Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][C:21]=1[C:10]([CH:9]([CH3:13])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:12]
Reactant: COc1cccc(OC)c1
Reactant: COc1ccc(C(C)C(=O)O)cc1
Product: COc1ccc(C(C)C(=O)c2ccc(OC)cc2OC)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
2-(p-Methoxyphenyl)propionic acid (0.39 g, 4 mmol) and 1,3-dimethoxybenzene (0.5 g, 0.5 ml, 4 mmol) were mixed in polyphosphoric acid (PPA) (10 g) and the reaction mixture was mechanically stirred at 75° C. for 5 h. The reaction mixture was then allowed to cool to room temperature and mechanically stirred for a further 12 h. The reaction was then quenched with ice water and the product extracted with CHCl3(3×25 ml). The CHCl3 layer was dried (Na2SO4) and the solvent removed under reduced pressure. The residual crude product was purified by silica gel column chromatography (eluent 7:2 CH2Cl2:EtOAc) to give the pure 2,4,4′-trimethoxy-α-methyldesoxybenzoin (0.68 g, 58%)
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:24](=[O:26])[CH3:25])[CH:15]=[C:16]([NH:20][CH:21]([CH3:23])[CH3:22])[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:27]N1C(=O)CCC1=O.C(OCC)(=O)C>O1CCCC1>[Br:27][CH2:25][C:24]([C:14]1[CH:15]=[C:16]([NH:20][CH:21]([CH3:22])[CH3:23])[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:13]=1)=[O:26]
Reactant: COc1c(NC(C)C)cc(C(C)=O)cc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(NC(C)C)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Triethylamine (0.63 ml, 4.5 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.6 g, 2.3 mmol) were added to a solution of the 1-[3-(tert-butyl)-5-(isopropylamino)-4-methoxyphenyl]-1-ethanone (0.4 g, 1.5 mmol) in tetrahydrofuran (50 ml) while cooling on ice and the mixture was stirred at the same temperature for 30 minutes, after which N-bromosuccinimide (0.53 g, 3.0 mmol) was added and stirring was continued for 30 minutes. Ethyl acetate was added to the reaction mixture, the mixture was washed with brine and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (410 mg) as a light yellow oil.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:33][C:34](=[O:37])[CH2:35][C:27]1[C:21]2[NH:20][C:19]([S:18][CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]([O:9][CH3:8])=[O:28])=[N:23][C:22]=2[CH:24]=[CH:25][CH:26]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccccc1CSc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1CSc1nc2cccc(CC(=O)OC(C)(C)C)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
Sodium hydride (400 mg, 10.0 mmol) and dimethylformamide (30 ml) were added to a previously dried reaction vessel. To the mixture were added 2-(benzimidazole-2-ylthiomethyl)benzoic acid methyl ester (1500 mg, 5.0 mmol) and bromoacetate t-butyl ester (1463 mg, 7.5 mmol), and the mixture was stirred at 80° C. for 2 hours. Water was added thereto, followed by extraction with ether. After the ether phase was dried with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 2-(2-((2-(methoxycarbonyl)phenyl)methylthio)benzimidazolyl)acetic acid t-butyl ester (1298 mg, yield 63%).
Reaction SMILES: [CH3:1][CH:2](OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:17]=1.CCO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CO>[CH2:1]([O:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:17]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(O)c2cc([N+](=O)[O-])cnc21
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(C(=O)OC(C)(C)C)c2ncc([N+](=O)[O-])cc12

Procedure:
A solution of DIAD in THF (10 mL) was added slowly via a syringe pump under N2 at room temperature for 1 hour to a solution of tert-butyl 3-hydroxy-5-nitro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.35 g, 1.2 mmol), EtOH (0.069 g, 1.5 mmol), and PPh3 (0.49 g, 1.9 mmol). The reaction mixture was poured onto water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give the crude material. The crude material was treated with MeOH to give tert-butyl 3-ethoxy-5-nitro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate as a precipitate. The filtrate was concentrated and treated with a solution (10:1 hexane:EtOAc) to precipitate triphenylphosphineoxide. Then, the filtrate was concentrated and flash chromatographed (SiO2, 10:1=hexane:EtOAc) to afford tert-butyl 3-ethoxy-5-nitro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (total 0.237 g, 62% yield). LRMS (ACPI pos) m/e 209.0 ((M-Boc)+1).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].COCCOC[C:13]1[C:26]2[NH:27][N:28]=[C:24]3[C:25]=2[C:16]([C:17](=[O:30])[C:18]2[C:23]3=[CH:22][CH:21]=[CH:20][C:19]=2[OH:29])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][O:29][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:30])[C:16]1[C:25]3[C:24]2=[N:28][NH:27][C:26]=3[CH:13]=[CH:14][CH:15]=1
Reactant: COCCOCc1ccc2c3c(n[nH]c13)-c1cccc(O)c1C2=O
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCOc1cccc2c1C(=O)c1cccc3[nH]nc-2c13
Temperature: 80 °C

Procedure:
Isopentyl bromide is added to a mixture of 3-(2-methoxyethoxymethyl)-7-hydroxyanthra[1,9cd]pyrazol-6(2H)-one and potassium carbonate in dimethylformamide at room temperature. After stirring the mixture for sixteen hours, water is added, and the mixture was extracted with ethyl acetate (×2). The combined organic layer is washed with aqueous sodium bicarbonate, water, 1 N hydrochloric acid, and brine, dried and evaporated. The residue is taken in 6N hydrochloric acid and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(OCC)(=O)C>CCCCCC>[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH:14][S:35]([CH3:34])(=[O:37])=[O:36])=[N:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
To a pyridine (2 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (106 mg, 0.247 mmol) obtained in Example 196 was added methanesulfonyl chloride (29 μl, 0.370 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed sequentially with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (58 mg, 0.114 mmol, 46%) as a white solid. The resulting white solid was washed with hexane-ether and collected by filtration to give the title compound (28 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH2:32]([O:34][C:35]([C:37]1[N:38]([CH3:48])[C:39]2[C:44]([C:45]=1[Cl:46])=[CH:43][C:42]([NH2:47])=[CH:41][CH:40]=2)=[O:36])[CH3:33]>C(Cl)Cl.CN(C=O)C>[CH2:32]([O:34][C:35]([C:37]1[N:38]([CH3:48])[C:39]2[C:44]([C:45]=1[Cl:46])=[CH:43][C:42]([NH:47][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17])=[CH:41][CH:40]=2)=[O:36])[CH3:33]
Reactant: CCOC(=O)c1c(Cl)c2cc(N)ccc2n1C
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4′-Trifluoromethyl-2-biphenylcarboxylic acid was converted to the corresponding acid chloride by treatment with oxalyl chloride in methylene chloride in the presence of catalytic amount of DMF. To a solution of the acid chloride (10.8 g, 38 mmol) and pyridine (3.27 mL, 40 mmol) in methylene chloride (200 mL) was added the product of step (c) (10.1 g, 40 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was diluted to 600 mL with CH2Cl2, washed with 0.1 N HCl solution (2×500 mL) and with brine (500 mL), and then dried (MgSO4). The solvent was evaporated in vacuo to give the crude product which was purified by recrystallization from EtOAc/isooctane to afford 13.8 g of the title compound.
Reaction SMILES: Cl.CN([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[N:7]=1)C.[OH-].[Na+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>O.C1(C)C(C)=CC=CC=1>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[N:7]=1
Reactant: CN(C)Cc1ccc(O)c(Cl)n1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Oc1ccc(Cc2ncc[nH]2)nc1Cl

Procedure:
This hydrochloride was dissolved in water and the solution was neutralised with dilute sodium hydroxide solution and evaporated. The residue was extracted several times with hot toluene and the combined extracts were filtered and evaporated to give the corresponding free base. The base (3.70 g) and imidazole (1.5 g) were heated under reflux in xylene (50 ml) for 3 hours. The mixture was then evaporated and the resulting dark residue was extracted several times with hot water. The aqueous solution was evaporated and the residue was crystallised first from ethyl acetate and then from water to give 2-(1-imidazolylmethyl)-5-hydroxy-6-chloropyridine (0.88 g), m.p. 157°-158°.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:25]
Reactant: CCN
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Product: CCNC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Yield: 78 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using ethylamine (2 M solution in THF) instead of isopropylamine, to the title compound (45 mg, 78%) which was obtained as a white solid. MS: m/e=340.0 [M+H]′.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[CH:18]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CCO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2/[CH:18]=[N:21]/[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1N2CC(CCC2/C=N/O)N1OCc1ccccc1
Yield: 42.3 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde (510 mg, 1.96 mmol), hydroxylamine hydrochloride (158 mg, 2.27 mmol) and pyridine (621 mg, 7.85 mmol) in EtOH (15 mL) was stirred at rt for 2 hrs. The reaction mixture was then concentrated and the residue was diluted with DCM (25 mL), washed with water (3×), saturated sodium chloride, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 3:1 to 3:2 petroleum ether/EtOAc) to afford (E)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde oxime (228 mg, 42%) as a white solid. ESI-MS (EI+, m/z): 276 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([CH3:35])[CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][C:28]=4[CH3:35])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@]2(CCN(c3ccc(N)cc3)C2)C1
Reactant: COc1ccc(C(=O)O)c(C)c1
Product: COc1ccc(C(=O)Nc2ccc(N3CC[C@]4(CCN(C(=O)OC(C)(C)C)C4)C3)cc2)c(C)c1

Procedure:
According to Method P, (S)-7-(4-amino-phenyl)-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester was reacted with 4-methoxy-2-methyl-benzoic acid. In this way the product was obtained with molecular weight 465.60 (C27H35N3O4); MS (ESI): 466 (M+H+).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C:9]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Cl[CH2:33][C:34]1[N:35]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:36]=[C:37]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:38](=[O:40])[CH:39]=1>CN(C)C=O>[O:40]=[C:38]1[C:37]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:36][N:35]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:34]([CH2:33][N:11]2[CH2:12][CH2:13][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9](=[O:15])[C:10]2=[O:14])=[CH:39]1
Reactant: [H][H]
Reactant: O=C1NCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Reactant: O=c1cc(CCl)n(Cc2ccccc2)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1Cc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of N-(triphenylmethyl)piperazine-2,3-dione (4.19 g, 11.77 mmol) in 95 ml of dry dimethylformamide was added 0.35 g (11.77 mmol) of sodium hydride (80% oil). After the hydrogen evolution had ceased, a solution of 2-(chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone (4.0 g, 11.77 mmol) in 25 ml of dry dimethylformamide was added to the thick suspension which then turned into a clear solution. After one hour of stirring at room temperature, precipitation started. After two hours, the crystals were filtered off, washed and dried in vacuo, yielding 5.13 g of the title compound, melting point 165°-168° C.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.CS(Cl)(=O)=O.[C:13]([O:17][CH2:18][CH2:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)(=[O:16])[CH:14]=[CH2:15].O[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[OH:45])[C:40]#[N:41]>CN(C)C1C=CN=CC=1.O.O1CCCC1>[C:13]([O:17][CH2:18][CH2:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C@H:27]2[CH2:28][CH2:29][C@H:30]([C:33]([O:35][C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=3[O:45][C:33]([C@H:30]3[CH2:29][CH2:28][C@H:27]([C@H:24]4[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][CH2:18][O:17][C:13](=[O:16])[CH:6]=[CH2:7])[CH2:22][CH2:23]4)[CH2:32][CH2:31]3)=[O:34])[C:40]#[N:41])=[O:34])[CH2:31][CH2:32]2)[CH2:23][CH2:22]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(O)c(O)c1
Reactant: C=CC(=O)OCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)OCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(C#N)cc3OC(=O)[C@H]3CC[C@H]([C@H]4CC[C@H](CCCOC(=O)C=C)CC4)CC3)CC2)CC1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
0.9 g of triethylamine and then 0.5 g of methanesulphonyl chloride were added dropwise at -25° C. while stirring to a solution of 2.0 g of trans-4-(trans-4-[3-acryloyloxypropyl]cyclohexyl)-cyclohexanecarboxylic acid and 40 ml of tetrahydrofuran. The reaction mixture was stirred at -25° C. for 1 hour, then treated with 0.28 g of 3,4-dihydroxybenzonitrile and 0.05 g of 4-(dimethylamino)pyridine, stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) and two-fold recrystallization from a cyclohexane/ethyl acetate mixture (vol. 8:2) of the fractions which were pure according to thin-layer chromaography gave 1.1 g of 3,4-bis[trans-4-(trans-4-[3-acryloyloxypropyl]cyclohexyl)-cyclohexanecarbonyloxy]benzonitrile.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9].O=S(Cl)[Cl:13].[CH:15](O)([CH3:17])[CH3:16]>>[ClH:13].[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH:15]([CH3:17])[CH3:16])=[O:9]
Reactant: O=C(O)C1COCCN1
Reactant: CC(C)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CC(C)OC(=O)C1COCCN1
Temperature: 80 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a suspension of morpholine-3-carboxylic acid hydrochloride (2 g, 12 mmol) in isopropanol (30 mL) was added SOCl2 (1.9 g, 15.6 mmol) at 5° C., then the mixture was stirred at 80° C. for 6 hours. The mixture was concentrated in vacuo to give the title compound as pale brown oil (2.39 g, 95%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](C(NCCC)=O)[CH:19]=3)[CH:17]=2)=[O:11])[C:5]2[CH:6]=[CH:7]C=CC=2N=N1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.C1C[O:38][CH2:37]C1>>[CH:31]1([NH:34][C:37]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[C:15]([CH3:30])=[CH:14][CH:13]=[C:12]([C:10]([NH:1][CH2:5][CH2:6][CH3:7])=[O:11])[CH:17]=3)=[CH:23][CH:22]=2)=[O:38])[CH2:33][CH2:32]1
Reactant: CCCNC(=O)c1cccc(-c2cc(C(=O)n3nnc4ccccc43)ccc2C)c1
Reactant: C1CCOC1
Reactant: NC1CC1
Product: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)NC3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5′-[(1H-1,2,3-Benzotriazol-1-yl)carbonyl]-2′-methyl-N-propyl-1,1′-biphenyl-3-carboxamide (25 mg, 0.062 mmol) in THF (1 ml) was mixed with cyclopropylamine (7.2 μl) in THF (0.6 ml) and the reaction stirred at room temperature for 4 h. The reaction was loaded onto an SPE (aminopropyl, 1 g) and eluted with chloroform, ethyl acetate and methanol. The solvent was evaporated from the product fractions to give N4′-cyclopropyl-6-methyl-N3-propyl-1,1′-biphenyl-3,4′-dicarboxamide. NMR: δH CDCl3 7.79, (2H, d), 7.67, (1H, dd), 7.60, (1H, d), 7.32, (3H, m), 6.56, (1H, s), 6.35, (1H, t), 3.41, (2H, q), 2.92, (1H, m), 2.25, (3H, s), 1.63, (2H, m), 0.97, (3H, t), 0.88, (2H, m), 0.65, (2H, m). LCMS: retention time 2.95 min, MH+337.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:19][CH2:18][C:17]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:14]3=[O:30])[CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:37][C:38]1[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.CCOC(C)=O.O>[F:24][C:20]1[C:17]2[CH2:18][CH2:19][CH:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:37][C:38]5[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=5)=[CH:3][CH:4]=4)[N:9]=[N:10]3)[C:14](=[O:30])[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:16]=2[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1C(n2cc(-c3ccc(Br)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: Cc1ncccc1O
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1

Procedure:
3-[4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl]-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (150 mg, 0.310 mmol), cesium carbonate (202 mg, 0.621 mmol), 3-hydroxy-2-methylpyridine (67.7 mg, 0.621 mmol), cuprous chloride (915.36 mg, 0.155 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (14.30 mg, 0.078 mmol) in NMP (1.55 mL) in a sealed microwave vial was heated to 120° C. overnight in an oil bath. The reaction vessel was allowed to cool before water was added to dilute the mixture; EtOAc was then added to extract the product. The organic phase was separated and washed with water (2×) and brine (1×) before being dried with Na2SO4 and evaporated to afford an oil. This material was chromatographed on silica (0-80% EtOAc in hexanes to yield 68.4 mg as a solid.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]#[N:34])=[CH:23][CH:22]=3)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]3[N:38]=[CH:39][N:40]=[C:14]23)[CH2:9][CH2:8]1)C.[OH-].[Na+].CO.Cl>O.O1CCCC1>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:17]2[C:18](=[O:19])[N:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][C:4]([OH:41])=[O:3])[CH2:8][CH2:9]3)[C:14]3[N:15]([N:38]=[CH:39][N:40]=3)[C:16]=2[CH2:35][CH2:36][CH3:37])=[CH:22][CH:23]=1)#[N:34]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (1.1 g), 1N aqueous sodium hydroxide solution (10 mL), methanol (10 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water (20 mL) and 1 N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.9 g, 90%).