Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[C@@H:15]([OH:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:23][C@@H:10]3[C:11]2=[O:22])[CH2:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[C@@H:15]([OH:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:23][C@@H:10]3[C:11]2=[O:22])[CH2:3]1)(=[O:26])[CH3:25]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)[C@H]3C[C@H]3[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2[C@@H](O)C[C@]2(C)C(=O)[C@H]4C[C@H]4[C@@H]32)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 7.9 g of 3β,11β-dihydroxy-15β,16β-methyleneandrost-5-en-17-one in 39.5 ml of pyridine and 39.5 ml of acetic anhydride is left to stand at room temperature for 5 hours, diluted with 800 ml of ice-water and, after standing for 1 hour, extracted with ethyl acetate. The organic phase is washed in succession with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution, dried, and concentrated under a water-jet vacuum. Chromatography of the crude product over 30 times the amount by weight of silica gel and elution with a mixture of methylene chloride/acetone (98:2) yield 3β-acetoxy-11β-hydroxy-15β,16β-methyleneandrost-5-en-17-one which, after being dissolved and recrystallised once from methylene chloride/ether/petroleum ether, melts at 209°-211°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][N:12]1[C:20]2[C@@:19]3([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:16]([CH2:17][CH2:18]3)[C:15]=2[C:14](=[O:25])[N:13]1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])C.O.[OH-].[Na+]>O1CCCC1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:13]1[C:14](=[O:25])[C:15]2[C@@H:16]3[C:21]([CH3:22])([CH3:23])[C@@:19]([CH3:24])([CH2:18][CH2:17]3)[C:20]=2[N:12]1[CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
A solution of lithium aluminum hydride in tetrahydrofuran (Aldrich; 2 M; 80 μL; 0.16 mmol) was added to a solution of [(4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-yl]-acetic acid ethyl ester (Example 92; 57 mg, 0.15 mmol) in dry tetrahydrofuran (EMScience DriSolve; 700 μL) over 1 min, and the solution was stirred at room temperature for 18 h. Water (4 mL) was added and the mixture was stirred for 10 min. 2M aqueous sodium hydroxide solution (4 mL, 8 mmol) was added and the mixture was stirred for 10 min. The mixture was extracted with dichloromethane (50 mL) and the organic extract was dried (magesium sulfate), filtered, evaporated, and purified using an ISCO 4 g column, eluting with 0-10% methanol/ethyl acetate. Fractions containing the product were combined, evaporated, co-evaporated successively with methanol and ether, and then dried under high vacuum at 75° C. to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(2-hydroxy-ethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (8 mg, 16%) as a white solid. ES(+)-MS (M+H) 349.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([NH:16][C:17]1[N:22]=[C:21]([C:23]2[N:27]3[CH:28]=[CH:29][N:30]=[C:31]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[C:26]3=[N:25][CH:24]=2)[CH:20]=[CH:19][N:18]=1)[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)(C)(C)C.Cl>C(O)C>[CH3:38][N:35]1[CH2:34][CH2:33][N:32]([C:31]2[C:26]3[N:27]([C:23]([C:21]4[CH:20]=[CH:19][N:18]=[C:17]([NH:16][CH:10]([C:11]5[CH:15]=[CH:14][S:13][CH:12]=5)[CH2:9][CH2:8][NH2:7])[N:22]=4)=[CH:24][N:25]=3)[CH:28]=[CH:29][N:30]=2)[CH2:37][CH2:36]1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5ccsc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCN)c5ccsc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester (400 mg, 0.182 mmol) in ethanol (3 mL) was added concentrated hydrochloric acid (3 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N1-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-propane-1,3-diamine; hydrochloride. (Yield 27 mg, 14.9%). 1H NMR (300 MHz, CD3OD): δ 8.76 (s, 2H), 8.41 (brs, 1H), 7.68-7.52 (m, 4H), 7.32 (d, 1H, J=5.1 Hz), 5.55 (brs, 1H), 4.85 (brs, 2H), 3.75-3.72 (m, 4H), 3.40(brs, 2H), 3.18-3.15 (m, 2H), 3.00 (s, 3H), 2.44 (brs, 2H). LC-MS: [M+H]+ 450.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][OH:45])[CH2:41][CH2:42]4)[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1cccc(N2CCN(CCO)CC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCN(CCO)CC4)c3)nn12
Yield: 23.9 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (150.0 mg, 0.0005220 mol), N,N-Diisopropylethylamine (0.136 mL, 0.000783 mol) and 2-[4-(3-Amino-phenyl)-piperazin-1-yl]-ethanol (231.0 mg, 0.001044 mol) were dissolved in 2-Methoxyethanol (3.66 mL) and the The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 55.38 mg of 2-(4-{3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanol as a lyophilated powder. (M+H)=445.21. 1H NMR (400 MHz, DMSO, d6) δ 9.16 (s, 1H), 8.94 (s, 1H), 7.72 (d, 1H, J=5.85 Hz), 7.44 (t, 1H, J=7.64 Hz), 7.26 (s, 1H), 7.19 (d, 1H, J=7.68 Hz), 7.08 (m, 2H), 7.01 (t, 1H, J=7.80 Hz), 6.90 (q, 2H, J=4.61 Hz), 6.46 (d, 1H, J=6.89 Hz), 3.76 (s, 3H), 3.53 (m, 4H), 3.04 (m, 2H), 2.87 (m, 2H), 2.67 (m, 2H), 2.44 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[O:12]C3C(=CC(C)=C(C)C=3)[C:5]3([C:30]4[CH:29]=CC=CC=4[C:24]4[C:19]3=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:4]=2[CH:3]=1>CS(C)=O>[OH:12][C:13]1[CH:14]=[C:15]([CH3:16])[C:2]([CH3:1])=[CH:29][C:30]=1[C:5]1([C:4]2[CH:3]=[C:2]([CH3:1])[C:15]([CH3:16])=[CH:14][C:13]=2[OH:12])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Cc1cc2c(cc1C)C1(c3cc(C)c(C)cc3O2)c2ccccc2-c2ccccc21
Solvent: CS(C)=O
Product: Cc1cc(O)c(C2(c3cc(C)c(C)cc3O)c3ccccc3-c3ccccc32)cc1C

Procedure:
H-1 NMR: (DMSO) delta from tetramethylsilane 1.82 (singlet, CH3, 3H), 2.01 (singlet, CH3, 3H), 6.32-6.46 (doublet, 4H), 7.17-7.33 (multiplet, 4H ), 7.78-7.88 (multiplet, 4H), 8.69 (singlet, 2H, OH); C-13 NMR: (DMSO) (ppm) 18.8 (CH3), 19.0 (CH3), 61.5 (quaternary carbon), 117.2, 119.8, 124.7, 126.2, 126.9, 127.3, 127.9, 128.2, 134.2, 139.3, 152.6, 153.5. 2',3',6',7'-tetramethylspiro[fluorene-9,9'-xanthene] H-1NMR: (CDCl3) delta from tetramethylsilane 1.87 (singlet, CH3, 3H), 2.16 (singlet, CH3, 3H), 6.08 (singlet, 2H), 6.97 (singlet, 2H), 7.15-7.36 (multiplet, 6H), 7.76-7.79 (doublet, 2H). C-13 NMR: (CDCl3) (ppm) 18.9 (CH3), 19.4 (CH3), 53.7 (quaternary carbon), 117.4, 119.8, 121.7, 125.6, 127.5, 128.2, 128.3, 131.1 136.6, 139.6, 149.5, 155.5
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]1(=O)[CH2:15][CH2:14][CH2:13]1.N1CCCC1>>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:12]1([CH2:15][CH2:14][CH2:13]1)[CH2:10][C:9]2=[O:11]
Reactant: O=C1CCC1
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: C1CCNC1
Product: O=C1CC2(CCC2)Oc2ccc(O)cc21

Procedure:
The title compound was prepared from 2′,5′-dihydroxyacetophenone (10 g, 65.724 mmol) and cyclobutanone (13.29 ml, 131.44 mmol), in the presence of pyrrolidine (10.79 ml) by similar procedure as described in Step 1 of Intermediate 1 to give 10 g of the product; 1H NMR (300 MHz, CDCl3) δ 1.63-1.73 (m, 2H), 1.84-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.23-2.33 (m, 2H), 6.85 (d, J=8.7 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 7.33 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[OH:9].[OH:10]O>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:10])[CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: OO
Solvent: CC(=O)O
Product: O=C1C=CC(=O)C(Cl)=C1
Temperature: 65 °C

Procedure:
A mixture of 2,4-dichlorophenol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 60-70° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and corresponding quinone formed (25%) was separated by chromatographic purification.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Br:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([OH:48])=O)=[N:44][CH:45]=1>CN(C)C=O>[Br:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([N:3]([O:4][CH3:5])[CH3:2])=[O:48])=[N:44][CH:45]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (500 mg, 5 mmol) was added to a mixture of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1400 mg, 3.7 mmol), N,N-diisopropylethylamine (1000 μL, 7 mmol) and 5-bromopyridine-2-carboxylic acid (500 mg, 2 mmol, Frontier Scientific catalog# B1704) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred overnight at room temperature and was complete by LC/MS. The reaction was partitioned between water and EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified on by FCC on silica gel eluting a hexane: EtOAc (0-30%) gradient to give 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide clear oil (0.50 g, 60%). LCMS calculated for C8H10BrN2O2(M+H)+: m/z=244.9, 246.9; found: 244.9, 246.9.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:14][CH:13]=2)[CH2:7]1)=[O:5].[CH3:28][Mg]Br.O.C(OCC)(=O)C>O1CCCC1.C1CCCCC1>[C:4]([C@H:6]1[CH2:7][N:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:17]=2)[C:9](=[O:11])[CH2:10]1)(=[O:5])[CH3:28]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (0.050 g, 0.143 mmol) was dissolved under argon in tetrahydrofurane (1 ml) and methyl magnesium bromide (0.188 mmol, 0.063 ml) was added at 0° C. The resulting solution was stirred at 0° C. for two hours. Water was added at 0° C. and the mixture was stirred for one hour. Extraction with ethyl acetate gave a residue which after chromatography on silica gel using a 9:1-mixture of ethyl acetate and cyclohexane as the eluent yielded 0.040 g (91% of theory) of the title compound as a white solid. MS: m/e=328.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8]O)[CH:4]=[N:3]1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cc(CCO)cn1
Reactant: O=S(Cl)Cl
Product: Cn1cc(CCCl)cn1

Procedure:
To excess thionyl chloride (250 mL) at 0° C. was added 2-(1-methyl-1H-pyrazol-4-yl)ethanol (82 g, 0.651 mol). The reaction mixture was heated to reflux for 15 minutes. The excess thionyl chloride was removed in vacuo and the crude product was purified by recrystallization from EtOH to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27]>CO.[OH-].[Na+]>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([OH:27])[C:6]=2[CH2:24][CH2:25][CH3:26])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CCCc1c(OCCCc2ccc(OC)c(OC)c2)ccc(C(=O)OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCc2ccc(OC)c(OC)c2)ccc(C(=O)O)c1O

Procedure:
A solution of 7.1 g of 4-[3-(3,4-dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid methyl ester in 180 mL of methanol and 90 mL of 1N sodium hydroxide was stirred at reflux for 1 hour. The solvent was removed under reduced pressure, the residue was acidified and the product was extracted with methylene chloride. The dried (MgSO4) extract was concentrated to 6.5 g, mp 104°-110°, of 4-[3-(3,4-dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][S:6](=[O:20])(=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16].[OH-].[Na+].Cl>O1CCOCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][S:6]([CH2:5][CH2:4][C:3]([OH:21])=[O:2])(=[O:20])=[O:19])=[C:9]([C:15]([F:18])([F:16])[F:17])[CH:10]=1
Reactant: COC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
3.293 g (10 mmol) of the ester prepared in (a) is dissolved in 50 ml of dioxane and combined with 10 ml (20 mmol) of 2N sodium hydroxide solution. The mixture is stirred at 50° C. until no starting material can be detected any longer. The solution is set to a pH of 4 with hydrochloric acid and concentrated to dryness under vacuum. The residue is distributed between dichloromethane and acidified water. The organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 2.572 g (81.6% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J36) (239 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (292 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)C.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[CH:30]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:30][C:29]#[CH:28])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: C#CCBr
Reactant: COC(=O)CC(C)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(N2CCN(CCC(=O)OC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a mixture of the compound from step 1 (278 mg, 1.0 mmol) and K2CO3 (152 mg, 1.1 mmol) in DMF (5 mL) was added 3-bromopropyne (130 mg, 1.1 mmol) dropwise at rt. The reaction mixture was stirred at rt overnight and then partitioned between water and ethyl acetate. The organic payers were combined and washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give a brown oil. The crude product was purified by silica gel flash chromatography (30% ethyl acetate in hexane) to furnish the title compound (120 mg, 38%) as a light yellow solid; MS; m/z 317 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1.[NH3:21]>S(Cl)(Cl)=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:21])=[O:18])=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A stirred suspension of 1-(4-fluoro-phenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carboxylic acid (1 g, 3.7 mmol) in thionyl chloride (25 mL) was heated at reflux for 25 min, during which time the solid dissolved. The thionyl chloride was then evaporated, and the residue was dissolved in toluene, and again evaporated. The residue was dissolved in toluene (15 mL) and was treated with a solution of ammonia in ether and a heavy precipitate formed. The mixture was stirred overnight, diluted with toluene and aqueous ammonia solution, and filtered. The residue was dried to give the title compound as a white solid (0.80 g, 80%). 1H NMR (d6-DMSO): δ 6.81 (s, 1H), 7.25 (t, 2H), 7.40 (dd, 2H), 7.54 (d, 1H), 7.59 (bs, 1H), 8.24 (bs, 1H), 8.24 (dd, 1H), 8.42 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=C(O)C1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCCC(C(=O)O)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.449 mg, 1.66 mmol) in CH2Cl2 was added 5 equivalents of triethylamine followed by the addition of piperidine-3-carboxylic acid as a TFA salt. The reaction was stirred for 2 hours and quenched with water. The layers were separated, and the organic extracts were dried over MgSO4, filtered, and concentrated to give 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxylic acid which was used without further purification. LC/MS: m/z 364.3 (M+H)+ at 2.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:12]1([C:9]2[N:10]=[C:11]3[CH:2]=[CH:3][CH2:4][N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:6]3=[N:7][C:8]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC=Cc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-Butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (5 g, 10.72 mmol) in DCM (250 ml) was treated with DBU (1.939 ml, 12.87 mmol) and was stirred at RT under an atmosphere of nitrogen overnight. The solvent was removed in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-20% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])=[O:11].C(Cl)CCl.[NH3:26]>CN(C1C=CN=CC=1)C.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:26])=[O:16])=[O:11]
Reactant: O=C(Nc1ncccc1C(=O)O)c1cc2ccccc2s1
Reactant: N
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)c1cccnc1NC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 2-[(1-benzothien-2-ylcarbonyl)amino]nicotinic acid (112 g, 4.0 mmol), EDC (2.3 g, 12.0 mmol) and DMAP (1.46 g, 12.0 mmol) in anhyd dichloromethane (50 mL) was stirred at room temperature for 2 h. To this mixture was added 40% aqueous ammonia (4.0 mL), and the resulting solution stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid was washed with satd NH4Cl solution, NaHCO3 solution, and water. The solid was dried to give product as white powder (0.92 g, 77%). HPLC/MS: (M+H)+298.15 m/z Retention time (LC-MS)=2.44 min. 1H NMR (DMSO-D6): 12.25 (1H, s); 8.54(1H, m); 8.21(1H, s); 8.18(1H, d); 8.07(2H, m); 7.52(2H, m); 7.32(1H, m).