Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cnc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.40 g, 1.14 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.303 g, 1.37 mmol) according to the general procedure VI. Obtained as a white solid (0.050 g, 10%). MS (ISP) 409.2 [(M+H)+]; mp 264° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11]C)[C:8]=1[O:9][CH3:10].OO.[N+]([O-])(O)=[O:17].O>CC(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][C:8]1[C:7](=[O:11])[CH:6]=[C:5]([CH3:13])[C:4](=[O:17])[C:3]=1[O:2][CH3:1]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: COC1=C(OC)C(=O)C(C)=CC1=O
Temperature: 75 °C
Yield: 175.7 %

Procedure:
To a round-bottom flask (20 mL) equipped with a reflux condenser was added a solution of commercial 3,4,5-trimethoxy-toluene (0.547 g, 3 mmol) in AcOH (3 mL), followed by para-toluenesulfonic acid monohydrate (57 mg, 0.3 mmol) as catalyst. The oxidant H2O2 (30%, 0.65 mL, 6 mmol) was then added. The reaction mixture was stirred and heated at 75° C. for 30 min. The resulting dark-red solution was cooled to 0-5° C., and concentrated HNO3 (90%, 1.5 mmol) was then slowly added. The cold solution was poured into H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with H2O (80 mL) in order to remove traces of AcOH, dried (Na2SO4) and filtered. When the solvent was evaporated under vacuum, the final crude (0.528 g, dark-red oil) was dissolved in boiling hexane (70 mL), filtered, and the solvent was removed to give the pure 2,3-Dimethoxy-5- methyl-[1,4]benzoquinone (0.480 g, 88% yield) as red needles. 1H NMR (400 MHz, CDCl3, ppm): δ2.04 [d, 3H, J=1.6 Hz, CH3], 4.00 [s, 3H, OCH3], 4.02 [s, 3H, OCH3], 6.43-6.44 [q, 1H, Jm=1.6 Hz]. 13C NMR (400 MHz, CDCl3, ppm): δ15.4, 31.1, 61.2, 131.3, 144.0, 144.9, 145.1, 184.1, 184.4. MS m/z (%): 182 (85), 167 (32), 153 (13), 137 (100), 121 (6), 111(23), 96 (12), 83 (67), 69 (31), 53 (15).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[NH:9][CH:8]=[C:7]([C:18]#[N:19])[C:6]2=O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:18]#[N:19]
Reactant: COCCOc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COCCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Yield: 87.5 %

Procedure:
A mixture of 6-methoxy-7-(2-methoxyethoxy)-4-oxo-1,4,-dihydro-3-quinolinecarbonitrile (180 mg , 0.66 mmol) and 2.02 g of phosphorous oxychloride is heated at reflux for 40 minutes then concentrated in vacuo. The residue is added to water and the pH is adjusted to 8 by the addition of aqueous sodium bicarbonate. The solids are collected by filtration, washing with water and hexane, to provide 169 mg of 4-chloro-6-methoxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 178-180° C.
Reaction SMILES: CC([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=C.OO.[OH:19]S(O)(=O)=O>CC(C)=O>[OH:19][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1
Reactant: C=C(C)c1ccc(OC(C)C(=O)OC)cc1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(O)cc1
Yield: 57 %

Procedure:
A solution of 10 g methyl 2-(4-(1-methylethenyl)phenoxy)propanoate, 1.2 equivalents 30% aqueous H2O2 in 30 ml acetone, and 0.1 equivalent 98% H2SO4 was refluxed for about 2 hours. Workup gave a 57% yield of methyl 2-(4-hydroxyphenoxy)propanoate.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[C:12]([F:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[F:15])#[N:2].B.[H][H].Cl>O1CCCC1.CO>[NH2:2][CH2:1][CH2:3][C:4]1[CH:13]=[C:12]([F:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[F:15]
Reactant: N#CCc1cc(F)c2c(c1F)OCCO2
Reactant: [H][H]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1cc(F)c2c(c1F)OCCO2

Procedure:
6-Cyanomethyl-5,8-difluoro-1,4-benzodioxane (30.34 g, 0.158 mole) dissolved in 300 ml of dry tetrahydrofuran is treated with 308 ml of 1 M borane in tetrahydrofuran under nitrogen. After 2 hours of reflux 300 ml of methanol is added continuously (hydrogen evolution occurs, vigorously at first), then the mixture is refluxed for 30 minutes. Then 50 ml of 10% hydrochloric acid is added very carefully (hydrogen gas evolution again) and the mixture refluxed another 30 minutes. The reaction mixture is concentrated under vacuum to a small volume, then 300 ml of water is added and the mixture made basic with 40% sodium hydroxide. This is extracted with ether, dried, and concentrated to give 6-(2-aminoethyl)-5,8-difluoro-1,4-benzodioxane.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccc(Cl)c1N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A 100 mL round-bottom flask was charged with 3-chloro-2-fluorobenzaldehyde (3.00 g, 18.9 mmol, 1.00 equiv), morpholine (2.50 g, 28.7 mmol, 1.52 equiv), potassium carbonate (6.50 g, 47.0 mmol, 2.49 equiv), and dimethyl sulfoxide (30 mL). The resulting solution was stirred for 3 hours at 100° C. in an oil bath and diluted with H2O (30 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to provide 1.40 g (33% yield) of 3-chloro-2-(morpholin-4-yl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 226 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of ethyl [4-({butyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (105 mg, 0.21 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL), was added 2M NaOH (2 mL) aq. After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×20 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a pale yellow foam (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I-].[K+].[CH2:28]([NH2:31])[CH:29]=[CH2:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:28][CH:29]=[CH2:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: C=CCN
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 31, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylamino)-methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([NH:28][C:29]4[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=4)=[O:27])[CH2:21]3)([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([N:41](C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C=O)C>[C:33]([C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][CH:20]([C:6]3([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:21]2)=[O:27])=[CH:37][CH:36]=1)(=[O:34])[NH2:41]
Reactant: O=C(O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid (50 mg, 0.093 mmol) (from Example 64 supra) in DMF (1.5 mL) was added diisopropyl ethylamine (48.0 mg, 0.37 mmol) (Aldrich), followed by the addition N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (35.5 mg, 0.18 mmol) (Aldrich), 1-hydroxybenzotriazole (25.0 mg, 0.18 mmol) (Aldrich) and ammonium chloride (9.8 mg, 0.18 mmol) (Aldrich). The mixture was stirred at room temperature for 2 hours and then heated at 60° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid. (Yield 25 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:22][CH:19]3[CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: NC1CC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CC3)c2n1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclopropanamine (0.038 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 μmmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine (0.060 g, 54%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 0.76-0.79 (2H, m), 0.99-1.03 (2H, m), 3.02-3.06 (1H, m), 7.12 (1H, brs), 7.61-7.63 (1H, m), 8.04-8.07 (1H, m), 8.73 (1H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)=[O:5])C.[K]>[OH-].[K+].CO>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CNc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CNc1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A suspension of 2-ethoxycarbonyl-1-(3,4-methylenedioxyanilino)methyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 13) (500 mg, 1.1 mmol) in 2M potassium hydroxide (50 ml) and methanol (50 ml) was stirred at 60° C. for 4 h. The reaction mixture was concentrated to half volume and the precipitate isolated by filtration to give 375 mg (74%) of the title compound as the potassium slat. M.p. >250° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:24][CH2:23][C:13]3([CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)[C:12]2=[O:25])=[CH:7][CH:6]=1)[OH:4].Cl>C1COCC1>[F:27][C:2]([F:1])([F:26])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:24][CH2:23][C:13]3([CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]3)[C:12]2=[O:25])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C1N(c2ccc([C@@H](O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)CCN(c1ccc([C@@H](O)C(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 133, step 5 from 10-[4-((R)-2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (4.09 g) by treatment with 2 M HCl (64 ml) in THF (127 ml) as a white solid. (4.06 g). MS (m/e): 342.130 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].[C:37]([C:41]1[S:45][C:44]([C:46](O)=[O:47])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:37]([C:41]1[S:45][C:44]([C:46]([NH:1][C@@H:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][CH:28]=4)=[CH:19][N:18]=3)=[CH:15][CH:16]=2)[C:3]([OH:5])=[O:4])=[O:47])=[CH:43][CH:42]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)O)cc3)nc2)cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
A stirring solution of (S)-tert-butyl 2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-9 (5.50 g, 11.23 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (2.13 g, 11.57 mmol) in DMF (50 mL) and DIEA (6.22 ml, 33.70 mmol) was treated portion wise with HATU (4.48 g, 11.79 mmol). After stirring for 1 h, the mixture was treated with water (200 mL) and iso-hexanes (20 mL) and stirred for 10 min. The product was collected by filtration, washed with iso-hexanes (2×30 mL), water (2×50 mL) then MeOH (20 mL) and iso-hexanes (30 mL). The ester was taken up in DCM (50 mL) and treated with TFA (10 mL). After 1 h, additional TFA (15 mL) was added. After a further 5 h, the mixture was treated with toluene (20 mL) and concentrated. The residue was washed with acetonitrile (25 mL) then taken up in DMSO (20 mL) then treated with water (100 mL) and stirred for 1 h. The product was collected by filtration, washed with water (4×50 mL) then acetonitrile (3×30 mL), and dried in a vacuum oven to give 5.30 g (75%) of (S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid, Compound 192 as an off-white solid. LCMS-ESI (m/z) calculated for C35H41N3O4S: 599.3; no m/z observed, tR=11.10 min (Method 10). The chiral purity was 98% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.17 (s, 2H), 8.68 (d, J=8.3 Hz, 1H), 8.47-8.17 (m, 2H), 7.96-7.71 (m, 2H), 7.64 (d, J=3.8 Hz, 1H), 7.55-7.29 (m, 2H), 7.26-7.02 (m, 2H), 6.93 (d, J=3.8 Hz, 1H), 4.79-4.48 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.27 (dd, J=13.9, 4.5 Hz, 1H), 3.12 (dd, J=13.9, 10.6 Hz, 1H), 1.90-1.58 (m, 2H), 1.58-1.01 (m, 17H), 1.01-0.69 (m, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C(Cl)Cl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C#Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 108.6 %

Procedure:
4-Iodophenyl acetate (50.00 g, 0.191 mol), phenylacetylene (23.40 g, 0.229 mol), and triethylamine (54 mL) are added to a 250-mL round bottom flask fitted with a condenser/nitrogen inlet, a thermometer, and a stopper. PdCl2 (PPh3)2 (0.200 g, 0.286 mmol) and PPh3 (1.50 g, 5.73 mmol) are then added and the mixture heated to reflux. When the reaction mixture reaches 40° C., CuI (0.054 g, 0.286 mmol) is added. After 2 hours, the reaction is allowed to cool. The mixture is diluted with methylene chloride and poured into water (500 mL). The aqueous layer is extracted with methylene chloride (100 mL). The combined organic layers are washed with three 300-mL portions of water, dried (MgSO4), and filtered. The solvent is removed in vacuo to give 49 g of a yellow solid. The material is recrystallized from hexanes to give light yellow crystals, mp 104.5° C. to 105.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C(O[N:40]=O)CC(C)C>C1C=CC=CC=1>[NH:1]1[C:2]2[C:3](=[C:4]([O:5][CH:6]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]3)[CH:18]=[CH:19][CH:20]=2)[CH:21]=[N:40]1
Reactant: Cc1c(N)cccc1OC1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3[nH]ncc23)C1
Temperature: 25 °C

Procedure:
A solution of t-butyl 3-(3-amino-2-methylphenoxy)pyrrolidin-1-Carboxylate (4.6 g, 15.4 mmol), potassium acetate (1.81 g, 18.5 mmol) and acetic anhydride (5.02 g, 49.2 mmol) in benzene is treated dropwise with isoamylnitrite (4.13 ml, 30.8 mmol), heated at reflux temperature overnight, cooled to room temperature and filtered. The filtercake is washed with benzene. The combined filtrates are concentrated to give a yellow oil residue. The residue is purified by chromatography (SiO2, 25% EtOAc in hexanes). The resultant oil is dissolved in ethanol, treated with 40% aqueous NaOH, heated at reflux temperature for 45 min, cooled with an ice-water bath, neutralized to pH 9 with concentrated HCl and concentrated in vacuo. The resulting aqueous mixture is extracted with EtOAc. The combined extracts are washed with water and brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid, 2.6 g, mp 196-198° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:9]=2[CH3:26])[CH:5]=[CH:6][CH:7]=1.[O:27]1[C:31](B(O)O)=[CH:30][C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2>>[O:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[CH:30]=[C:31]1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:17]2)=[O:15])[C:9]=1[CH3:26]
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)c1cc2ccccc2o1
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3ccccc3-c3cc4ccccc4o3)c2C)C1
Yield: 39 %

Procedure:
In analogy to the procedure described in Example 14C], [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and benzo[b]furan-2-boronic acid gave the title compound in 39% yield as light brown foam. MS: 457.3 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:18])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:18][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Yield: 52.9 %

Procedure:
Intermediate 13a (10.0 g, 40.8 mmol) was dissolved in DCM (80.0 mL), and aluminium trichloride (28.0 g, 204.0 mmol) was added portionwise. The reaction was heated to reflux for 4 h. Additional aluminium trichloride (28.0 g, 204.0 mmol) was added portionwise, and the reaction heated at reflux overnight. After cooling, the mixture was carefully added portionwise to saturated aqueous NaHCO3 (300 mL). The mixture was extracted with ethyl acetate (300 mL) and separated. The aqueous layer was filtered under vacuo and acidified with 1N HCl until pH=7. This aqueous layer was then re-extracted into ethyl acetate, and the organic extracts were dried (MgSO4) and evaporated in vacuo. Purification by FCC, using 0-40% EtOAc in DCM, gave the title compound (5.0 g, 21.6 mmol, 53%). LCMS (method 1): Rt 2.77 min, m/z 232/233 [MH+].
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][CH2:14]O)C=CC=CC=1.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[Na].[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>C1COCC1.CO.[Pd]>[N:32]1([CH2:14][CH2:13][O:12][C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][CH:16]=2)[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: OCCOc1cccc(OCc2ccccc2)c1
Reactant: c1c[nH]cn1
Agent: [Pd]
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1cccc(OCCn2ccnc2)c1

Procedure:
A solution of 12.2 g (0.05 mole) 2-[3-(phenylmethoxy)phenoxy]ethanol and 5.6 g (0.555 mole) of triethylamine in 100 ml of THF was cooled to 0° C. with stirring and treated dropwise with 6.4 g (0.055 mole) of mesyl chloride over a 20-min period. The mixture was stirred at 10° C. or less for 1 hr, then filtered. The filtrate was combined with a slurry of 0.10 mole of imidazole sodium salt in 50 ml of THF and the mixture was heated at reflux for 8 hr. The 50 ml of THF and the mixture was heated at reflux for 8 hr. The cooled reaction mixture was filtered and the filtrate was partitioned between ethyl acetate/ether and water. The organic layer was concentrated to give 14.7 g (100%) of crude intermediate. This syrup (13.0 g) was dissolved in 100 ml of methanol and hydrogenated at 40° C. and 45 psi H2 using 1 g of 10% Pd/C catalyst. This mixture was filtered, and the filtrate was concentrated to give 9.0 g (100%) of crude, crystalline product. A portion was recrystallized from toluene/methyl isobutyl ketone to give the title compound as white crystals, mp 125.0° C.-127.0° C.