Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:18][CH2:17][C:13]2([CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[C:27]2=[O:35])=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]2([CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:28]3[CH2:29][CH2:30][C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)[C:27]3=[O:35])[CH2:14]2)[CH2:17][CH2:18]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2CCC3(CC2)CNC3)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
7-Benzyl-2,7-diazaspiro[3.5]nonane dihydrochloride from Example 7F (0.237 g, 0.749 mmol), the product from Example 14D (0.248 g, 0.749 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.199 ml, 1.123 mmol) and N-methylmorpholine (0.247 ml, 2.247 mmol) were stirred together in dichloromethane (2 mL). After stirring overnight, the reaction mixture was diluted with dichloromethane (20 mL) and washed with 1 N HCl (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv 40 gm silica gel column and the product was eluted with a gradient of 0.4% methanol/dichloromethane containing 0.2 N NH3 to 6% methanol/dichloromethane containing 0.2 N NH3 to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.15 (m, 9H), 6.99 (t, J=8.2, 4H), 3.97 (s, 2H), 3.72 (d, J=20.0, 4H), 3.53 (t, J=6.5, 2H), 3.46 (s, 2H), 2.75 (t, J=6.4, 2H), 2.32 (s, 4H), 1.73 (s, 4H); MS (ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:19])[CH2:5]1)[CH3:3].CC(C)([O-])C.[K+].[Br:26][C:27]1[N:32]=[C:31](Cl)[C:30]2[N:34]([CH3:37])[CH:35]=[N:36][C:29]=2[CH:28]=1>C1COCC1>[Br:26][C:27]1[N:32]=[C:31]([O:1][C@@H:2]([C@H:4]2[CH2:8][N:7]([C@@H:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[CH3:10])[C:6](=[O:19])[CH2:5]2)[CH3:3])[C:30]2[N:34]([CH3:37])[CH:35]=[N:36][C:29]=2[CH:28]=1
Reactant: Cn1cnc2cc(Br)nc(Cl)c21
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Br)cc4ncn(C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (135 mg, 0.51 mmol) in dry THF (6 mL) was added potassium tert-butoxide (72 mg, 0.64 mmol) and the reaction mixture was stirred at rt for 5 min. Then 6-bromo-4-chloro-3-methyl-3H-imidazo[4,5-c]pyridine 2.60 (105 mg, 0.43 mmol) was added and reaction mixture was heated to 60° C. After 12 h, cooled to rt, quenched the reaction mixture with water (0.5 mL) and concentrated. The residue was purified by flash column chromatography (SiO2, 0% MeOH/EtOAc to 20% EtOAc/hexanes) to give ((R)-4-((R)-1-(6-bromo-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.61.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[CH:7]([NH:20][C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2].Cl.[CH3:32]O>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[C@H:7]([NH:20][C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:32])=[O:28])=[CH:23][CH:22]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2C(Nc2ccc(C(=O)O)cn2)CC1C
Agent: Cl
Product: COC(=O)c1ccc(N[C@@H]2C[C@H](C)N(C(C)=O)c3ccc(-n4cnc(C)c4)cc32)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of 6-{[1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarboxylic acid (for a preparation see example 143) (40 mg, 0.099 mmol) in dry methanol (2 mL) was treated at room temperature with HCl (4M in 1,4-dioxane, 200 μl, 0.800 mmol) and the resulting mixture was stirred at this temperature for one hour. Another portion of HCl (4M in 1,4-dioxane, 200 μl, 0.800 mmol) was added and the mixture was refluxed for 1 hour then cooled to room temperature and concentrated in vacuo. The residue was purified using MDAP (modifier: ammonium formate) to give methyl 6-{[(cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarboxylate (12 mg, 0.029 mmol, 29%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[C:5]([CH3:18])([CH3:17])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21]>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[C:5]([CH3:17])([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: COC/C=C/c1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Solvent: O=C(O)C(F)(F)F
Product: COC/C=C/c1ccc2c(c1)C(C)(C)C(=O)C(C(=O)NCC(=O)O)=C2O
Yield: 23.1 %

Procedure:
1,1-Dimethylethyl N-((4-hydroxy-1,1-dimethyl-7-((1E)-3-(methyloxy)-1-propen-1-yl)-2-oxo-naphthalen-3-yl)carbonyl)glycinate (75 mg, 181 μmol) was dissolved in TFA (2 mL) at ambient temperature for 30 minutes before it was concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (15 mg) as a yellow solid. MS m/e=360 (M+H)+. Calculated for C19H21NO6 359.14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]1[CH:20]([CH3:22])[S:21][C:7]1=[C:6]([C:23]([O:25]CC)=[O:24])[C:5]2=[O:28].[OH-].[K+].C(O)(C)(C)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:19])[C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]1[CH:20]([CH3:22])[S:21][C:7]1=[C:6]([C:23]([OH:25])=[O:24])[C:5]2=[O:28]
Reactant: CCOC(=O)c1c2n(c3c(F)c(N4CCN(C)CC4)c(F)cc3c1=O)C(C)S2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCN(C)CC4)c(F)c3n21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To 0.5 g of ethyl 6,8-difluoro-1-methyl-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate was added 10 ml of 5% solution of potassium hydroxide in 3:1 mixture of tert-butanol and water and stirred at 60° C. for 30 minutes. tert-Butanol was evaporated therefrom in vacuo, the residue was neutralized with acetic acid, extracted with a 3:1 mixture of chloroform and methanol, the extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, the solvent was evaporated therefrom, and the residue was subjected to a silica gel column chromatography (30 g of Wakogel C-300 being used) and eluted with chloroform-methanol (10:1) to give 0.18 g of desired product, m.p. 238° C. (decompn.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:15][S:16]([C:19]1[CH:20]=[C:21]([C:31](O)=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([C:31]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)=[O:32])[CH:20]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from ′1-(4-metoxyphenyl)-piperazine [38212-30-5] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 451.1 MH+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[N:26][CH:25]=1>O1CCCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[O:32])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)N(C)OC)cn1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cn1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
1,4-Dibromobenzene (6.5 g, 27 mmol) was dissolved in tetrahydrofuran (120 mL), and a solution of n-butyllithium in hexane (2.6 M, 10 mL, 27 mmol) was added at −78° C., followed by stirring at the same temperature for 30 minutes. A solution of N,6-dimethoxy-N-methylnicotinamide (2.7 g, 14 mmol) in tetrahydrofuran (20 mL) was added to the reaction solution, followed by stirring at −78° C. for further 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=10/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.8 g, 9.4 mmol) as a white solid (yield 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH:26][S:27]([C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:29])=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][S:27]([C:30]1[NH:31][C:32]2[C:37]([C:38]=1[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:12]1[CH:21]=[CH:22][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:29])=[O:28])([CH3:25])[CH3:24]
Reactant: OC(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 84.3 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4-benzyloxybenzhydrol (1.31 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.92 g (yield: 84%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16].CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:21]([CH2:20][CH2:19][NH:18][C:15](=[O:17])[CH3:16])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: CC(=O)NCCN
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: CC(=O)NCCn1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (5.00 g, 0.0235 mol), N-Acetylethylenediamine (7.21 g, 0.0706 mol) and methanol (150 mL, 3.7 mol). The mixture was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and was stirred overnight. LC-MS showed that the starting material was completely consumed. Volatiles were removed and the resulting oil was purified in a methanol:methylene chloride (0-10%) gradient. Fractions containing the desired product, as determined by TLC and LC-MS, were combined and concentrated to produce a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].O.O.[Sn](Cl)Cl.C(OCC(C)C)(=O)C.O[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([O:18][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21]
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: OCCN1CCOCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)OCC(C)C
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A mixture of mycophenolic acid (192 g, 0.6 mol) and 4-(2-hydroxyethyl)-morpholine (440 ml, 6 molar equivalents) was stirred at 150-155° C. for 4 hours in the presence of tin(II) chloride dihydrate (20.4 g, 0.15 molar equivalents) under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was allowed to cool to room temperature. The obtained dark liquid was poured into isobutyl acetate (4.0 l). The solution was extracted with 2% of aqueous sodium bicarbonate solution (1.2 l, then 2×0.4 l). After the first addition of sodium bicarbonate solution the formed two-phase system was treated with charcoal (40 g) and filtrated (an emulsion was filtered off). The solution was extracted with water (1 l). -After phase separation the organic phase was washed with water (1 l) and evaporated to dryness at 40-50° C. under vacuum. To the solid material acetone (400 ml) and isopropanol (3.8 l) were added and the mixture was warmed to 40-45° C. (the material was dissolved). The solution was cooled to −5° C. during 6 hours and it was stirred at this temperature for 10-12 hours. After filtration, the crystals were washed with 2:19 acetone/isopropanol mixture (420 ml). The crude compound was dried in vacuum at 60° C. The yield was 169-195 g (65-75%). HPLC impurity profile: MPA=0.1%. Assay: 99.85%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])[C@H:4]([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[CH2:3]1.[Cl:33][CH2:34][C:35](Cl)=[O:36].CCN(C(C)C)C(C)C>CC#N>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:10][C:8]([C@@H:5]2[CH2:6][CH2:7][C@@H:2]([NH:1][C:35](=[O:36])[CH2:34][Cl:33])[CH2:3][C@H:4]2[C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)=[O:9])=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@H]1CC[C@@H](C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)[C@H](c2ccc(Br)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CCl)N[C@@H]1CC[C@@H](C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)[C@H](c2ccc(Br)cc2)C1
Reaction time: 1.5 h

Procedure:
To the product from Example 54 (120 mg, 0.24 mmol) in MeCN (4 mL) was added chloroacetyl chloride (24 mg, 0.3 mmol). The reaction was aged for 90 min at rt and DIEA (45 μL, 0.24 mmol) was added. After 15 min, another portion of chloroacetyl chloride (12 mg, 0.15 mmol) was added, along with DIEA (45 μL, 0.24 mmol). The reaction was concentrated, diluted with CHCl3 and washed with Na2CO3/brine 1:1. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound. HPLC/MS: 575.1/577.0 (M+1); Rt=3.36 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)C>ClCCl>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:14]
Reactant: O=C(Cl)CCCCCCCBr
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CCCCCCCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 74 h

Procedure:
To a stirring suspension of aluminium chloride (33.6 g) in dry dichloromethane (474 ml) was added 8-bromo-n-octanoyl chloride (67.8 g) over 10 min. Chlorobenzene (123 ml) was then added over 10 min and the mixture allowed to stir at 25° C. for 74 h and stood for 64 h. The mixture was poured into ice/water (540 ml) and diethyl ether (1.3 L). The organic layer was removed and was washed with water (540 ml), saturated sodium hydrogen carbonate (540 ml), water (400 ml) and brine (400 ml) and dried over magnesium sulfate. Removal of the organic layer under reduced pressure and chromatography of the residue on silica gel using 5% ethyl acetate in hexane gave 8-bromo-1-(4-chlorophenyl)octan-1-one (35.5 g). 1H-NMR (CDCl3) δ 1.2-1.6 (6H, m), 1.6-1.95 (4H, m), 2.95 (2H, t), 3,42 (2H, t), 7.43 (2H, m) and 7.90 (2H, m).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16](=[O:31])[N:17]2[C@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:23])[CH2:20][CH:19]=[N:18]2)[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:32].O1CCOCC1>>[ClH:32].[CH:1]1([CH2:6][C@@H:7]([C:16](=[O:31])[N:17]2[C@H:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:23])[CH2:20][CH:19]=[N:18]2)[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a 500 ml round bottom flask was added 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{(5S)-5-[(2-pyridinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (29.1 g, 58.4 mmol) and 4 M HCl in 1,4-dioxane (240 mL, 960 mmol). The mixture was stirred at room temperature and monitored by LCMS. After 90 min, no starting material remained. The mixture was concentrated to dryness and co-evaporated with dioxane (2×15 mL) to afford the crude (3R)-3-(cyclopentylmethyl)-4-oxo-4-{(5S)-5-[(2-pyridinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoic acid, hydrochloride (34.0 g, 58.5 mmol, 100% yield) as a light brown foamy solid that was used directly for the next step. LCMS: [M+H]+: 373.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(COC)OC.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: Oc1ccc(Br)cc1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Oc1ccc(-c2cccc(F)c2F)cc1
Yield: 74.9 %

Procedure:
First, 34.6 g of 4-bromphenol, 37.9 g of 2,3-difluorophenylboronic acid, 380 ml of dimethoxyethane, 380 ml of water, 97.8 g of cesium carbonate, and 7 g of tetrakis(triphenylphosphine)palladium were placed in a 1 L flask. The mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=9/1) and recrvstallized from hexane to obtain 30.9 g of 2,3-difluoro-4'-hydroxybiphenyl (Y: 75%). The compound thus obtained had a purity of 99.8% by GC and an m.p. of 132° C. to 134.4° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14](=O)(O)[O-].[Na+].IC>CN(C=O)C.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
To a solution of 0.69 g of 4-(4-hydroxyphenyl)butyric acid in 10 mL of DMF was added 0.956 g of sodium bicarbonate followed by 0.36 mL of iodomethane and the resulting mixture was stirred at room temperature for 5 h. The reaction was then diluted with water, extracted with ether, dried over MgSO4, filtered and concentrated in vacuo to provide 0.553 g of methyl 4-(4-hydroxyphenyl)butyrate.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](O)[CH2:23][CH2:24][CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH2:1]([O:8][N:9]([CH2:12][C:13]1[CH:14]=[C:15]([Cl:21])[C:16]([O:20][CH2:22][CH2:23][CH2:24][CH3:25])=[C:17]([Cl:19])[CH:18]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN(Cc1cc(Cl)c(O)c(Cl)c1)OCc1ccccc1
Reactant: CCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOc1c(Cl)cc(CN(C=O)OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-benzyloxy-N-(3,5-dichloro-4-hydroxybenzyl)formamide in methylene chloride (5 ml) was added n-butanol (110 ul, 1.2 mmol) and Polymer-bound triphenyl phosphine resin (500 mg, 1,2 mmol/g, 0.6 mmol). The reaction mixture was stirred for 0.5 h at room temperature then cooled to 0° C. A solution of DEAD (0.6 mmol, 95 ul) in methylene chloride (1 ml) was added and the reaction mixture stirred at room temperature for 16 h. The resin was filtered and washed with methylene chloride three times and the filtrate was evaporated to afford the crude N-benzyloxy-N-(4-butoxy-3,5-dichlorobenzyl)formamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.38 (m, 3H), 7.28 (m, 2H), 7.19 (s, 2H), 4.78 (s, 2H), 4.57 (s, 2H), 4.00 (t, j=6.4 Hz, 2H), 1.82 (quint, j=7.6 Hz, 2H), 1.55(sext, j=7.6 Hz, 2H), 0.98 (t, j=7.6 Hz, 3H). M+1=382
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=C)[C:6]=2[CH:16]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[O:18])[C:6]=2[CH:16]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
6-Chloro-4-(2-propen-1-yl)-1,2,4-benzotriazin-3(4H)-one 1-oxide (104 mg, 0.438 mmol) was dissolved in 1,4-dioxane (4 ml) and water (2 ml). Sodium periodate (234 mg, 1.096 mmol) was added, followed by osmium tetroxide (0.09 ml of 4% aqueous solution). The mixture stirred at rt for 6 h, and then extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give (6-Chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)acetaldehyde as an impure yellow oil (89 mg, 85%).