Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][C:30]=1[C:39]#[N:40]>O1CCCC1>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:36])=[O:37])=[CH:31][C:30]=1[C:39]#[N:40]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Br)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a nitrogen purged solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 448 mg, 1.78 mmol) in tetrahydrofuran (7.5 mL) at −78° C. was added lithium hexamethyl disilazane (1.0 M in tetrahydrofuran, 1.96 mL). The reaction was stirred for 15 minutes before a solution of 4-bromo-3-cyanobenzenesulfonyl chloride (Preparation 27, 500 mg, 1.78 mmol) in tetrahydrofuran (7.5 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (3×10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The material was purified by silica gel column chromatography (ISCO™ companion, 40 g column, 0-30% ethyl acetate in heptane gradient elution). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless solid (883 mg, 73%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:4][CH:3]=1
Reactant: Clc1ccc(NCc2ccccn2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccccn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 3.3 g. portion of 2-(4-chlorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.7 g. of potassium carbonate and 1.5 ml. of methanesulfonyl chloride were added. The mixture was stirred overnight at ambient temperature, and then was stirred for 1 day under gentle reflux. Another 0.5 ml. of methanesulfonyl chloride was added, and the reflux was continued for several hours. Then the mixture was cooled and filtered, and the filtrate was chromatographed on a silica gel column, eluting with chloroform. The product-containing fractions were combined and evaporated to obtain 1 g. of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].O>C(OCC)C.C1CCCCC1>[C:5]1([C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:4])[CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCCCC1
Product: CCC(O)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a well-stirred solution of propiophenone (20.1 g, 0.15 mol) in dry diethyl ether (125 ml) kept under nitrogen at room temperature was added a solution of phenylmagnesium bromide (55 ml, 3 M in diethyl ether) in dry diethyl ether (25 ml). The reaction mixture was stirred for 1 h and a mixture of a saturated ammonium chloride solution (100 ml) and water (50 ml) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic phases was washed with a 0.5 N hydrochloric acid solution and dried over sodium sulphate. The solvent was evaporated in vacuo to give a solid residue which was trituated with cyclohexane (100 ml). The solid was collected by filtration and dried to give 26.4 g (83%) of 1,1-diphenyl-1-propanol.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].S(=O)(=O)(O)O>>[OH:1][CH:2]([CH3:7])[CH2:3][C:4]([O:6][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])=[O:5]
Reactant: CC(O)CC(=O)O
Reactant: CCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCOC(=O)CC(C)O
Temperature: 120 °C
Yield: 117.65 %

Procedure:
A 500 mL one neck round bottom flask equipped with a Dean Stark trap, condenser, and a nitrogen inlet/outlet was charged with 72.0 g (69 mmole) of 3-hydroxybutyric acid, 268.5 g (1.45 mole) of dodecyl alcohol, and 0.36 g of sulfuric acid. The mixture was heated to 120° C. for 48 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 100 mL saturated NaHCO3 solution. The organic layer was collected and dried over MgSO4 and concentrated. Excess dodecanol was removed by high vacuum distillation to yield 117.65% (60% yield) of clear oil (91% pure by GC).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[NH:5][C:4]1=[O:13])[CH3:2].[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[N:5]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:4]1=[O:13])[CH3:2]
Reactant: CCn1c(=O)[nH]c2c(C)cccc21
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(C)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.500 g of 1-ethyl-4-methyl-1,3-dihydrobenzimidazol-2-one in 40 ml of anhydrous N,N-dimethylformamide is admixed at 0° C. with 0.874 g of sodium hydride dispersion (60%). The reaction mixture is stirred at 0° C. over a further 30 minutes and 4.06 ml of 2-(trimethylsilanyl)ethoxymethyl chloride are added dropwise. The reaction mixture is stirred at 20° C. over 14 hours, poured onto 150 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (2×200 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:3 EtOAc-heptane); Rt=5.62.
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.OS(O)(=O)=O>O>[CH2:13]([O:11][C:10]([C:2]1[N:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[CH:4][CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cccc(C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.8 %

Procedure:
A mixture of 2,6-pyridinedicarboxylic acid (10 g, 0.06 mol) and benzyl alcohol (68 mL, 0.66 mol) were taken in water (25 mL), and concentrated H2SO4 (3.5 mL) was added. The reaction mixture was refluxed for 10 h and further allowed to stir at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the organic product was extracted with CHCl3. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CH2Cl2) to afford 6-((benzyloxy)carbonyl)picolinic acid (4.6 g, yield 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.54 (br s, 1H), 8.29-8.24 (m, 2H), 8.20-8.16 (m, 1H), 7.52-7.50 (m, 2H), 7.44-7.36 (m, 3H), 5.43 (s, 2H). MS (ESI) m/z: Calculated for C14H11NO4: 257.07. found: 258.2 (M+H)+.
Reaction SMILES: C[Si](I)(C)C.O[C@:7]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([C:26](=[O:30])[CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:31])[CH:21]=[CH:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:8](=[O:11])[CH2:9][OH:10].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[OH:10][CH2:9][C:8](=[O:11])[C@@H:7]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([C:26](=[O:30])[CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:31])[CH:21]=[CH:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: C[Si](C)(C)I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Reaction time: 0.5 h

Procedure:
Trimethylsilyl iodide (5.12 ml, 7.20 g, 36.0 mmol) is added dropwise to a solution of 17α,21-dihydroxypregna-1,4-diene-3,11,20-trione (3.23 g) in freshly distilled acetonitrile. After 30 min, sodium sulfite solution (5%, 150 ml) is added to the reaction mixture. The mixture is partitioned with chloroform (400 ml). The phases are separated, and the aqueous phases is extracted twice with chloroform. The organic layers are combined, washed with sodium bicarbonate (5%), saline, dried over sodium sulfate and concentrated. The concentrate is flash chromatographed eluting with ethyl acetate/hexane (2.3/1). The appropriate fractions are pooled to give 21-hydroxypregna-1,4-diene-3,11,20-trione as an oil and 17-epi-21-hydroxypregna-1,4-diene-3,11,20-trione as a solid, mp 203-206°.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)[CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN[C@H]1CC[C@H](O)CC1
Product: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(Br)cc1

Procedure:
In analogy to example 11.9. trans-4-Methylamino-cyclohexanol and 4-bromobenzenesulfonylchloride were reacted to yield trans-4-Bromo-N-(4-hydroxy-cyclohexyl)-N-methyl-benzenesulfonamide as off-white solid, MS: 348 (MH+, 1Br).
Reaction SMILES: [CH:1]1([C:5]2[C:6](=[O:21])[NH:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][N:42]1[C:46]([CH2:47]O)=[N:45][CH:44]=[N:43]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([C:5]2[C:6]([O:21][CH2:47][C:46]3[N:42]([CH3:41])[N:43]=[CH:44][N:45]=3)=[N:7][C:8]3[N:9]([N:11]=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1ncnc1CO
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1C1CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncnc1COc1nc2c(-c3ccccc3F)nnn2cc1C1CCC1
Yield: 68.1 %

Procedure:
6-Cyclobutyl-3-(2-fluorophenyl)-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (33 mg, 0.12 mmol), triphenylphosphine (76 mg, 0.29 mmol) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (37 mg, 0.29 mmol) were dissolved in dry tetrahydrofuran (1.5 ml) with stirring. Diethyl azodicarboxylate (46μl, 0.29 mmol) was added and the reaction stirred at room temperature for 16 hours before purification by preparative thin layer chromatography to afford 6-cyclobutyl-3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[1,5-α]pyrimidine (31 mg, 70%) as a white crystalline solid, m.p. 181-184° C.; δH (400 MHz, d6-DMSO) 1.77-1.85 (1H, m, CH(CH2)3), 1.96-2.06 (1H, m, CH(CH2)3), 2.19-2.30 (4H, m, CH(CH2)3), 308 (1H, quintet, J=8.6 Hz, CH(CH2)3), 3.88 (3H, s, NMe, 5.65 (2H, s, OCH2), 7.34-7.38 (2H, m, ArH), 7.41-7.48 (1H, m, ArH), 7.94 (1H, s, triazole CH), 7.97 (1H, t, J=7.2 Hz, ArH), 9.25 (1H, s, pyrimidine CH); m/z (ES+) 380 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:43][CH2:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([Br:53])=[CH:49][CH:48]=1)=[O:46].CCN(C(C)C)C(C)C>[Cl-].[Na+].O.O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][C@H:9]1[C:15](=[O:17])[NH:43][CH2:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([Br:53])=[CH:49][CH:48]=1)=[O:46])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
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
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL pear-shaped flask, (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (1 g, 3.98 mmol, Eq: 1.00) and HATU (1.51 g, 3.98 mmol, Eq: 1.00) were combined with DMF (15 ml) to give a colorless solution and stirred at 23° C. for 10 min. 2-Amino-1-(4-bromophenyl)ethanone HCl (995 mg, 3.98 mmol) was added followed by drop wise addition of DIPEA (1.54 g, 2.09 ml, 11.9 mmol). The suspension became a orange solution once the addition of the amine was completed. It was stirred at room temperature for 1 hr and diluted with brine (100 ml) and H2O (50 ml). The precipitate was filtered, washed with H2O and dried to afford (S)-tert-butyl2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate as a light yellow solid. (1.8 g, >96%): ESI-LRMS m/e calcd for C18H21BrF2N2O4 [M+] 447. found 448 [M+H+].
Reaction SMILES: N1(N[C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.[NH2:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[C:47]2[OH:52]>>[OH:52][C:47]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:48]=1[CH:49]=[CH:50][CH:51]=[C:42]2[NH:41][C:8]([C:10]1[CH:40]=[CH:39][C:13]2[N:14]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=[N:20]4)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: Nc1cccc2c(O)cccc12
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(Nc1cccc2c(O)cccc12)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 25 %

Procedure:
The general procedure described for Compound 574 was used with 5-amino-naphthalen-1-ol (15.9 mg), producing 7 mg of the title compound (25% yield). MS: 590.24 (M+H+) HPLC Procedure A, retention time=15.26 min.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.[CH2:12]([O:14][C:15](=[O:50])[CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:32]([CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:31]=2)[CH:23]=1)[CH2:18][C:19](O)=[O:20])[CH3:13].C(N(CC)CC)C.O>CN(C=O)C>[NH2:3][C:19](=[O:20])[CH2:18][CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:32]([CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:31]=2)[CH:23]=1)[CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:50]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)CC(CC(=O)O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(N)=O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere, WSC (53.6 mg) was added to a suspension of 5-ethoxy-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-5-oxopentanoic acid (100 mg), 1-hydroxybenzotriazole monohydrate-ammonia complex (42.5 mg) and triethylamine (78 μL) in DMF (1 mL), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (47.1 mg) as a colorless oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([NH2:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[ClH:39]>CO>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([NH2:28])=[O:27])[CH:23]([CH3:24])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10].[ClH:39]
Reactant: CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C)C(N)=O
Agent: Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(C)C)C(N)=O

Procedure:
6 g of Z-Glu(OBut)-Val-Val-NH2 are suspended in 200 ml of methanol. After adding Pd-on-BaSO4 and 2 N methanolic hydrochloric acid, the mixture is subjected to catalytic hydrogenation at pH 4.5. When the reaction is complete, the catalyst is filtered off and the filtrate is concentrated. The residue crystallizes on being triturated with ether. Yield 4.8 g, melting point 211°-219°, [α]D23 =-18.7° (c=1, in methanol).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[N:7]2.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1.C(OCC)(=O)C.O>ClCCl>[Cl:12][C:11]1[C:2]([NH:1][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])=[C:3]2[C:8](=[CH:9][C:10]=1[Cl:13])[N:7]=[C:6]([O:14][CH3:15])[C:5]([O:16][CH3:17])=[N:4]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1nc2cc(Cl)c(Cl)c(NS(=O)(=O)c3ccccc3)c2nc1OC
Yield: 30.2 %

Procedure:
A mixture of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 1) (548 mg, 2.0 mmol), benzenesulphonyl chloride (1.28 ml, 10 mmol) and pyridine (0.8 ml, 10 mmol) in dry dichloromethane (30 ml) was stirred at reflux for 100 hours. The mixture was poured into ethyl acetate/water and a white solid was filtered off, washed with water, ethyl acetate, then ether, and dried at 80° C. in vacuo to give the title compound (250 mg, 30%), m.p. 292°-293° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3C(OC(C)(C)C)=O)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCCCN2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
1-(1-tert-Butoxycarbonylpiperidine-2-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (5) (1.41 g; 2.39 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 1.5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.10 g) as a white solid. ESMS: MH+ 490.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.[Cl:25][C:26]1[N:31]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][N:27]=1.N#N>CN(C=O)C.[Cu]I.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:25][C:26]1[N:31]=[C:30]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=3)[N:14]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1ccnc(Cl)n1)nn2C1CCCCO1
Temperature: 90 °C
Yield: 52.1 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 14 (0.2 g, 0.45 mmol) and 2-Chloro-4-tributylstannanyl-pyrimidine 20a (0.27 g, 0.68 mmol) in DMF was bubbled N2 for 15 min and added CuI (0.052 g, 0.54 mmol) and Pd(PPh3)4 (0.1 g, 0.025 mmol). The reaction mixture was heated at 90° C. for 2 h and cooled to RT. The reaction mixture was quenched with water and precipitate was formed. The resulting precipitate was collected by filtration, washed with water, and dried to yield crude product. Purification by silica gel column chromatography, eluting with 5-10% EtOAc and hexanes to obtain the title compound (0.1 g, 38%). MS (ESI, pos. ion) m/z: 427.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[N:12]([CH2:15][C@H:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:10]2)[CH:5]=[N:6][CH:7]=1.[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2[N:12]([CH2:15][C@H:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:13](=[O:14])[N:9]([CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[C:35]=4[Cl:36])[CH:3]=3)[N:10]=2)=[CH:23][CH:24]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cncc(-c3cccc(Cl)c3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 86, 34 mg (0.07 mmol) of the compound from Example 29A and 20 mg (0.10 mmol) of 2,3-dichlorophenylboronic acid were reacted with one another. This gave 26 mg (69% of theory) of the target compound.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]C)[CH:6]=1)C.ClCCl>B(Br)(Br)Br>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:12]1[CH2:13][CH2:14][CH2:15][C:11]=1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)c1cccc(C2=C(c3ccccc3OC)CCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cccc(C2=C(c3ccccc3O)CCC2)c1
Reaction time: 18 h

Procedure:
3-[2-(2-Methoxy-phenyl)-cyclopent-1-enyl]-benzoic acid ethyl ester (610 mg, 1.89 mmol) was dissolved in 1M boron tribromide in dichloromethane solution (18.9 ml, 18.9 mmol) and left at room temperature for 18 hours. The resulting solution was poured onto ice and extracted with dichloromethane. The organic extract was dried (MgSO4), evaporated to dryness and purified by chromatography using biotage with iso-hexane containing a gradient of ethyl acetate (20–40%) to yield the title compound as a light brown solid. (186 mg, 35%).