Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:23]1[CH:44]=[CH:43][C:26]([C:27]([NH:29][C@H:30]([C:38]([O:40]CC)=[O:39])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:28])=[CH:25][CH:24]=1)[CH2:4][CH:5]1[CH2:22][NH:21][C:8]2[N:9]=[C:10]([NH:14]C(=O)C(C)(C)C)[N:11]=[C:12]([OH:13])[C:7]=2[CH2:6]1.Cl>[OH-].[Na+]>[OH:1][CH2:2][CH:3]([C:23]1[CH:44]=[CH:43][C:26]([C:27]([NH:29][C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:28])=[CH:25][CH:24]=1)[CH2:4][CH:5]1[CH2:22][NH:21][C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[C:12]([OH:13])[C:7]=2[CH2:6]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(CO)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CC(CO)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C2
Yield: 77.8 %

Procedure:
A solution of 300 mg (0.49 mm) of diethyl N-[4-{1-hydroxy-3-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamate in 9 ml of 1N aqueous sodium hydroxide was stirred under nitrogen at ambient temperature for 72 hours. The reaction mixture was rendered slightly acidic (pH=~4) with 1N hydrochloric acid and filtered. The solid thus collected was washed with water (5 ml) and cold ethanol (5 ml) and dried to give 180 mg (78%) of N-[4-{1-hydroxy-3-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamic acid. mp 275° C. (dec.). Analysis calculated for C22H27N5O7.0.5H2O: C, 54.76; H, 5.80; N, 14.51. Found: C, 54.96; H, 5.88; N, 14.27. NMR (DMSOd6, CF3COOD), delta, 1.35-1.42 (m, 1H), 1.58-1.71 (m, 2H), 1.73-1.85 (m, 1H), 1.86-2.01 (m, 1H), 2.02-2.13 (m, 1H), 2.31 (t, 2H, J=7 Hz), 2.39-2.52 (m, 1H), 2.74-2.89 (m, 2H), 3.08-3.14 and 3.24-3.30 (m, m, 1H), 3.47 (d, 2H, J=3.7 Hz), 4.37 (dd, 1H, J=19.4 Hz, J=4.7 Hz), 7.27-7.30 (m, 2H), 7.78 (d, 2H, J=7.7 Hz).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)[C:3]([OH:5])=[O:4].[C:24](Cl)(=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O.C(N(C(C)C)C(C)C)C>[C:24]([NH:1][CH:2]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)[C:3]([OH:5])=[O:4])(=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NC(Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)NC(Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a mixture of 335 mg (±)-α-amino-3-(5-phosphonomethyl-[1.1'-biphenyl]3-yl) propanoic acid in 30 ml dimethylformamide and 0.76 ml N-ethyldiisopropylamine under nitrogen are added dropwise at room temperature within 10 minutes 0.4 ml palmitic acid chloride. The mixture is stirred at room temperature for 26 hours. The solvent is evaporated in vacuo. The oily residue is taken up in water, acidified with 2N HCl to pH 1 and extracted with diethyl ether. The extract is washed with saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated. The residue is recrystallized from diethyl ether/petroleum ether to yield the title compound, m.p. 130°-140°. MS (FAB):574(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:40])([F:39])[C:13]([CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([OH:33])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:34][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:12]([F:11])([F:40])[F:39])=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: O.S(=O)(=O)(O)O.C1([O:12][C:13]2[CH:14]=[C:15]([C@@H:21]([C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)[NH2:32])[CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])CCCC1>O1CCOCC1>[OH:12][C:13]1[CH:14]=[C:15]([C@@H:21]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc([C@H](Cc2ccncc2)c2cccc(N)c2)cc1OC1CCCC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@H](Cc2ccncc2)c2cccc(N)c2)cc1O
Temperature: 90 °C
Yield: 90.5 %

Procedure:
Water (25 ml) and sulphuric acid (40 ml, concentrated) was added to a solution of 3-[1-(R)-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline (3.8 g, 9.8 mmol prepared as described in International Patent specification No. WO95/17386) in 1,4-dioxane (50 ml) at RT. The mixture was heated at 90° C. for 1 h, cooled and concentrated in vacuo. The pH of the residue was adjusted to pH 8.0-8.5 by the addition of solid NaOH. The mixture was diluted with ethyl acetate (100 ml) and water (50 ml) and extracted with ethyl acetate (2×50 ml). The extract was washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo to give a crude product which was washed with ethyl acetate to afford 3-[1-(R)-(3-hydroxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline (Intermediate 1) as a pale yellow powder (2.84 g, 91%). (Found: C, 73.83; H, 6.44; N, 8.09. C20H20N2O2 +0.25 mol. eqv. of ethyl acetate requires C, 73.66; H, 6.48; N, 8.18%), δH (d4 -methanol) 3.3 (2H, d, J 8.0 Hz), 3.77 (3H, s), 4.06 (1H, t, J 8.0 Hz), 6.5 (1H, d, J 2.2 Hz), 6.53-6.78 (5H, m), 6.97 (1H, t, J 7.7 Hz), 7.13 (2H, d, J 5.8 Hz), and 8.25 (2H, d, J 5.6 Hz). m/z (ESI--MH+ 321 (25), 228 (100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([N:23]1[CH2:24][CH2:25][CH:26]([NH:29][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone (Example 7) and ethyl-4-amino-1-piperidine carboxylate (Aldrich) using the procedure described in Step B. Example 6. HRMS, observed: 386.1762, calcd for M+: 386.1754.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1.FC(F)(F)S([O-])(=O)=O.[Bi+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[O:21]=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16]1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C1C=CCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2ccccc2c1C1CCCC(=O)C1
Temperature: 65 °C

Procedure:
Ethyl 1H-indole-2-carboxylate (2.953 g) and cyclohex-2-enone (1.004 mL) were added to acetonitrile (50 mL). Bismuth (III) trifluoromethanesulfonate (341 mg) was added, and the solution was heated at 65° C. for two days. The solution was cooled, concentrated, and purified by flash column chromatography on silica gel with 10% increasing to 20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([SH:47])=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[C:3]=2[C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)=[O:12])=[CH:43][CH:42]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C2CCC(C2)C1=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Sc2ccc(Cl)cc2)C2CCC(C2)C1=O
Reaction time: 2 h

Procedure:
2.0 g (0.0058 mol) of 4-chloro-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one, 0.07 g of dimethylaminopyridine (0.00058 mol) and 1.61 ml of triethylamine are dissolved in 15 ml of methylene chloride. At 25° C., 0.092 g (0.0064 mol) of 4-chlorothiophenol are added. After 2 hours at 22° C., the reaction mixture is evaporated and purified over silica gel (hexane/ethyl acetate 2:1). Recrystallization (hexane/acetic acid at −25° C.) gives pure 4-(4-chlorophenylsulfanyl)-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one: m.p. 130-131 ° C.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][NH:8][C:9]([C:11]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:27])[C:13]2([CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:12]=1[OH:28])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.O>[Cl:27][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[C:25](=[O:26])[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:29])=[O:5])=[O:10])=[C:12]([OH:28])[C:13]12[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2cccc(Cl)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)C2(CCOCC2)c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of t-butyl-N-((5-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (51 mg, 121 μmol) in 1 mL TFA was stirred at room temperature for 30 minutes and diluted with 20 mL water. The solid was collected by filtration and washed with 20 mL water. The solid was then dried under high vacuum to give, 39 mg pale yellow solid. MS m/e: (M+H)+ 366.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].N.[CH3:26][N:27](C)C=O>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][CH:19]=3)=[CH:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C2C=CC(c3ccc(Br)cc3)=CC2)CC1
Reactant: CN(C)C=O
Agent: N
Product: CCCCC[C@H]1CC[C@H](C2C=CC(c3ccc(C#N)cc3)=CC2)CC1

Procedure:
In 20 ml of N,N-dimethylformamide, 7 g of the 1-(trans-4-pentylcyclohexyl)-4-(4-bromophenyl)dihydrobenzene, which had been obtained in Example 18, were dissolved, followed by the addition of 2.0 g of cuprous cyanide. The resulting mixture was reacted for 6 hours at reflux temperature. After the completion of the reaction, aqueous ammonia was added to the reaction mixture, followed by extraction with toluene. The extract was washed with aqueous ammonia and then with saturated NaCl. Anhydrous sodium sulfate was thereafter added to dry the extract. The toluene was distilled off under reduced pressure. The reaction product so obtained was recrystallized from ethanol, whereby 0.7 g of 1-(trans-4-pentylcyclohexyl)-4-(4-cyanophenyl)dihydrobenzene was obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:15][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[N:9][C:8]=3[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:22])[C:5]=2[CH2:4]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([O:1][CH2:2][CH:3]1[O:15][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[N:9][C:8]=3[N:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6](=[O:22])[C:5]=2[CH2:4]1)(=[O:25])[CH3:24]
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OC(CO)C2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)OCC1Cc2c(c3cccnc3n(-c3ccccc3)c2=O)O1

Procedure:
The product of Example 2 is refluxed with acetic anhydride in benzene, and the resultant product is recrystallized from isopropyl acetate to give the title compound, m.p. 207°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[CH:8]([CH3:35])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:32])([F:33])[F:34])([OH:26])[CH:8]([CH3:35])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(C)C3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1CCc2c([nH]c3cc(Cl)c(Cl)cc23)C1(O)C(F)(F)F
Temperature: 60 °C
Yield: 28.4 %

Procedure:
6,7-Dichloro-2-methyl-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.13 g, 0.26 mmol) was dissolved in THF (10 mL) and KOH (0.070 g, 1 mmol) in water (10 mL) was added followed by EtOH (3 mL). The reaction mixture was heated to 60° C. for 4 h, diluted with water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to give the title compound (0.025 g, 28%) 1H NMR (500 MHz, CDCl3, δ in ppm) (mixture of two diastereomers) 8.22 (br s, 1H), 8.15 (bs, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 2.82-2.63 (m, 2H), 2.51 (s, 1H), 2.46-2.43 (m, 1H), 2.33 (s, 1H), 2.28 (s, 1H), 2.14-2.10 (m, 2H), 2.03-1.98 (m, 1H), 1.82-1.79 (m, 1H), 1.22-1.20 (m, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[C:37]([C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1)#[CH:38].CCN(C(C)C)C(C)C>C1COCC1.CCOCC.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#Cc1cccc(O)c1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(-c5cccc(O)c5)nn4)nn23)CC1
Reaction time: 28 h
Yield: 60.7 %

Procedure:
To a stirred clear yellow solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.070 g, 0.140 mmol), 3-ethynylphenol (0.083 g, 0.701 mmol) and DIEA (0.122 ml, 0.701 mmol) in THF (5 mL) was added CuI (0.053 g, 0.280 mmol) at rt. After 28 h, the reaction mixture was diluted with Et2O (50 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to give yellow oil which was purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0528 g, 0.085 mmol, 61.0% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.75-7.99 (m, 2H), 7.52 (t, J=1.8 Hz, 1H), 7.22-7.30 (m, 2H), 6.84-6.89 (m, 1H), 6.51 (s, 1H), 5.97-6.07 (m, 1H), 5.86 (br. s., 1H), 5.78 (s, 2H), 5.44 (d, J=16.7 Hz, 1H), 5.19 (dd, J=1.6, 10.4 Hz, 1H), 4.14-4.29 (m, 2H), 4.00 (d, J=4.7 Hz, 2H), 2.62 (s, 3H), 1.82-2.03 (m, 3H), 1.65-1.73 (m, 1H), 1.31 (s, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.23 (s, 9H). LCMS (M+H)=618.6.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](C=CN2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC.[CH3:23][N:24]([CH3:27])[CH:25]=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:9][CH:10]=1)[N:24]([CH3:27])[CH:25]=[CH:5]2
Reactant: CN(C)C=O
Reactant: Clc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 130 °C
Yield: 96.1 %

Procedure:
6-Chloroindole (1.0 g, 6.59 mmol), potassium carbonate (0.5 g), N,N-dimethylformamide (10 mL) and dimethyl carbonate (1.7 mL, 20.21 mmol) were stirred and heated to reflux (˜130° C.). The starting indole was consumed within 3.5 h (as determined by HPLC). After the mixture was then cooled to ˜3° C., ice cold water (50 mL) was added and the resulting oily suspension was extracted with tert-butyl methyl ether (40 mL). The separated organic layer was washed with water (3×25 mL), then was evaporated under vacuum to furnish 5-chloro-1-methylindole as a light yellow oil (1.05 g, 96.1% yield).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.CN.[N:24]1(C2C=CN=CC=2)CCC[CH2:25]1.C(N=C=NC(C)C)(C)C>C(O)C.ClCCl>[CH3:25][NH:24][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: c1cc(N2CCCC2)ccn1
Agent: CC(C)N=C=NC(C)C
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid (0.8 g), methylamine in ethanol (0.27 ml of a 33% w/w solution), 4-pyrrolidinopyridine (0.47 g), diisopropylcarbodiimide (0.5 ml) and dichloromethane (30 ml) was stirred at ambient temperature for 20 hours. More methylamine in ethanol (0.3 ml of a 33% w/w solution), 4-pyrrolidinopyridine (0.5 g) and diisopropylcarbodiimide (1 ml) were added and the mixture was stirred for 3 hours at ambient temperature. The solvent was removed under reduced pressure at 50° C. The mixture was kept under vacuum for 2 hours and then dichloromethane (50 ml) was added. The mixture was stirred at ambient temperature for 20 hours and then allowed to stand for 72 hours. A solid was removed by filtration and purified by flash column chromatography on silica using toluene/acetic acid (10:1) and then ethyl acetate as the mobile phase to give N-methyl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, m.p. 182-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:9]5[CH:10]=[C:11]6[C:6]([CH:5]=[CH:4][CH:3]=[C:2]6[NH:1][S:45]([C:42]6[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=6)(=[O:47])=[O:46])=[CH:7][CH:8]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:36][CH:35]=2)[S:32]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2cccc3ccc(Oc4ccc5nc(COc6ccc(CC7SC(=O)NC7=O)cc6)n(C)c5c4)cc23)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
A mixture of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g), p-toluenesulfonyl chloride (0.30 g), triethylamine (0.16 g) and anhydrous tetrahydrofuran (8 ml) was stirred at 50° C. for 5 hours and then at 70° C. for 2 hours. The reaction mixture was concentrated. To the residue was added water and the precipitate was washed with water and tetrahydrofuran to afford the title compound (0.14 g, mp 137-144° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.O.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>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]([C:8]3[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:22]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:21]=1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1OCc1ccccc1
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: CCOCC
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccccc1-c1ccc(Cl)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 47 %

Procedure:
A mixture of ethyl 2′-bromo-2-biphenylcarboxylate (153 mg, 0.5 mmol), {4-chloro-2-[(phenylmethyl)oxy]phenyl}boronic acid (144 mg, 0.55 mmol), potassium carbonate (552 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was stirred and heated at 90° C. under nitrogen for 18 hours. After cooling the mixture was diluted with ether/water and the organic phase dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:19) to give 104 mg of colourless gum.
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]2[CH2:27][N:26]([CH:28]3[CH:33]4[CH2:34][CH2:35][CH2:36][CH:29]3[CH2:30][CH:31]([C:37]([OH:39])=O)[CH2:32]4)[C:25](=[O:40])[C:24]2([CH3:42])[CH3:41])=[N:19][CH:20]=1)#[N:14].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]2[CH2:27][N:26]([CH:28]3[CH:29]4[CH2:36][CH2:35][CH2:34][CH:33]3[CH2:32][CH:31]([C:37]([NH2:4])=[O:39])[CH2:30]4)[C:25](=[O:40])[C:24]2([CH3:41])[CH3:42])=[N:19][CH:20]=1)#[N:14]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC1(C)C(=O)N(C2C3CCCC2CC(C(=O)O)C3)CC1COc1ccc(C#N)cn1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CCCC2CC(C(N)=O)C3)CC1COc1ccc(C#N)cn1
Reaction time: 1 h

Procedure:
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.35 g, 1.81 mmol) was added in one portion to a stirred solution of the product of Example 7F (0.50 g, 1.21 mmol), 1-hydroxybenzotriazole hydrate (0.32 g, 2.42 mmol), and diisopropylethyl amine (0.63 mL, 3.63 mmol) in dry dichloromethane (7 mL). The resulting solution was stirred at room temperature for two hours before ammonia solution (2.5 mL, 2 M in isopropanol, 4.8 mmol) was added. The resulting white suspension was stirred for one hour before it was diluted with dichloromethane (50 mL) and washed with 20% NaHSO4 solution, 1 M NaOH, water, and brine. The solution was then dried (Na2SO4), filtered, and evaporated. The residue was purified over silica gel using 1-10% methanol in dichloromethane to give the title product as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.08 (s, 3H) 1.24 (s, 3H) 1.32-1.51 (m, 2H) 1.50-2.14 (m, 8H) 2.17-2.59 (m, 3H) 2.57-2.75 (m, 1H) 3.27-3.45 (m, 1H) 3.64-3.83 (m, J=9.66, 7.63 Hz, 1H) 3.92 (s, 1H) 4.31-4.45 (m, 1H) 4.46-4.61 (m, 1H) 5.38 (s, 1H) 5.54 (s, 1H) 6.83 (dd, J=8.82, 0.68 Hz, 1H) 7.81 (dd, J=8.82, 2.37 Hz, 1H) 8.48 (dd, J=2.37, 0.68 Hz, 1H).). MS (ESI+) m/z 411.2 (M+H)+.