Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:26](O)(=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:20]([F:25])[CH:19]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1ncc(-c2ccc(O)c(F)c2)cn1
Reactant: CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCC)c(F)c2)cn1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
In a 200 ml-round bottom flask, 2.00 g (5.81 mM) of 2-undecyl-5-(3-fluoro-4-hydroxyphenyl)pyrimidine, 0.60 g (5.87 mM) of valeric acid and 50 ml of dichloromethane were placed and dissolved. To the solution, 1.21 g (5.86 mM) of N,N'-dicyclohexylcarbodiimide and 0.10 g of 4-pyrrolidinopyridine were successively added under stirring at room temperature, followed by further stirring for 4 hours and 45 minutes at room temperature. After stirring, the mixture was left standing at room temperature to precipitate N,N'-dicyclohexylurea. The resultant, N,N'-dichclohexylurea was filtered off and the solvent of the filtrate was distilled-off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized two times from a minute solvent of acetone-methanol to obtain 1.91 g of 2-undecyl-5-(3-fluoro-4-pentanoyloxyphenyl)pyrimidine (Yield: 76.8). ##STR28##
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH3:31])[CH:25]=1)=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH3:31])[CH:25]=2)=[O:23])=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Reactant: Cc1cc(C(=O)CBr)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(C(=O)COC(=O)CC2(NC(=O)OCc3ccccc3)COC2)ccc1Cl

Procedure:
(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 0.3 g, 1.13 mmol), 2-bromo-1-(4-chloro-3-methylphenyl)ethanone (0.294 g, 1.19 mmol) and cesium carbonate (0.553 g, 1.70 mmol) were stirred in acetonitrile (10 mL) at room temperature for 2 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound which was used without purification in the next step.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH2:36]([NH-:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [NH-]Cc1ccccc1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 220 μl (2 mmol, 2.14 mg) of benzylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.52) disappeared and the product (Rf=0.69) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 3:7). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 8:2 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (135 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:17]COCC>CO>[ClH:1].[CH3:17][O:15][C:14](=[O:16])[C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:2]
Reactant: CCOCC
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 120 h

Procedure:
A 1.2 M solution of HCl in MeOH (440 mL; 0.528 mol) was added to a suspension of L-tryptophan (commercial product) (30.6 g; 150 mmol) in MeOH (70 mL). The resulting clear solution was stirred for 5 days at 20° C. The solution was concentrated (35° C.; 1.3 kPa) to yield a solid which was dissolved in MeOH (10 mL). Et2O (300 mL) was added to the solution and the mixture was vigorously stirred for 1 h. The mixture was filtered and the solid was washed with Et2O (70 mL). The combined solutions were concentrated (35° C.; 1.3 kPa) to a volume of 100 mL and filtered. The solid materials were combined and dried (40° C.; P205; 1.3 kPa) to give as a white solid the desired product (38.5 g; 149.5 mmol). Quantitative yield.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:15])[N:3]=1.[CH3:16][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([Si:11]([CH3:13])([CH3:12])[CH3:14])=[C:4]([F:15])[N:3]=1.[F:1][C:2]1[N:3]=[C:4]([F:15])[C:5]([Si:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][C:7]=1[C:8]([O:10][CH3:16])=[O:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: C[Si](C)(C)c1cc(C(=O)O)c(F)nc1F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc([Si](C)(C)C)c(F)nc1F
Temperature: 25 °C

Procedure:
2,6-Difluoro-5-(trimethylsilyl)pyridine-3-carboxylic acid (1.17 g, 5.05 mmol) was dissolved in a mixture of DCM (20 mL) and MeOH (5 mL) and treated with (trimethylsilyl)diazomethane (2.0 m in diethyl ether, 5.0 mL, 10.00 mmol). [2,6-Difluoro-5-(trimethylsilyl)pyridine-3-carboxylic acid was synthesized according to M. Schlosser and T. Rausis, Eur. J. Org. Chem., 2004, pp 1018-1024]. The derived solution was maintained at rt for 1 hour. Evaporation under reduced pressure and purification using the by silica gel chromatography (hexane to ethyl actetate gradient) gave the desired methyl 2,6-difluoro-5-(trimethylsilyl)nicotinate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:19](=O)[C:18]2[C:13](=[N:14][C:15](SC)=[N:16][CH:17]=2)[N:12]2[CH:23]=[CH:24][N:25]=[C:11]12.ClC1C=C(C=CC=1)C(OO)=[O:31].[NH2:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]3([CH2:56][CH2:55]3)[CH2:43][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]2)=[CH:40][CH:39]=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:19]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:13]2=[N:25][C:24]([NH:37][C:38]3[CH:47]=[C:46]4[C:41]([C:42]5([CH2:55][CH2:56]5)[CH2:43][N:44]([C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH2:45]4)=[CH:40][CH:39]=3)=[CH:23][N:12]2[C:11]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C2(CC2)C1
Reactant: CSc1ncc2c(=O)n(-c3c(Cl)cc(F)cc3Cl)c3nccn3c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2cc(Nc3cn4c(=O)n(-c5c(Cl)cc(F)cc5Cl)c5ncncc5c4n3)ccc2C2(CC2)C1
Reaction time: 0.42 h

Procedure:
A mixture of Example 123A (600.0 mg, 1.514 mmol) and m-chloroperoxybenzoic acid (407 mg, 1.817 mmol) in CH2Cl2 (14 ml) was stirred for 20 minutes. tert-Butyl 7′-amino-1′H-spiro[cyclopropane-1,4′-isoquinoline]-2′(3′H)-carboxylate (499 mg, 1.817 mmol) was added to the reaction mixture. After 25 minutes, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with hexane/ethyl acetate (6:4 to 4:6) to provide the title compound.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.[NH2:23][C:24]1[N:29]=[C:28]([OH:30])[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][OH:39])=[CH:34][C:33]=2[O:40][CH3:41])=[C:26]([CH3:42])[N:25]=1>C1COCC1.O>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:30][C:28]1[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][OH:39])=[CH:34][C:33]=2[O:40][CH3:41])=[C:26]([CH3:42])[N:25]=[C:24]([NH2:23])[N:29]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 84.8 %

Procedure:
2-Mesitylenesulfonyl chloride (7.2 g) was added to a suspension of diisopropylethylamine (5.5 mL) and the product from step (iii) (6.1 g) in THF (200 mL) and the mixture was stirred under reflux for 12 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (8.6 g) as a white solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.86 (1H, s), 6.77 (2H, s), 4.67 (2H, br s), 4.64 (2H, d), 3.82 (3H, s), 3.81 (2H, s), 2.57 (6H, s), 2.29 (3H, s), 2.21 (3H, s), 1.81 (1H, t).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[CH2:11]([N:18]=[N+:19]=[N-:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[CH2:11]([N:18]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 86.1 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.095 g, 0.603 mmol) was reacted with benzyl azide (0.096 g, 0.723 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol 2-ylamine hydrochloride (0.151 g, 86%) of a pale yellow solid. 1H NMR (300 MHz, D2O) δ 7.79 (s, 1H), δ 7.42-7.35 (m, 5H), δ 6.43 (s, 1H), δ 5.58 (s, 21-1), δ 3.86 (s, 2H) ppm; 13C δ 145.4, 136.6, 136.4, 128.8, 128.7, 126.9, 126.8, 126.3, 124.1, 121.8, 109.6, 53.3, 24.1 ppm; HRMS (ESI) calcd for C13H16N6O (M+) 254.1352. found 254.1352.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([Br:25])[C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18])(=[O:13])[CH3:12].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl>C1COCC1.O.C(Cl)Cl>[Br:25][C:22]1[CH:21]=[C:16]([CH:15]=[C:14]([C:11](=[O:13])[CH2:12][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])[C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(O)c(C(=O)CC(=O)N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.41 L, 1406 mmol) at −65° C. under nitrogen was added dropwise methyl 3-acetyl-5-bromo-4-hydroxybenzoate (120 g, 439 mmol) in THF (1.2 L). The solution was allowed to warm to 0° C., and maintained at this temperature for 1 hr. The solution was cooled back to −65° C. and morpholine-4-carbonyl chloride (0.055 L, 483 mmol) was added. The mixture was stirred at RT for 2 hrs then cooled to −30° C., DCM (1.5 L) and water (1 L) were added followed by dropwise addition of HCl 6N (500 mL) then HCl2N (300 mL) until pH 7, the aqueous solution was extracted with DCM (3×). The combined extracts were dried over magnesium sulfate and evaporated. The crude product was triturated in MTBE to obtain methyl 3-bromo-4-hydroxy-5-(3-morpholino-3-oxopropanoyl)benzoate (153 g, 90%) as a beige solid. Mass Spectrum: M+H+ 388.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([NH:10][NH2:11])=O)=[C:5]([CH3:7])[N:6]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:8]2[N:13]([CH3:12])[C:14]([SH:15])=[N:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)NN)s1
Reactant: CN=C=S
Solvent: CCO
Product: Cc1nc(C)c(-c2nnc(S)n2C)s1
Yield: 47.6 %

Procedure:
To a 2,4-dimethylthiazole-5-carbohydrazide (Prep26, 23 g, 0.13 mol) in ethanol (100 ml), methyl isothiocyanate (49.1 g, 0.67 mol) was added. The mixture was refluxed overnight. Then the ethanol was partially removed under vacuum and the residue was filtered. The solid was dried under vacuum to afford 14 g of the title compound (y=46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>N1CCCCC1.O.[Cu]I.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:10][CH:9]=1
Reactant: Nc1ccccc1-c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccc2N)cc1
Temperature: 60 °C
Reaction time: 26 h

Procedure:
To 2.5 g 2-amino-4′-bromo-biphenyl (WO0264562) in piperidine (25 ml) under nitrogen were added in sequence CuI (0.1 g), bis(triphenylphosphino)palladium dichloride (0.35 g) and trimethylsilylacetylene (2.8 ml). The mixture was stirred for 22 hours at room temperature and for a further 26 hours at 60° C. After cooling the reaction mixture was diluted with water and extracted with ethylacetate. Then the organic phase was washed with water and dried over sodium sulfate. After evaporation of the solvents in vacuum the mixture was chromatographed on silica gel (hexane:ethylacetate 9:1) to yield 2- amino-4′-(trimethylsilyl)ethinyl-biphenyl (2 g) (Compound No.12.02).
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].C(O)(=O)C.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1CCOCC1.C(O)(=O)C>C(#N)C>[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[CH:3]=[CH:4][C:5]#[N:6]
Reactant: C1COCCN1
Reactant: N#CC=CO
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: N#CC=CC1COCCN1
Temperature: 65 °C
Yield: 75.3 %

Procedure:
30.3 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 75%) is added to a solution of morpholine acetate (prepared from 26.1 g (0.3 mol) of morpholine and 18 g (0.3 mol) of acetic acid) in 200 ml of acetonitrile and is heated for 8 h at 65° C. After working up as in Example 55, 26.0 g (75.4%) of 3-morpholine acrylonitrile was obtained.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:14]=3[N+:28]([O-:30])=[O:29])=[C:11]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:10]=[N:9]2)[CH2:5][O:4][CH2:3][CH2:2]1.O1[CH2:41][CH2:40][O:39][CH2:38]C1>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:4]1[CH2:5][CH:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:41]4[C:40]([O:39][CH3:38])=[N:8][C:12]([CH3:11])=[CH:13][C:14]=4[CH3:15])=[CH:15][C:14]=3[N+:28]([O-:30])=[O:29])=[C:11]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:10]=[N:9]2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Water (0.3 mL), 3-bromo-2-methoxy-4,6-dimethylpyridine (32.5 mg) obtained in Preparation Example 26, Pd(PPh3)4 (7.2 mg) and cesium carbonate (122 mg) were added to a solution of ethyl 1-(1,4-dioxepan-6-yl)-5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole-4-carboxylate (61 mg) in 1,4-dioxane (1.2 mL), and the reaction mixture was stirred at 100° C. for 4 hours. Pd(PPh3)4 (7.2 mg) was added to the reaction mixture, and the reaction mixture was stirred at 100° C. for 1 hour and 10 minutes. The reaction mixture was returned to room temperature and partitioned by adding ethyl acetate and water, and the organic layer was separated. The resulting organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 15 to 20%) to give the title compound (15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.Br[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.[Pd](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:12]2[C:13]([C:14]#[N:15])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
4-methoxyphenylmagnesium bromide (280 g, 15% solution in tetrahydrofuran) is added dropwise over seven hours to a refluxing solution of 2-bromobenzonitrile (32 g), palladium (II) chloride (1.3 g) and triphenylphosphine (3.8 g) in tetrahydrofuran (210 ml). [HPLC: yield 94-95%]. After cooling to room temperature and the addition of water (50 ml), tetrahydrofuran is removed under vacuum. The residue is extracted with toluene (230 ml). Insoluble material is filtered off and the solvent distilled off. The crude product is recrystallised from ethanol to give 4'-methoxybiphenyl-2-carbonitrile as a solid, m.pt. 82-83° C. 1H NMR (CDCl3): 3.90(s,3H), 7.02(d,2H), 7.36-7.52(m,4H), 7.59-7.65(m,1H), 7.74(d,1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[N:21][CH:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,4]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 162) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (114 mg, 46%).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(O[C:6](C)([CH3:8])[CH3:7])=O.[N+:17]([C:20]1[CH:21]=[N:22][NH:23][CH:24]=1)([O-:19])=[O:18].CC(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:6]([N:22]1[CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:24]=[N:23]1)([CH3:8])[CH3:7]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 149 %

Procedure:
Di-tert-butyl azodicarboxylate (1.59 g, 6.91 mmol) was added to a solution of 4-nitro-1H-pyrazole (601 mg, 5.32 mmol), 2-propanol (319 mg, 5.32 mmol) and triphenylphosphine (1.67 g, 6.36 mmol) in tetrahydrofuran (25 mL) over 3 minutes and the mixture was stirred at room temperature for 16 h. After this time, the reaction was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, 1:4 ethyl acetate/heptane to 7:3 ethyl acetate/heptane) to afford 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g, >100%) as an impure off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.24 (s, 1H), 4.58 (m, 1H), 1.42 (d, J=6.6 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([Cl:34])(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[ClH:34].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:3]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: CC(C)(C)C(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Product: Cl

Procedure:
50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114) and 33.4 mg (0.28 mmol) of pivaloyl chloride are reacted together by general method F. 15.2 mg (20.7% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.CI.[Na+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@:11]([CH3:25])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CC[C@H](c2cncc(F)c2)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CI
Product: CCOC(=O)[C@]1(C)CC[C@H](c2cncc(F)c2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of (2S,5R)-1-tert-butyl 2-ethyl 5-(5-fluoropyridin-3-yl)pyrrolidine-1,2-dicarboxylate (250 mg, 0.739 mmol) in THF (10 mL) was cooled to −78° C. and 0.5 M KHMDS in toluene (1.77 mL, 0.885 mmol) was added dropwise. The reaction was stirred for 1 hour at −78° C. and MeI (59.9 μL, 0.960 mmol) was added. The reaction was allowed to warm to ambient temperature and saturated aqueous NaCl (20 mL) was added. The mixture was extracted with EtOAc (2×50 mL) and the combined organic extracts were filtered and concentrated to afford (2S,5R)-1-tert-butyl 2-ethyl 5-(5-fluoropyridin-3-yl)-2-methylpyrrolidine-1,2-dicarboxylate (255 mg, 98% yield) as a clear oil. MS (apci) m/z=353.1 (M+H).