Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(F)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-fluorobenzenesulfonyl chloride according to METHOD A, giving 0.29 g (42%) of a pink powder: MS (electrospray, [M−H]−) m/z 343.1
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N([O-])=[O:19].[Na+].O>Cl.CO>[OH:19][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(N)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)cc(N(C)S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of methyl 3-amino-5-[methyl(methylsulfonyl)amino]benzoate 1.29 g (5.0 mmol) in 2N hydrochloric acid (10 mL) and methanol (15 mL) was added sodium nitrite 0.759 g (11 mmol) under ice-cooling. Thereto was further added water (20 mL) and the mixture was stirred at 70° C. for 2 hours. The mixture was extracted twice with ethyl acetate (30 mL) and dried on magnesium sulfate and the solvent was evaporated to give 1.33 g (5.0 mmol) of the title compound (yield: 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.C([Li:23])CCC>C1(C)C=CC=CC=1.CCCCC>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Li:23]
Reactant: [Li]CCCC
Reactant: Cc1ccc2c(c1)c1c(n2C)-c2ccccc2C1
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: [Li]c1cccc2c1Cc1c-2n(C)c2ccc(C)cc12
Temperature: 25 °C

Procedure:
Under the nitrogen protection, 1.52 grams (0.0077 mole) of 5,8-dimethyl-5,10-dihydroindeno[1,2-b]indole is dissolved in 15 mL of toluene. To the solution is added 3.9 mL of n-butyllithium solution in pentane (2.0 mole/L). The mixture is refluxed for three hours and then cooled to 25° C. The precipitate is isolated by filtration, washed with hexane, and dried under vacuum, yielding 1.26 grams of 5,8-dimethyl-5,10-dihydroindeno [1,2-b]indolyllithium.
Reaction SMILES: [Na].CO.[CH2:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]1[O:7][CH2:6]1.[C:17](O)(=[O:19])C>>[CH2:9]([O:8][CH2:4][CH:5]([CH2:6][O:19][CH3:17])[OH:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)O
Reactant: CC(C)CCCCCOCC1CO1
Agent: [Na]
Solvent: CO
Product: COCC(O)COCCCCCC(C)C
Temperature: 25 °C

Procedure:
Sodium metal (2.3 g; 0.1 mole) is dissolved in methanol (160 g; 5 moles). The solution is heated to reflux and treated dropwise over 2 hours with isooctyl glycidyl ether (186 g; 1 mole). After complete addition, the reaction mixture is maintained under reflux conditions for a further 6 hours. After cooling to ambient temperature, the reaction mixture is treated with acetic acid (5.8 g; 0.1 mole) and then the excess solvent is removed under vacuum. The oily residue is treated with water (250 ml) and then extracted with ether (250 ml). The ether extract is dried over MgSO4, filtered and evaporated. The residue is distilled under vacuum to yield 1-isooctyl-3-methyl glycerol, as a colourless oil, bp 75°-80° C./0.07 mbar, yield 145.6 g (67%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@H:10]([O:22]C(=O)C2C=CC=CC=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[OH-].[Na+]>[CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH2:11][C@H:10]([OH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](O)CN(Cc2ccccc2)C1
Temperature: 70 °C
Yield: 17 %

Procedure:
To a solution of 1.8 g (5.6 mmol) (3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol in 50 ml THF were consecutively added 0.75 g (6.2 mmol) benzoic acid, 1.1 g (6.2 mmol) diethyl azodicarboxylate and 1.6 g (6.2 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 0.80 g (3S,5R)-benzoic acid 1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-yl ester as a light brown oil. The ester was dissolved in a mixture of 50 ml dioxane and 18 ml 1N aqueous sodium hydroxide solution. The reaction mixture was heated at 70° C. for 5 h. After cooling to room temperature the mixture was extracted with tert-butyl methyl ether. The organic extract was washed with a 2N aqueous solution of sodium carbonate. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic extracts were washed with brine and dried over sodium sulfate. Flash chromatography gave 0.10 g (17%) of the title compound as a light brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[C:38]([NH:41][NH2:42])(=[O:40])[CH3:39].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O>[C:38]([NH:41][NH:42][C:34]([C@H:31]1[CH2:30][CH2:29][C@H:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:33][CH2:32]1)=[O:35])(=[O:40])[CH3:39]
Reactant: CC(=O)NN
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)NNC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylic acid (0.5 g), acetohydrazide (0.09 g), 1-hydroxybenzotriazole (0.19 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 72%).
Reaction SMILES: Cl[C:2](=[CH2:12])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[OH-].[K+].C(O)(=O)C>CN(C)C=O>[C:6]1([CH:4]([CH2:3][C:2]#[CH:12])[OH:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(Cl)CC(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C#CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40.00 Grams of 2-chloroallylphenylcarbinol were dissolved in 400 g of dimethylformamide, and 36.85 g of potassium hydroxide in a flake form were added. The mixture was stirred at room temperature for 2 hours and then neutralized with a 20% acetic acid aqueous solution. The resultant mixture was subjected to extraction with toluene. The toluene phase was washed with water and then dried over magnesium sulfate. The desiccant was filtered off, and the toluene was distilled off under reduced pressure to give 31.35 g of phenylpropargylcarbinol, nD20 =1.546, FI-MS m/e 146 (M+), propargyl compound/allene compound=92.3/7.7.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCCCCC.C([Li])CCC.[B:27](OC)([O:30]C)[O:28]C.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[B:27]([OH:30])[OH:28])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1c2ccccc2cc2ccccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
9-Bromoanthracene 38.6 g was dissolved in dehydrated toluene 80 ml and dehydrated THF (tetrahydrofuran) 160 ml, and the solution was cooled to −40° C. A 1.58M n-butyllithium hexane solution 106 ml was dropwise added thereto and stirred at −40° C. for 30 minutes, the temperature was elevated up to −10° C. The solution was cooled again down to −70° C., and a dehydrated THF solution of trimethyl borate 50.0 ml was gradually dropwise added thereto. The solution was stirred at −70° C. for 2 hours and then slowly heated up to room temperature. After left standing for a night, a 10% hydrochloric acid aqueous solution 100 ml was added thereto and stirred, and then it was extracted twice with toluene. The organic layer was washed with saturated brine and dried on anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized from toluene/hexane, filtered and dried, whereby targeted 9-anthraceneboronic acid 24.4 g was obtained in the form of pale brown crystal (yield: 73%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].[Cl-].[NH4+]>CCOCC.C1COCC1>[O:19]=[C:13]1[CH2:18][CH:17]2[CH2:16][CH2:15][CH:14]1[CH2:22][CH:21]2[C:20]([O:24][CH3:25])=[O:23]
Reactant: C=CC(=O)OC
Reactant: O=C1C=CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1CC2CCC1CC2=O
Temperature: -11 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a cooled solution of diisopropylamine (7.72 mL, 54.62 mmol) in ether (40 mL) at −78° C. was added 2.5M n-butyllithium (21.8 mL) dropwise. The reaction mixture was allowed to warm to −11° C. A solution of cyclohex-2-en-1-one (5.04 mL, 52.01 mmol) in diethyl ether (60 mL) was added over 45 minutes. During the addition, the temperature was maintained between −11° C. and −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl prop-2-enoate (4.68 mL, 52.01 mmol) in THF (40 mL) was added dropwise over 60 minutes. The reaction mixture was stirred at this temperature for 1 h and stored in a freezer overnight. The reaction mixture was poured into saturated ammonium chloride solution (200 mL) and stirred for 15 minutes. A brown sticky polymer was formed and removed using tweezers. The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (Biotage; 0-60% ethyl acetate in heptane) in 2 batches, to afford the title compound (2.98 g, 31%) as the trans isomer as a clear colourless liquid. δH (500 MHz, CDCl3) 3.70 (s, 3H), 2.76 (ddt, J 10.6, 6.4, 1.8 Hz, 1H), 2.53-2.48 (m, 1H), 2.47-2.38 (m, 1H), 2.37-2.31 (m, 1H), 2.22 (ddt, J 14.2, 6.3, 2.5 Hz, 1H), 2.13 (ddd, J 19.1, 2.9, 1.8 Hz, 1H), 2.02 (ddd, J 14.3, 11.0, 3.5 Hz, 1H), 1.89-1.74 (m, 3H), 1.70-1.60 (m, 1H).
Reaction SMILES: FC(F)(F)C(O[C:6]1[C:15]2[CH2:14][C@H:13]([O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O.[C:36](=[NH:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Si:17]([O:16][C@H:13]1[CH2:14][C:15]2[C:6]([N:49]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1)([C:30]([CH3:32])([CH3:31])[CH3:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](O[C@@H]1CCc2cccc(OC(=O)C(F)(F)F)c2C1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)[Si](O[C@@H]1CCc2cccc(N=C(c3ccccc3)c3ccccc3)c2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of Example 26D (291 mg, 0.544 mmol), benzophenone imine (0.18 mL, 1.1 mmol), cesium carbonate (390 mg, 1.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (22 mg, 0.035 mmol) in dimethoxyethane (2.2 mL) was heated at 150° C. for 25 minutes in a microwave reactor. The mixture was cooled to room temperature, and the solution was pipetted away from the residual solid and concentrated. Chromatography of the resulting residue on silica gel (1 to 5% ethyl acetate-hexane, eluant) afforded 263 mg (85% yield) of the title compound as a sticky yellow oil/foam. 1H NMR (300 MHz, DMSO-d6) δ 7.19-7.74 (m, 18H), 6.92 (m, 2H), 6.77 (m, 1H), 6.60 (m, 1H), 6.18 (m, 1H), 4.12 (m, 1H), 2.53-2.62 (m, 3H), 2.38 (m, 1H), 1.84 (m, 1H), 1.72 (m, 1H), 0.99 (s, 9H). MS (DCI+) m/z 566 (M+H)+.
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:47])[N:9]=[C:10](SC)[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:26]=1[F:44])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[N+:48]([C:51]1[C:52]([NH:57][NH2:58])=[N:53][CH:54]=[CH:55][CH:56]=1)([O-:50])=[O:49]>C(N(CC)CC)C>[Si:37]([O:36][CH2:35][CH2:34][O:33][C:27]1[C:26]([F:44])=[C:25]([CH:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:15][CH:14]=2)[C:10]2[NH:9][C:8](=[O:47])[N:57]([C:52]3[C:51]([N+:48]([O-:50])=[O:49])=[CH:56][CH:55]=[CH:54][N:53]=3)[N:58]=2)[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:38])[CH3:39]
Reactant: NNc1ncccc1[N+](=O)[O-]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To 3 ml of a DMF solution containing 70 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester, 19 mg of (3-Nitropyridin-2-yl)hydrazine and 0.017 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours and concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (55 mg).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[C:29]([F:33])[C:30]=1[CH2:31][F:32].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([O:21][C:27]4[CH:26]=[C:25]([F:24])[C:30]([CH2:31][F:32])=[C:29]([F:33])[CH:28]=4)=[O:20])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Oc1cc(F)c(CF)c(F)c1
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(=O)Oc4cc(F)c(CF)c(F)c4)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
First, 1.5 g (4.8 mmol) of 4-(trans-4-(trans-4-ethylcyclohexyl)cyclohexyl)benzoic acid, 0.8 g (4.8 mmol) of 3,5-difluoro-4-fluoromethylphenol, 0.2 g (1.4 mmol) of DMAP, and 25 ml of dichloromethane were mixed. To this mixture was added dropwise 5 ml of dichoromethane solution containing 1.2 g (5.7 mmol) of DCC at room temperature in 5 minutes, and reacted as they were while stirring for 12 hours. The crystal thus precipitated were filtered off. Toluene in an amount of 30 ml was added to the filtrate, and washed with 2N-sodium hydroxide 5 times and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.1 g of a crude 3,5-difluoro-4-fluoromethylphenyl 4-(trans-4-(trans-4-ethylcyclohexyl) cyclohexyl)benzoate. This product was recrystallized from a mixed solvent of heptane/ethyl (1/1) acetate to obtain 1.9 g (yield: 86.3%) of the subject compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15](OCC)=[O:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[Si:1]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
23.82 g of ethyl 5-(t-butyldimethylsilanyloxymethyl)-isoxazole-3-carboxylate was dissolved in 100 ml of ethanol, and 3.16 g of sodium borohydride was then added. The mixture was stirred at room temperature for 4 hours. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 18.74 g of [5-(t-butyldimethylsilanyloxymethyl)isoxazol-3-yl]methanol.
Reaction SMILES: [C:1](=[S:3])=S.[OH-].[K+].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17])([O-])=O.COC1C=C(O)C=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O.CO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[N:6]=[C:1]([SH:3])[O:17][C:10]=2[CH:11]=1
Reactant: S=C=S
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: COc1cccc(O)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(S)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Carbon disulphide (9 ml, 0.15 mol) was added dropwise over a period of 1 minute to a solution of potassium hydroxide (6.5 g, 0.12 mol) in a mixture of water (10 ml) and methanol (100 ml), followed by 2-nitro-5-methoxyphenol (16.9 g, 0.1 mol). ]The 2-nitro-5-methoxyphenol required as starting material was prepared by nitration of 3-methoxyphenol as described in Synthetic Communications, 1993, 23(3) 343-348.] To this mixture was added dropwise a solution of potassium hydroxide (39 g, 0.7 mol) and sodium dithionite (65 g, 0.3 mol), over a period of 15 minutes, so that the temperature did not exceed 40° C. The reaction mixture was then cooled to room temperature and carbon disulphide (0.9 ml, 0.15 mol) added and the resulting solution heated to 80° C. for 2 hours. The mixture was then cooled and acidified with concentrated hydrochloric acid to a pH of 3. The pale yellow precipitate was collected and air dried to yield 6-methoxy-2-mercaptobenzoxazole (16.6 g, 89%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:19]([C:17]1[S:16][C:14]2[N:15]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)[N:11]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:13]=2[CH:18]=1)=[O:21]
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to 2,2,2-trifluoroethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 15 mg of 127. MS (Q1) 463.1 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=[O:18].[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:6]1[N:5]=[N:4][C:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]=[O:18])=[CH:2][CH:7]=1
Reactant: O=Cc1c[nH]c2ccc(-c3nnccc3Br)cc12
Reactant: OB(O)c1ccccc1O
Product: O=Cc1c[nH]c2ccc(-c3ccc(-c4ccccc4O)nn3)cc12

Procedure:
The title compound was prepared in analogous manner as described for 2. Thus, starting from 3 (0.1 g, 0.33 mmol) and 2-hydroxy benzeneboronic acid instead of 6-bromo-3-iodopyridineboronic acid following the above described procedure gave 50 mg of pure 4.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)C2=C(C)OCCS2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Thionyl chloride (6.5 g, 0.055 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (8.0 g, 0.050 mole) and methylene chloride (50 ml). The mixture was warmed to 35°-40° C. for 4 hours and the resulting dark solution evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml). On the following day, the solution was treated dropwise at 15°-20° C. over 2 hours with a solution of ethyl 3-aminobenzoate (8.2 g, 0.050 mole) and triethylamine (5.5 g, 0.054 mole) in methylene chloride (50 ml). The reaction mixture was stirred at room temperature for a further 5 hours and worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml). Evaporation of the solvent left an oil, which slowly solidified. Recrystallization from ethanol (75 ml) gave yellow-tan crystals, m.p. 100°-102° C. (11.2 g, 73% yield).