Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[N+:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11](=[O:13])[CH3:12])=[CH:3][C:2]=1[O:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:10])=[O:9]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Yield: 44 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (3.0 g), phenol (2.5 g), and potassium carbonate (4.0 g) in xylene (70 ml) was refluxed for 8 hours. The insoluble was filtered off and the filtrate was concentrated under reduced pressure. The oily residue (2.7 g) was subjected to column chromatography on silica gel (70 g) eluting with toluene. The fractions containing the desired compound were combined and concentrated under reduced pressure to give crystals of 4'-nitro-3'-phenoxyacetophenone (1.7 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].N#N.[CH2:9]([N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]#[N:14])[CH3:10]>C1COCC1>[CH2:9]([N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13][NH2:14])[CH3:10]
Reactant: CCCCCCCN(CC)CC#N
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCN(CC)CCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Suspend 1.2 g (0.032 moles) lithium aluminum hydride in 20 ml THF. Chill the suspension to -10° C. under a stream of N2. Slowly add 7.90 g (0.043 moles) 2-[ethyl(heptyl)amino]acetonitrile to the suspension. Stir for 2 hrs at ambient temperature. Quench the reaction mixture with Na2SO4 10H2O and H2O. Filter the quenched reaction mixture and evaporate the solvents to provide the title compound. (B.P.: 42°-45° C./0.015 mmHg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:10]=1)[N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:6]=[CH:5]2.C([Li])(C)(C)C>O1CCCC1>[C:27]1([C:14]2([CH2:13][O:12][CH2:11][C:9]3[CH:10]=[CH:2][CH:3]=[C:4]4[C:8]=3[N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:6]=[CH:5]4)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cccc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (55 mg, 0.09 mmol) was dissolved in dry tetrahydrofuran (1.5 mL) and stirred at room temperature for 15 min. The stirred mixture was cooled to −78° C. and treated with a solution of tert-butyllithium (1.7M in pentane, 103 μL, 0.17 mmol) over several minutes. The mixture was stirred at −78° C. for 20 min, quenched by addition of a few drops of methanol and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) afforded 34 mg (91%) as a clear oil. 1H-NMR (CDCl3, 300 MHz) δ 7.93 (s, 1H), 7.66 (dd, J=7.0, 1.1 Hz, 1H), 7.04-7.23 (m, 7H), 5.38 (s, 2H), 4.70 (s, 2H), 3.39 (s, 2H), 3.35-3.41 (m, 2H), 2.94-3.03 (m, 2H), 2.05-2.09 (m, 2H), 1.71-1.80 (m, 2H), 1.39 (s, 9H), 0.72-0.78 (m, 2H), 0.14 (s, 9H). Mass spec.: 552.15 (MH)+.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][CH:17]3[NH:20][C:21]3[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=3)[O:24][CH2:25][C:26]([O:28]C(C)C)=[O:27])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][CH:17]3[NH:20][C:21]3[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=3)[O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)OC(=O)COc1cccc(NC2CCCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(NC2CCCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
Aqueous lithium hydroxide (1 N, 1 mL, 1 mmol) was added to a solution of isopropyl 2-(3-((7-(3-fluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenoxy)acetate (5 mg, 0.012 mmol) in THF (1 mL) in a scintillation vial. The vial was sealed and heated at 40° C. After 24 h, the reaction mixture was allowed to cool and the volatiles were concentrated in vacuo. The residue was acidified with hydrochloric acid (1 N, 1 mL), and extracted with ethyl acetate (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 3 mg (66%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:9])=[C:6]([Br:8])[N:7]=1.[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][C:14]#[CH:15]>C1COCC1.O.[Cl-].[Na+].O.[Cu]I.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>[Br:8][C:6]1[N:7]=[C:2]([C:15]#[C:14][CH2:13][Si:12]([CH3:17])([CH3:16])[CH3:11])[C:3]([NH2:10])=[N:4][C:5]=1[Cl:9]
Reactant: Nc1nc(Cl)c(Br)nc1Br
Reactant: C#CC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CC#Cc1nc(Br)c(Cl)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,5-Dibromo-6-chloropyrazin-2-amine (step 1) (400 mg, 1.392 mmol) in dry THF (10 ml) was degassed with nitrogen and treated with trimethyl(prop-2-ynyl)silane (0.218 ml, 1.462 mmol), TEA (0.582 ml, 4.18 mmol), CuI (26.5 mg, 0.139 mmol) and Pd(PPh3)2Cl2 (98 mg, 0.139 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (100 ml) and brine and extracted with DCM (×3). The combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:7]=[C:8]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([F:21])(=[O:20])=[O:19])[CH:13]=2)[CH:9]=1)[CH:5]=O.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:7]=[C:8]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([F:21])(=[O:20])=[O:19])[CH:13]=2)[CH:9]=1)[CH:5]=[N:24][OH:25]
Reactant: O=Cc1cc(N=Nc2cccc(S(=O)(=O)F)c2)cc(Cl)c1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(F)c1cccc(N=Nc2cc(Cl)c(O)c(C=NO)c2)c1
Temperature: 25 °C

Procedure:
3-Chloro-5-(3-fluorosulfonylphenylazo)-2-hydroxy-benzaldehyde (23.8 g, 0.07 mol) was added to 250 ml ethanol, followed by hyroxylamine hydrochloride (5.04 g, 0.072 mol) and sodium hydroxide (2.88 g, 0.072 mol). The reaction was brought to reflux for 30 minutes and then cooled to room temperature. The mixture was then poured into ice and hydrochloric acid, resulting in the formation of a precipitate which was filtered off, washed with water, and dried in a vacuum oven (55° C.). The yield was 22.5 g (90%).
Reaction SMILES: [CH2:1](O)[C:2]#[CH:3].[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([O:9][CH2:3][C:2]#[CH:1])=[O:8]
Reactant: C#CCO
Reactant: CC(C)(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCOC(=O)C(C)(C)Br
Reaction time: 24 h

Procedure:
Propargyl alcohol (12.8 mL, 0.218 mol) and 2-bromoisobutyric acid (36.4 g, 0.218 mol) were dissolved in methylene chloride (150 mL). The reaction mixture was cooled in an ice-water bath and a solution of dicyclohexyl carbodiimide (45.0 g, 0.22 mol) in methylene chloride (50 mL) was slowly added while stirring. A solution of 4-dimethylaminopyridine (1.5 g) in methylene chloride (50 mL) was then added over a period of 10 min. The mixture was stirred in the cooling bath for 1 h and then at room temperature for 24 h. The precipitated dicyclohexylurea was filtered and washed on the filter with methylene chloride (50 mL). The solvent was removed on a rotary evaporator and the product was distilled under vacuum. Yield: 33.0 g (0.161 mol, 74%). 1H NMR spectrum in CDCl3 (δ, ppm): 4.77 (d, 2H, CH2O), 2.51 (t, 1H, C≡CH), and 1.96 (s, 6H, (CH3)2C). IR spectrum (neat liquid, NaCl plates): 3296 cm−1 (ν≡C—H), 2131 cm−1 (νC≡C), and 1741 cm−1 (νC═O).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:16]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]([F:15])([F:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O1CCOCC1.[ClH:34]>CO.[Pd]>[ClH:34].[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH2:16])[CH2:5][C:6]([F:15])([F:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A solution of (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenyl-pentanoic acid methyl ester (7.806 g, 20.68 mmol) in 120 mL of methanol and 4 M HCl in dioxane (41.4 mmol, 10.3 mL) is hydrogenated over 10% Pd/C (1.0 g) at 50 psi. After 8 hr, another portion of 10% Pd/C (1.0 g) is added. After 24 hr, the catalyst is removed by filtration over a pad of Celite, and the filtrate is concentrated in vacuum. The resulting solid is dissolved in a minimum amount of methanol and slowly added to ether (150 mL). The resulting slurry is aged for 30 min and then filtered. The solid is dried under suction to afford (S)-2-amino-4,4-difluoro-5-phenyl-pentanoic acid methyl ester hydrochloride (4.950 g, 85.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(OC)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(OC)cc1[N+](=O)[O-]
Yield: 40.5 %

Procedure:
By using 420 mg of N-(5-fluoro-4-methoxy-2-nitrophenyl)glycine ethyl ester, 420 mg of imidazole and 2.5 ml of DMF, 200 mg (41%) of N-[5-(1H-imidazol-1-yl)-4-methoxy-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:24])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].[CH3:25][CH:26]([CH2:29][CH3:30])[CH2:27]N.S>C(O)C>[CH3:25][CH:26]([CH2:29][CH3:30])[CH2:27][NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:6]([CH3:7])[CH2:5][N:3]([CH2:1][CH3:2])[CH3:4])[C:21]=2[CH:20]=1)=[S:24]
Reactant: CCC(C)CN
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCC(C)CNC(=S)c1ccc2c(c1)N(C(C)CN(C)CC)c1ccccc1S2
Temperature: 100 °C

Procedure:
A solution of 10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbothioamide (1 g) and (2RS)-2-methylbutylamine (4.9 cc) in absolute ethanol (15 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After being cooled, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily orange residue is purified by chromatography on a column (height: 25 cm; diameter: 2 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (500 cc) of ethyl acetate and cyclohexane and collecting 40-cc fractions Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-[(2RS)-2-Methylbutyl]--10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (1.88 g) is obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[C:4]=1[OH:12])=[O:2].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([C:1]([OH:14])=[O:2])=[C:4]([OH:12])[C:5]=1[CH3:11])#[N:8]
Reactant: O=P([O-])(O)O
Reactant: Cc1c(C#N)ccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Product: Cc1c(C#N)ccc(C(=O)O)c1O
Temperature: 17 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a solution of 4-formyl-3-hydroxy-2-methylbenzonitrile (3.90 g) in DMSO (21.0 mL) were added sodium dihydrogenphosphate (7.26 g) and an aqueous solution (16.0 mL) of sodium chlorite (5.46 g) under ice-cooling, and the mixture was stirred at 17° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium carbonate solution, and the mixture was extracted with tert-butyl methyl ether. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.00 g: containing DMSO).
Reaction SMILES: CC(C([O:6][CH:7]1[C@@:12]2(C)[C:13]([CH3:15])(C)[C@H:9]([CH2:10][CH2:11]2)[CH2:8]1)=O)=C.[CH3:17][CH:18]([CH2:20][C:21]([CH3:23])=O)[CH3:19]>>[CH2:7]([OH:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:15][CH2:12][CH2:7][CH2:8][CH2:9][CH2:23][CH2:21][CH2:20][CH:18]([CH3:19])[CH3:17]
Reactant: CC(=O)CC(C)C
Reactant: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Product: CC(C)CCCCCCCCCCCCCCCO
Temperature: 65 °C

Procedure:
In a second step, a 3-necked reaction flask equipped with a thermometer, Dean Stark condenser, mechanical stirrer, heating mantle and nitrogen inlet, was charged with 60.7 g of the iBMA oligomer solution as prepared above (30 meq.), 8.1 g isostearylacohol (30 meq.) and 138.4 g MIBK. 50 g MIBK/H2O azeotrope was distilled off via the Dean Stark condenser. After replacing the Dean Stark by a normal reflux condenser, the mixture was cooled to 65° C. and 30.3 g MDI (240 meq.) were added. The reaction mixture was heated for 2 hours at 75° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCC1COc2ccccc2O1
Yield: 6 %

Procedure:
The title compound was prepared in 6% yield from 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (br s, 1H), 8.37 (s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.77 (br s, 1H), 7.57 (d, 1H, J=5.0 Hz), 6.80-6.90 (m, 4H), 4.37-4.48 (m, 2H), 4.02-4.07 (m, 1H), 3.55-3.75 (m, 2H). [M+H] calc'd for C15H14N2O4, 287. Found 287.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OB(O)c1cc(F)ccc1O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(F)ccc2O)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a degassed mixture of 1,4-dioxane:water (4:1, 15 mls) was added (5-fluoro-2-hydroxyphenyl)boronic acid (0.781 g, 5.0 mmol), methyl 6-chloronicotinate (0.86 g, 5.0 mmol), potassium carbonate (2.08 g, 15.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) and the resulting mixture stirred at 80° C. for 2 h. After this time additional tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) was added and then heating continued at 80° C. for 3 h. The mixture was then stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue suspended in ethyl acetate (50 ml). The suspension was filtered through a plug of arbocel and the filtrate concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (3×100 ml). The aqueous washings were combined and extracted with ethyl acetate (3×50 ml). The ethyl acetate layers were combined, dried with anhydrous MgSO4 and concentrated in vacuo to afford a solid which was recrystallised from dichloromethane/heptane to afford the title compound as a yellow solid (0.71 g) (57%). 1H NMR (400 MHz, CDCl3) □ ppm 9.14 (1H, s), 8.46-8.40 (1H, m), 7.91-7.86 (1H, m) 7.53-7.46 (1H, m), 7.11-7.03 (1H, m), 7.02-6.96 (1H, m), 3.99 (3H, s). LRMS: AP m/z 248 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:9][CH2:8][NH:7][NH:6][CH2:5][CH2:4]1.[CH2:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH3:20])[C:13]=1[CH:21]([C:25](N)=[O:26])[C:22](N)=[O:23])[CH3:11]>ClCCCl>[CH2:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH3:20])[C:13]=1[CH:21]1[C:25](=[O:26])[N:6]2[CH2:5][CH2:4][N:3]([O:2][CH3:1])[CH2:9][CH2:8][N:7]2[C:22]1=[O:23])[CH3:11]
Reactant: CCc1cc(C)cc(CC)c1C(C(N)=O)C(N)=O
Reactant: CON1CCNNCC1
Solvent: ClCCCl
Product: CCc1cc(C)cc(CC)c1C1C(=O)N2CCN(OC)CCN2C1=O

Procedure:
A degassed solution in a microwave vial of 5-methoxy-[1,2,5]triazepane (free base, 50 mg, 0.38 mmol) and 2-(2,6-diethyl-4-methyl-phenyl)-malonamide (95 mg, 0.38 mmol) in 1,2-dichloroethane (2.5 ml) under argon was irradiated with microwaves at 180° C. for 5 minutes. The solvent was evaporated, the residue dissolved in 5N aqueous sodium hydroxide, the aqueous layer extracted twice with ethyl acetate and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 4N HCl solution and the product thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Yield: 20 mg of 8-(2,6-diethyl-4-methyl-phenyl)-3-methoxy-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.3) as a tan solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClC1C(Cl)=C(S(N2CCC(O)CC2)(=O)=O)C=CC=1N[C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29].[CH3:35][O:36][C:37]1[CH:43]=[C:42]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])[C:41]([O:50][CH3:51])=[CH:40][C:38]=1[NH2:39].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:35][O:36][C:37]1[CH:43]=[C:42]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])[C:41]([O:50][CH3:51])=[CH:40][C:38]=1[NH:39][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29]
Reactant: COc1cc(S(=O)(=O)N(C)C)c(OC)cc1N
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)N2CCC(O)CC2)c(Cl)c1Cl)C(F)(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(S(=O)(=O)N(C)C)c(OC)cc1NC(=O)[C@@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Oxalyl chloride (0.15 ml, 1.8 mmol) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.18 g, 1.15 mmol) (Method 3) in DCM (10 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature overnight, then 2,5-dimethoxy-4-[dimethylaminosulphonyl]aniline (200 mg, 0.77 mmol)‡ and 2,6-di-t-butylpyridine (0.19 ml, 0.9 mmol) was added and the resulting mixture stirred a further 2 hours at room temperature. Dichloromethane (25 ml) was added and the mixture was washed with water (2×50 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50% EtOAc/iso-hexane to give the title compound as a foam (212 mg, 0.53 mmol); NMR: 1.74 (s, 3H), 2.83 (s, 6H), 3.91 (s, 6H), 7.40 (s, 1H), 8.27 (s, 1H), 9.17 (s, 1H); m/z 399.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:17][C:18]([C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1)=[O:19])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][C:22]3[S:23][CH:24]=[C:20]([C:18]([OH:19])=[O:17])[N:21]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Product: O=C(O)c1csc(COc2ccc(-c3ccc(Br)cc3)cc2)n1

Procedure:
2-(4′-Bromo-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 4-bromo-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 82 mg. Mass spectrum (ES) MH+=390.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11]CC3C=CC=CC=3)=[CH:8][CH:9]=2)[C:4]([O:19][CH:20]([CH3:22])[CH3:21])=[C:3]1[C:23]([NH2:25])=[O:24]>CO.[Pd]>[OH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:23]([NH2:25])=[O:24])=[C:4]2[O:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Oc1c(C(N)=O)n(C)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1c(C(N)=O)n(C)c2ccc(O)cc12

Procedure:
A suspension of 1-methyl-(1-methylethoxy)-5-(phenylmethoxy)-1H-indole-2-carboxamide (2.1 g, 6.2 mmol) in 100 mL of methanol is hydrogenated using 0.5 g of 20% palladium on carbon catalyst. The catalyst is filtered and the filtrate evaporated. Recrystallization of the residue from aqueous acetonitrile gives. 0.87 g (58%) of product; mp 234°-237° C.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][N:5]12.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:14][CH:11]2[CH2:10][N:5]3[C:6]4[C:2]([CH:3]=[C:4]3[CH2:13][CH2:12]2)=[CH:1][CH:9]=[CH:8][CH:7]=4)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NC1CCc2cc3ccccc3n2C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CCc2cc3ccccc3n2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of (+/−) 6,7,8,9-tetrahydropyrido[1,2-α]indol-7-amine from Step 9 in CH2Cl2 (0.14 M) at rt were added 4-fluorobenzenesulfonyl chloride (1.2 equiv.), triethylamine (5 equiv.) and DMAP (0.03 equiv). The reaction mixture was stirred at rt for 2 h. It was poured into aqueous NaHCO3 and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (0:100 to 50:50 for 15 min, then at 50:50 for 5 min) to give the title compound (78%) as a light yellow foam.