared solution of 2-hydroxy-3,5-diisopropyl benzonitrile (2.78 g, 13.7 mmole) and dry THF (70 mL) was added. After 7 hours under the reflux the reaction mixture was mixed with water (100 mL), acidified with concentrated hydrochloric acid (50 mL) and refluxed for one more hour. After cooling and extraction with ethyl acetate an oily product was obtained, which was purified on a silica gel column, whereat there were obtained 380 mg (12.5%) of 2′-hydroxy-3′5′-diisopropylacetophenone:
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)=[O:10])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:20][C:21]([O:24][C:25]([NH:27][C@H:28]([C:35](O)=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])([CH3:23])[CH3:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([O:24][C:25]([NH:27][C@H:28]([C:35]([NH:1][C@@H:2]([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)=[O:10])=[O:36])[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:26])([CH3:22])([CH3:20])[CH3:23]
Reactant: COC(=O)CC[C@H](N)C(=O)NCc1ccc(I)cc1
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC)C(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
A solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-(4-iodobenzylamino)-5-oxopentanoate (2.129 g, 4.47 mmol) in DCM (15 mL) and TFA (10 mL) was stirred at room temperature for 4 h. After the solvent was evaporated, the reaction mixture was diluted with DCM, washed with sat. K2CO3 aqueous solution and concentrated in vacuo to afford (S)-methyl 4-amino-5-(4-iodobenzylamino)-5-oxopentanoate (1.67 g). A solution of (S)-methyl 4-amino-5-(4-iodobenzylamino)-5-oxopentanoate (1.67 g), Boc-Glu(OMe)—OH.DCHA (1.97 g, 4.44 mmol), EDCI (1.02 g, 5.33 mmol), HOBt (0.599 g, 4.44 mmol) in DCM (100 mL) containing DIPEA (2.26 mL) was stirred at room temperature under nitrogen for 20 h. The reaction mixture was diluted with DCM, washed with 1N HCl aqueous solution, sat. NaHCO3 aqueous solution and brine. The organic phase was separated and evaporated under reduced pressure to give a crude product, which was purified by flash chromatography with hexane/ethyl acetate as eluent to give (S)-methyl 4-(tert-butoxycarbonylamino)-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate (2.137 g, 77% over 2 steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.4 Hz, 2H), 5.44 (brs, 1H), 4.48-4.30 (m, 3H), 4.06-4.02 (m, 1H), 3.69 (s, 6H), 2.54-2.37 (m, 4H), 2.20-1.93 (m, 3H), 1.37 (s, 9H); MS (ESI), 620 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]C)=[O:12])=[C:4]2[CH2:3]1.[OH-].[Li+].O>C(O)(=O)C>[O:1]=[C:2]1[CH:3]=[CH:4][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[NH:7]1
Reactant: COC(=O)c1cnn2c1CC(=O)N=C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnn2ccc(=O)[nH]c12
Yield: 93.5 %

Procedure:
A solution of methyl 5-oxo-4,5-dihydropyrazolo[1,5-c]pyrimidine-3-carboxylate (0.75 g 3.89 mM, 1.0 equiv), lithium hydroxide (0.466 g, 19.4 mM, 5.0 equiv) and 20 mL of water was stirred at ambient temperature for 3 hours. HPLC indicated complete reaction. Acetic acid (5 mL) was added and the precipitated solid was collected by vacuum filtration to give 0.65 g (93%) 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ: 12.5 (br s, 1H,), 11.3 (br s, 1H), 8.57 (d, 1H), 8.08 (d, 1H), 6.15 (d, 1H).
Reaction SMILES: O1CCCC1.[CH3:6][CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40]Br>O>[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40][O:10][CH:7]([CH2:8][CH3:9])[CH3:6]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: CCC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 4 ml of dehydrated tetrahydrofuran solution containing 0.96 ml of 2-butanol was added 0.30 g of sodium hydride (60% dispersed material in mineral oil), and the mixture was stirred at room temperature for 3 hours. Then, 0.85 g (1.50 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture under cooling in ice-bath, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.46 g of the title compound as a colorless oil. (Yield: 55%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:19][C:20]([F:22])([F:21])[CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)F
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1.0 g 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde and 0.55 ml (trifluoromethyl)trimethylsilane in 10 ml tetrahydrofuran were added 100 mg tetrabutylammoniumfluoride. The reaction mixture was stirred at room temperature for thirty minutes. Then 20 ml 2NHCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo to obtain 2,2,2-Trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:31][CH:32]=[CH2:33]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:33][CH:32]=[CH2:31])[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (5.3 g, 18.50 mmol) in THF (56 ml) was cooled to −78° C. and then potassium hexamethyldisilazide (KHMDS) (74.0 ml, 37.0 mmol) (0.5M in toluene) was added slowly and reaction mixture was stirred at −78° C. for 10 min., then warmed to 0° C. for 5 mins and cooled back down to −78° C. 3-Bromo-propene (2.401 ml, 27.8 mmol) was added via syringe, and the reaction mixture was kept at −78° C. for another 10 mins before it was allowed to warm to room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride, and volatile solvents were removed under reduced pressure. The product was extracted from water with ether and concentrated. The crude oil was purified on biotage SP1, on column 65i, using gradient 5-35% EtOAc in heptane, with 25×150 tubes. Since the product as not UV active, it was detected by iodine staining. The product was a clear oil (4.88 g, 71%). LCMS [M+H]=327.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][N:17](CC2C=CC=CC=2)[CH3:18])([O:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:14][CH3:15])([CH2:16][NH:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1(CN(C)Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNCC1(OC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 23 h
Yield: 85.7 %

Procedure:
Amine (36) (55 g, 158 mmol) was dissolved in ethyl acetate (500 ml). Pd—C (10%, wet, 5 g) was added and the mixture was stirred for 23 h under hydrogen atmosphere (1 bar). TLC analysis revealed incomplete conversion. Extra Pd—C (2.5 g) was added and the mixture was stirred under H2 (1 bar) for 110 h. NMR analysis revealed complete conversion. The mixture was filtrated over Celite, the Celite crop was washed with ethyl acetate and the filtrate was evaporated to dryness. The residue was purified by distillation (bulb to bulb, 0.04 mbar, 130° C.) giving 35 g of compound (37) (86%) as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:30]([NH:37][CH2:22][C:19]1[CH:20]=[CH:21][N:17]([C:14]2[CH:15]=[C:16]3[C:11]([NH:10][C:9](=[O:28])[C:8](=[O:29])[N:7]3[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:13]=2[C:24]([F:25])([F:27])[F:26])[CH:18]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(CNCc4ccccc4)c3)cc21
Reaction time: 16 h
Yield: 59.9 %

Procedure:
1.2 g (2.9 mmol) of the compound of Example 70, 0.31 g (2.9 mmol) of benzylamine and 0.2 ml (2.9 mmol) of acetic acid were dissolved in 50 ml of ethanol and, at room temperature, 0.18 g (2.9 mmol) of sodium cyanoborohydride was added a little at a time. The mixture was stirred for 16 h and then concentrated under reduced pressure, and the organic phase was dried and finally concentrated again under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: methylene chloride/methanol=5:1) to yield 0.87 g (60%) of the product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)c2c[nH]c3ncc(Nc4ccccc4)cc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1cccc(O)c1)c1c[nH]c2ncc(Nc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 293 (26.6 mg, 0.079 mmol) was dissolved in methylene chloride (10 mL) under an atmosphere of nitrogen. Into the reaction mixture was added 1.0 M boron tribromide in methylene chloride (0.3 mL). The reaction was stirred at room temperature overnight. The solvent evaporated over time, so methylene chloride (10 mL) was added, followed by 1.0 M boron tribromide in methylene chloride (0.6 mL). The reaction was stirred overnight. The reaction was quenched with methanol (10 mL), concentrated under reduced pressure, and extracted with brine and ethyl acetate. The organic portion was dried with anhydrous magnesium sulfate and concentrated to dryness to provide a yellow solid. The material was purified by prep TLC (5% methanol:methylene chloride). The appropriate band was scraped and the compound eluted from the silica with ethyl acetate. The mixture was filtered and the filtrate concentrated to provide compound 294 as a yellow solid as identified by 1H-NMR and MS (1.2 mg, LRMS (ESI) [M+H+]+=330.1).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[C:20]([O:21][CH2:22][CH2:23][CH3:24])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)C(=O)O1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:22]([O:21][C:20]1[C:11]2[NH:10][CH:9]=[CH:5][C:6](=[O:8])[C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[CH:19]=1)[CH2:23][CH3:24]
Reactant: CCCOc1cc2ccccc2cc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCOc1cc2ccccc2c2c(=O)cc[nH]c12
Temperature: 25 °C
Yield: 106.3 %

Procedure:
2,2-Dimethyl-5-[(3-propoxynaphthalen-2-ylamino) methylene][1,3]dioxane-4,6-dione (4.19 g, 11.7 mmol) was added to diphenyl ether (15 ml), and the mixture was heated with a mantle heater and then maintained under reflux for 2 hours. The mixture was cooled to room temperature and purified using silica gel column chromatography (dichloromethane:methanol=70:1→9:1). The purified product was concentrated to dryness under reduced pressure, giving a dark brown powder of 5-propoxy-4H-benzo[f]quinolin-1-one (3.15 g, yield: 61%).