Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:4]([OH:12])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.CO[C:23]([CH3:25])=[CH2:24]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:4]([C:5]2[CH:6]=[CH:7][C:8]([I:11])=[CH:9][CH:10]=2)[O:12][C:23]([CH3:25])([CH3:24])[N:13]1[C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20]
Reactant: C=C(C)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CF)[C@H](O)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A 1 L round bottom flask containing tert-butyl ((1R,2S)-3-fluoro-1-hydroxy-1-(4-iodophenyl)propan-2-yl)carbamate (24.4 g, 61.8 mmol) is charged with CH2Cl2 (250 mL) followed by 2-methoxypropene (9.0 mL, 92.8 mmol). The solution is cooled via ice bath and para toluene sulfonic acid (59 mg, 0.31 mmol) added. The reaction is stirred for 2 hours at room temperature then quenched with saturated sodiumbicarbonate solution (200 mL). The organics were separated, dried over MgSO4 and concentrated to give the title compound (26.5 g): 1H NMR (400 MHz, CDCl3) 7.73 (d, 2H), 7.20 (d, 2H), 5.08 (d, 1H), 5.03-4.69 (m, 1H), 4.54-4.31 (m, 1H), 3.91-3.68 (m, 1H), 1.70 (s, 3H), 1.58 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=2[Br:19])=[CH:7][CH:6]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Br:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2Br)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(O)cc2Br)cc1
Temperature: 0 °C
Yield: 94.1 %

Procedure:
To a 0° C. solution of 2′-bromo-4′-methoxy-biphenyl-4-carboxylic acid methyl ester (0.200 g) in methylene chloride (5 mL) is added boron tribromide (0.176 mL). The reaction mixture is maintained at 0° C. for 2 h. The reaction mixture is slowly quenched with 50 mL methanol, diluted with 150 mL 2N hydrochloric acid, and extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (0.180 g, 94%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].C(Cl)(=O)C>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:3](=[O:4])[CH3:2])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1
Yield: 80 %

Procedure:
Following general procedure GP-G1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and acetyl chloride were converted to give 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone as a white solid (29.2 g, 80%): 1H NMR (500 MHz, CDCl3) δ10.59 (br, 1H), 7.36-7.29 (m, 1H), 7.15 (m, 1H), 4.81 (br, 2H), 4.77 and 4.65 (s, 2H), 3.85 (br, 1H), 3.68 (m, 1H), 3.26-2.69 (m, 5H), 2.21 and 2.19 (s, 3H), 1.89-1.73 (m, 4H) MS (ESI+) m/z 457 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:17]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:18]1>C(#N)C>[O:10]([CH2:9][CH2:8][N:17]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)/C=C/c1cn[nH]c1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cnn(CCOc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
Cesium carbonate (0.490 g, 1.5 mmol) and 1-(2-bromoethoxy)benzene (0.261 g, 1.30 mmol) were added to a solution of (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.167 g, 1 mmol) in ACN (8 mL) at room temperature. The suspension was stirred overnight at 80° C. The reaction mixture was then cooled down to room temperature and the precipitated solids were filtered off. The filtrate was concentrated and purified by silica gel column chromatography using a gradient of 0-60% of EtOAc in hexanes to provide the title compound (0.203 g, 71%) as a colorless oil. ES+(M+H)+287
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:41]=[CH:40][CH:39]=[CH:38][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]([NH:30]C(=O)OC(C)(C)C)[CH3:29])=[CH:24][CH:23]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:30][CH:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:13]2[N:12]=[C:11]([CH2:10][CH2:9][C:8]3[CH:38]=[CH:39][CH:40]=[CH:41][C:7]=3[C:4]3([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]3)[C:16]([C:17]([F:19])([F:20])[F:18])=[CH:15][N:14]=2)=[CH:27][CH:26]=1)[CH3:29]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 1-(4-(4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate 70 (0.11 g, 0.19 mmol) in DCM (4 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at ambient temperature for 16 hours before the volatiles were removed in vacuo. The crude residue was purified using an SCX conditioned with MeOH, product was eluted off with 2 M ammonia in EtOH) to give the title compound 70A as a cream solid (0.073 g, 81%). LCMS-C: rt 4.48 min; m/z 470 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].O[Li].O>C1COCC1.CO.O>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]3[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]3)=[O:12])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)cc1N(C(=O)C1CC=C(C)CC1)C(C)C
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1=CCC(C(=O)N(c2cc(-c3ccc(F)cc3)sc2C(=O)O)C(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
5-(4-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.140 g, 0.34 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 10 mL) and then added 1N aqueous solution of LiOH.H2O (2.1 mL, 2.04 mmol). The reaction mixture was stirred at 50° C. for 1 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC using dichloromethane:methanol (9:1) to obtain 5-(4-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid (compound 53) (31 mg, 23%). 1H NMR (CDCl3, 400 MHz): δ 7.81 (m, 2H), 7.43 (d, 1H), 7.28 (m, 2H), 5.38-5.16 (m, 1H), 4.72 (m, 1H), 2.20 (d, 2H), 1.95-1.20 (m, 8H), 1.12 (m, 3H), 0.90 (d, 3H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH:7]=[CH:6][C:5]1=2>CO>[OH:3][CH:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH:7]=[CH:6][C:5]1=2
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3O)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.4 %

Procedure:
Add NaBH4 (79.4 mg, 2.10 mmol) to a suspension of 6-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (Intermediate 2, 395 mg, 1.40 mmol) in MeOH (10 ml), stirring at ambient temperature. After 24 hours, concentrate the reaction mixture and redissolve in EtOAc. Wash with 5% aqueous KOH, water, and brine before drying (MgSO4) and concentrating to a solid. Purify material on silica gel (50% THF/DCM) to give 6-(5-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (288 mg) as a white solid. Mass spectrum (ion spray): m/z=285 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.16 (d, 1H), 7.50 (d, 1H), 6.97 (m, 2H), 6.88 (s, 1H), 5.95 (broad, 2H), 4.80 (t, 1H0, 2.82-2.74 (m, 2H), 2.03-1.77 (m, 4H), 1.68 (s, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][OH:15]>>[CH3:14][O:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Br
Reactant: CO
Product: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
An argon filled Schlenk flask was charged with 25.77 g (104 mmol) of 2-bromo-1,3-dinitrobenzene, 150 mL of absolute methanol was added and the reaction mixture was chilled in an ice bath. 2.4 g (104 mmol) of Na was added, and the resulting reaction mixture was purged with argon until all Na was dissolved and stirred at RT over night. The solvent was removed, the residue was re-suspended in acetone and filtered through Celite to remove NaBr. The solvent was removed, and the crude product was recrystallized from iPrOH. Yield: 19.8 g (90%). 1H NMR (CDCl3): δ 8.05 (d, JHH=8.2 Hz, 2H, Ar), 7.38 (t, JHH=8.2 Hz, 1H, Ar), 4.07 (s, 3H, OCH3) ppm.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[OH-:12].[Na+].OO>CO>[OH:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[C:2]([OH:12])=[O:1]
Reactant: [OH-]
Reactant: COc1ccc(C=O)cc1O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1O

Procedure:
Methanol (350 ml), isovanillin (50 gm) and 30% methanolic sodium hydroxide solution (1 ml), were heated to 45° C. To this solution, 35% hydrogen peroxide solution (107 ml) was charged slowly maintaining pH at 10.5 to 11.5 using methanolic sodium hydroxide solution over a period of 2-3 hours. The reaction mass was quenched into chilled water (1 lt) and the pH adjusted to 2-3 using hydrochloric acid. The solids were filtered, washed with 50% aqueous methanol (50 ml) and dried at 45-50° C. to yield 3-hydroxy-4-methoxy benzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:18])[N:10](COC)[C:9]=2[CH:22]=1)[CH3:3].[ClH:23]>C(O)C>[ClH:23].[ClH:23].[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:18])[NH:10][C:9]=2[CH:22]=1)[CH3:1]
Reactant: COCn1c(=O)c2c(c3ccc(CN(C)C)cc31)NCCC2
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccc2c3c(c(=O)[nH]c2c1)CCCN3
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
The compound (57.8 mg, 0.192 mmol) prepared in step 7 was dissolved in ethanol (3 ml), added with 12 N hydrochloric acid aqueous solution (3.0 ml). The resulting mixture was heated to 90° C. and stirred for 3 hours. The mixture was concentrated to dryness and dissolved in ethyl acetate. After stirring for 30 minutes, the precipitate was filtered and washed with diethyl ether to obtain the title compound (53.5 mg, yield: 84.5%, ivory solid).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3](=[O:5])[CH3:4].[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]([CH3:8])([CH2:6][O:7][C:14]1[CH:15]=[CH:16][C:11]([C:10]([F:19])([F:18])[F:9])=[CH:12][N:13]=1)[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(C)(C)CO
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)C(C)(C)COc1ccc(C(F)(F)F)cn1
Temperature: 115 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
3,3-Dimethyl-4-hydroxybutan-2-one (11.2 g) was dissolved in 50 ml of dimethyl sulfoxide, and nitrogen gas was passed therethrough for 20 minutes. Then, 18.2 g of 3-trifluoromethyl-6-chloropyridine and 15 g of anhydrous potassium carbonate were added thereto, and the solution was gradually heated to 115° C. and reacted under stirring for 4 hours at that temperature. After completion of the reaction, the product was put into ice water, extracted with methylene chloride, washed with water and dried over Glauber's salt. The solvent was distilled off to give 24.8 g of oily 3,3-dimethyl-4-(5-trifluoromethylpyridine-2-yloxy)butan-2-one.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@H]1(N)CCCC[C@@H]1N>CN(C)C=O.[Cu](I)I.C(Cl)Cl.CO.C(Cl)Cl>[CH3:29][C:25]1[CH:24]=[C:23]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])[CH:28]=[CH:27][CH:26]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Cc1cccc(I)c1
Agent: I[Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(N2c3nc(N4CCOCC4)cc(=O)n3CC[C@H]2C(F)(F)F)c1

Procedure:
The product is prepared according to the procedure described in Example 12, but using 250 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 4 ml of dimethylformamide, 251 mg of 1-iodo-3-methylbenzene, 349 mg of tripotassium phosphate, 156 mg of copper iodide and 93 mg of (1S,2S)-cyclo-hexane-1,2-diamine. After 1 hour at 150° C. under microwave irradiation and silica column purification of the resulting reaction mixture (elution gradient of CH2Cl2 to CH2Cl2/MeOH 98/02), 195 mg of (88)-9-(3-methylphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are obtained in the form of a green solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.C(O)(=O)C.Cl>O>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnoc1C1CC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnoc1C1CC1
Yield: 82.1 %

Procedure:
Ethyl 5-cyclopropylisoxazole-4-carboxylate (203.0 g, 1.12 mole) [prepared in Step B]was added to a solution of 405 ml of glacial acetic acid plus 505 ml of 6 N HCl and the mixture was heated in an oil bath a 105°-110° C. for 3 h. After 18 h at ambient temperature the thick mixture was diluted with water, cooled in an ice bath and filtered to give 140.8 g of the title acid. Recrystallization of an aliquot from acetonitrile gave an analytical sample, mp 163°-165° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([Li])CC.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[O:22])[CH2:15]2.Cl>O1CCCC1.C1CCCCC1.O>[OH:8][C:7]1[C:2]([CH2:1][C:16]2([OH:22])[CH:17]3[CH2:20][CH2:21][N:14]([CH2:19][CH2:18]3)[CH2:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ncccc1O
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Oc1cccnc1CC1(O)CN2CCC1CC2
Temperature: -56 °C
Yield: 55.1 %

Procedure:
52.9 g (484 mmol) of 2-methyl-3-hydroxypyridine dissolved in 1300 ml of tetrahydrofuran are introduced into a 2000 ml three-neck flask under argon. The solution is cooled to −56° C. and 750 ml (975 mmol) of a 1.3 M 1-methylpropyllithium solution in cyclohexane is added dropwise in the course of 3 h, keeping the temperature lower than −50° C. At the end of the addition, the temperature is allowed to rise to −4° C. in the course of 45 min and the mixture is then again cooled to −58° C. to add 60.6 g (484 mmol) of 1-azabicyclo[2.2.2]octan-3-one dissolved in 250 ml of tetrahydrofuran dropwise in the course of 40 min. The temperature is allowed to rise to ambient and stirring is maintained for 20 h. The reaction mixture is cooled to 4° C. and hydrolysed by addition of 110 ml of an aqueous solution of 36% hydrochloric acid. 400 ml of water are added, the two phases are allowed to settle and the organic phase is extracted with water. The aqueous phases are reunited, the mixture is cooled to 4° C. and a concentrated aqueous solution of sodium hydroxide is added to pH 8.4. The precipitate obtained is filtered and dried in vacuo at 80° C. 62.5 g of product are thus obtained.
Reaction SMILES: [CH3:1][NH:2]C[C@H](C1C=CC=CN=1)O.Cl[CH2:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15]>>[CH3:1][NH:2][CH2:13][C@H:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[OH:15]
Reactant: CNC[C@@H](O)c1ccccn1
Reactant: O=C(CCl)c1cccnc1
Product: CNC[C@@H](O)c1cccnc1

Procedure:
As described for the preparation of (1R)-2-(methylamino)-1-pyridin-2-ylethanol (Preparations 68-69), 3-chloroacetylpyridine (Chem. Ber. 1951, 84, 147-149) is converted to the title compound, isolated as a pale yellow amorphous solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]3[C:19]([C:30]4[O:31][CH:32]=[CH:33][CH:34]=4)=[N:20][C:21]([NH2:29])=[N:22][C:23]=3[C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[NH2:29][C:21]1[N:20]=[C:19]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH:17]=2)=[C:23]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)[N:22]=1
Reactant: CCOC(=O)C1CCN(c2cc(-c3c(-c4ccco4)nc(N)nc3-c3ccco3)ccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(-c2ccco2)c(-c2ccnc(N3CCC(C(=O)O)CC3)c2)c(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.2 %

Procedure:
In a reaction vessel, ethyl1-{4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarboxylate (59 mg, 0.128 mmol) was suspended in methanol (0.8 ml). A 5N aqueous sodium hydroxide solution (0.2 ml) was added therto, followed by stirring at room temperature for 15 hours. After the reaction was terminated, the reaction mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and then the filtrate was concentrated, to give the title compound (20 mg, 36%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:48])([CH3:47])[CH2:34][CH2:35][O:36][C:37](ON1C(=O)CCC1=O)=[O:38].S([O-])(O)(=O)=O.[K+]>CS(C)=O.O>[CH3:32][Si:33]([CH2:34][CH2:35][O:36][C:37]([NH:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)=[O:38])([CH3:48])[CH3:47]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOC(=O)N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of thyroxine (1.66 g, 2.14 mmol) in DMSO (15 mL) was added triethylamine (3.21 mmol) followed by solid Teoc-0Su (610 mg, 2.35 mmol). The mixture was stirred at room temperature overnight then diluted with water (22 mL), acidified with saturated potassium hydrogen sulfate solution and extracted with ether (3×45 mL). The combined organic extracts were washed with water (4×45 mL), dried with magnesium sulfate, and evaporated to dryness. (Yield: 1.87 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[C:6]1[CH2:9][N:8](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]1)[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:9][NH:8][CH2:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CNC1

Procedure:
To a solution of (1-benzhydrylazetidin-3-ylidene)-acetic acid ethyl ester (5.0 g, 16 mmol) in ethanol (200 mL) was added palladium hydroxide on carbon (1.5 g). This mixture was vigorously shaken under a 50 psi hydrogen atmosphere for 24 hrs, then filtered and concentrated to give an oil, used without additional purification.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][N:9]=[C:8](O)[N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.P(Cl)(Cl)([Cl:23])=O>>[S:1]1[C:5]([C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][N:9]=[C:8]([Cl:23])[N:7]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(C(F)(F)F)c(-c2cc3ccccc3s2)n1
Product: FC(F)(F)c1cnc(Cl)nc1-c1cc2ccccc2s1
Temperature: 100 °C

Procedure:
4-(Benzo[b]thiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-ol (0.28 g, 0.94 mmol) was treated with phosphorous oxychloride (6 mL) and the mixture was heated to 100° C. overnight. The volatiles were removed in vacuo and residual phosphorous oxycloride was azeotroped with toluene. The resulting residue was dissolved in chloroform, washed successively with cold water, saturated aqueous solution of sodium bicarbonate, water again and brine. The organic solution was dried with sodium sulfate and passed through a plug of silica gel. The filtrate was concentrated to yield a yellow solid (0.2 g). MS (M+H)+ 315.
Reaction SMILES: CC([CH:5]([N:25]([C:29]([C:31]1[N:35](COCC[Si](C)(C)C)[CH:34]=[N:33][C:32]=1[Cl:44])=[O:30])C(=O)[O-])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=2)[C:7]=1[F:24])(C)C.[B-](F)(F)(F)F.[CH3:50]C[O+](CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:44][C:32]1[N:33]([CH3:50])[CH:34]=[N:35][C:31]=1[C:29]([NH:25][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=2)[C:7]=1[F:24])=[O:30]
Reactant: CC[O+](CC)CC
Reactant: CC(C)(C)C(c1ccc(Cl)c(Oc2cc(C#N)cc(CO)c2)c1F)N(C(=O)[O-])C(=O)c1c(Cl)ncn1COCC[Si](C)(C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(CO)c3)c2F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To a solution of 1,1-dimethylethyl[(4-chloro-3-{[3-cyano-5-(hydroxymethyl)phenyl]oxy}-2-fluorophenyl)methyl]{[4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-5-yl]carbonyl}carbamate (66 mg, 0.099 mmol) in DCM (5 ml) was added Meerwein's reagent (16.13 mg, 0.109 mmol) and the reaction mixture was stirred for 4 hours at RT. TFA (2.0 ml, 26.0 mmol) was added and the reaction mixture was stirred at RT for another 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give the title compound (34 mg, 76% yield). 1H NMR (DMSO-d6) δ ppm 8.66 (t, 1H) 7.87 (s, 1H) 7.44-7.57 (m, 2H) 7.25-7.39 (m, 2H) 7.19 (s, 1H) 4.51 (s, 2H) 4.45 (d, 2 H) 2.50 (s, 3H). LC-MS (ES+) m/z 449.11 [M+H].