Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:22][C:20]1[CH:19]=[C:18]([C:23]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26][N:25]([C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=3)[CH2:24]2)[CH:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: COC(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To the solution of methyl 4-fluoro-2-nitrobenzoate (1.1 g) and 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.5 g) in 1-methyl-2-pyrrolidinone was added potassium carbonate (1.5 g) and the mixture was heated with stirring at 100° C. for two hours. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield methyl 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoate (1.24 g). 1H-NMR (CDCl3) δ: 2.53-2.67 (1H, m), 2.89-2.97 (1H, m), 3.50-3.71 (2H, m), 3.83 (1H, d), 3.85 (3H, s), 4.15 (1H, d), 6.69 (1H, dd), 6.75 (1H, d), 7.26 (2H, d), 7.42 (1H, t), 7.81 (1H, d)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.O.[OH-].[Li+].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)N(C)C)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc(C(=O)O)n(CC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a solution of methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylate (90 mg, 0.26 mmol) in THF (1 mL) was added lithium hydroxide monohydrate (22 mg, 0.52 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 18 h (monitored by LCMS). A aqueous solution of NaOH (1 M) (25 mL) was added and the mixture washed with EtOAc (25 mL) to remove the remaining starting material. The aqueous layer was then acidified to pH 2-3 with an aqueous solution of HCl (1 M) and extracted with a mixture of 20% of propan-2-ol/DCM (2×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylic acid as a yellow solid (90 mg, quantitative yield). ESI-MI m/z [M+H]+ 335.1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[O:18]=[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][C:29](=[O:33])[C:30](O)=[O:31])=[CH:27][C:21]=2[O:20]1>>[O:31]=[C:30]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)[C:29]([NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19](=[O:18])[O:20][C:21]=2[CH:27]=1)=[O:33]
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Reactant: FC(F)(F)c1ccc(CC2CCNCC2)cc1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-trifluoromethyl-benzyl)-piperidine [J. Org. Chem., 64, 3763. (1999)] and N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) according to the method described in Example 43f. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 217° C. (isopropanol)
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: Cc1ccccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Reactant: C#CCCO
Product: Cc1ccccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 419 (0.40 mmol) and but-3-yn-1-ol (0.40 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 0:100 as the eluent to afford the title compound as light yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].I[CH3:12]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([O:8][CH3:12])=[CH:6][CH:7]=1
Reactant: CI
Reactant: N#Cc1[nH]c(=O)ccc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(C#N)n1

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15/Step 2) (1.0 eq.), silver carbonate (1.3 eq.), and iodomethane (1.2 eq.) in toluene (0.2 M) was stirred in the dark at room temperature overnight. The solvent was concentrated en vacuo, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 3-bromo-6-methoxypicolinonitrile.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.[C:37]1([C:43]2[N:47]([C:48]3[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=3)[C:46]3[CH:57]=[CH:58][CH:59]=[CH:60][C:45]=3[N:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:37]1([C:43]2[N:47]([C:48]3[CH:53]=[CH:52][C:51]([C:2]4[CH:15]=[CH:14][C:13]5[C:4](=[C:5]([C:27]6[CH:36]=[CH:35][C:34]7[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=7)[CH:28]=6)[C:6]6[C:11]([C:12]=5[C:16]5[CH:25]=[CH:24][C:23]7[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=7)[CH:17]=5)=[CH:10][C:9]([C:51]5[CH:50]=[CH:49][C:48]([N:47]7[C:46]8[CH:57]=[CH:58][CH:59]=[CH:60][C:45]=8[N:44]=[C:43]7[C:37]7[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=7)=[CH:53][CH:52]=5)=[CH:8][CH:7]=6)[CH:3]=4)=[CH:50][CH:49]=3)[C:46]3[CH:57]=[CH:58][CH:59]=[CH:60][C:45]=3[N:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3cc(Br)ccc3c(-c3ccc4ccccc4c3)c2c1
Reactant: OB(O)c1ccc(-n2c(-c3ccccc3)nc3ccccc32)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: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2nc3ccccc3n2-c2ccc(-c3ccc4c(-c5ccc6ccccc6c5)c5cc(-c6ccc(-n7c(-c8ccccc8)nc8ccccc87)cc6)ccc5c(-c5ccc6ccccc6c5)c4c3)cc2)cc1
Yield: 73 %

Procedure:
2.0 g (3.4 mmol) of 2,6-dibromo-9,10-di(2-naphthyl)anthracene, 2.4 g (7.5 mmol) of 4-(2-phenyl-1H-benzimidazol-1-yl)phenylboronic acid, and 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 30 mL of 1,2-dimethoxyethane. Then, 15 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. The resultant was stood to cool. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 2.4 g of a greenish white solid (73% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 966 with respect to a molecular weight of 966.37.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1cccnc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2cccnc2Cl)OCCO1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
1-(2-Chloro-pyridin-3-yl)-ethanone (2.21 g, 14.2 mmol, 1.0 equiv), ethylene glycol (4.41 g, 71.0 mmol, 5.0 equiv) and p-toluenesulfonic acid monohydrate (1.35 g, 7.1 mmol, 0.5 equiv) are dissolved in toluene (100 mL). The resulting mixture is heated overnight under Dean Stark conditions. After cooling to room temperature the mixture is washed twice with saturated NaHCO3 solution, brine, dried over Na2SO4 and evaporated in vacuo. The residue is purified by flash column chromatography (10% to 50% ethyl acetate in heptane) to yield 2.19 g of the title compound.
Reaction SMILES: N#N.[F:3][C:4]1[C:5]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:35])[CH:31]([OH:34])[CH2:32][OH:33])[CH:26]=[CH:27][CH:28]=2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.C(OCC)(=O)C>[CH3:36][S:37]([O:33][CH2:32][CH:31]([OH:34])[C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:5]2[C:4]([F:3])=[CH:9][N:8]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=3)[N:6]=2)[CH:24]=1)=[O:35])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)CO)c3)n2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)COS(C)(=O)=O)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
In a 25 mL 3-neck RBF equipped with N2-bubbler and thermo-pocket, N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-2,3-dihydroxypropanamide (I-4) (0.08 g) was dissolved in THF (5 mL), TEA (0.0212 g) was added at room temperature. The reaction mixture was cooled to 0° C. Methane sulphonyl chloride (0.021 g) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored on TLC by using ethyl acetate (100%) as mobile phase. (Only 50% of the reaction was complete on TLC). The reaction was diluted with ethyl acetate (20 mL), washed with saturated NaHCO3 (25 mL). The organic layer was separated and dried over sodium sulfate. Ethyl acetate was removed under reduced pressure at 40° C. Crude material was purified by Combiflash chromatography eluted with 7% ethyl acetate in hexane. The solvent was removed under vacuum to give 0.03 g of 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-2-hydroxy-3-oxopropyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[NH:28])=[CH:25][C:24]=3C)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl[C:34]([O:36][CH3:37])=[O:35]>ClCCl>[CH3:37][O:36][C:34](=[O:35])[NH:29][C:27](=[NH:28])[C:26]1[CH:25]=[CH:24][C:23]([C:21]([N:18]2[CH2:17][CH2:16][N:15]([S:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)(=[O:13])=[O:14])[CH2:20][CH2:19]2)=[O:22])=[CH:31][CH:30]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C(=N)N)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Solvent: ClCCl
Product: COC(=O)NC(=N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1

Procedure:
By reaction of 4-[4-(6-chloro-2-naphthylsulphonyl)piperazine-1-carbonyl]-3-methylbenzamidine with methyl chloroformate in dichloromethane, the compound methyl(imino-{4-[4- (6-chloro-2-naphthylsulphonyl)piperazine-1-carbonyl]phenyl}methyl)carbamate is obtained after customary work-up
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.Br[CH2:27][C:28]([NH2:30])=[O:29]>CCN(CC)CC>[NH2:30][C:28](=[O:29])[CH2:27][NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNCC(N)=O)no1

Procedure:
Method as for preparation 106 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (250 mg, 0.71 mmol) and 2-bromoacetamide (98 mg, 0.71 mmol) as starting materials and Et3N as the base.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:7]([C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)=[O:8].I[CH2:21][CH3:22].Cl>CN(C)C=O>[F:19][C:17]1[CH:16]=[C:6]([CH:5]=[C:4]([F:3])[CH:18]=1)[C:7]([C:9]1[C:10](=[O:15])[N:11]([CH2:21][CH3:22])[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1cc(F)cc(F)c1)c1ccc[nH]c1=O
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cccc(C(=O)c2cc(F)cc(F)c2)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
187 mg (4.68 mmol) of sodium hydride 60% dispersion in oil is added to 0.44 g (1.87 mmol) of 3-(3,5-difluorobenzoyl)pyridin-2(1H)-one dissolved in 15 ml of anhydrous dimethylformamide at 0° C. 379 mg (2.43 mmol) of iodoethane is added to this mixture. The reaction mixture is stirred at 0° C. for 10 minutes and then for 1 hour at room temperature. 1 N HCl solution is added and then the product is extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (eluent: 10:1 dichloromethane/methanol) to yield 221 mg (50%) of 3-(3,5-difluorobenzoyl)-1-ethylpyridin-2(1H)-one in the form of a yellow solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([F:45])=[C:20]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:21]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:38])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F-].[Cs+].[NH2:48][C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1.O>COCCOC.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>[NH2:48][C:49]1[CH:54]=[C:53]([C:2]2[S:3][C:4]([C:13]([C:15]3[CH:23]=[C:22]4[C:18]([C:19]([F:45])=[C:20]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:21]4[CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])=[CH:17][CH:16]=3)=[O:14])=[CH:5][C:6]=2[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:52]=[CH:51][CH:50]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(N)c1
Yield: 76.4 %

Procedure:
A mixture of 6 (40 mg, 0.058 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), CsF (27 mg, 0.18 mmol), 3-aminophenylboronic acid (12 mg, 0.088 mmol), and H2O (80 μL) in DME (8 mL) was degassed with N2 for 10 minutes and then refluxed. When the reaction was over by TLC monitoring, the mixture was poured into H2O (10 mL) and then extracted with 70 mL Et2O. The organic layer was washed with brine (2×10 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 7 as a yellow amorphous solid (31 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.78-7.67 (m, 7H), 7.51-7.41 (m, 5H), 7.23 (t, J=8.0 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.85 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 4.26 (t, J=7.0 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.82 (brs, 2H), 3.70 (s, 2H), 3.48 (t, J=6.8 Hz, 2H), 1.66-1.60 (m, 2H), 1.48-1.45 (m, 2H), and 1.25 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.13, 171.26, 168.49, 149.66, 147.09, 143.16, 141.68, 140.71, 137.58, 134.19, 132.51, 132.44, 132.38, 132.14, 130.54, 130.05, 129.97, 129.54, 129.15, 129.06, 128.94, 128.58, 127.31, 127.10, 123.47, 121.43, 120.02, 119.86, 119.71, 116.81, 115.88, 115.69, 112.56, 61.31, 43.61, 37.25, 34.77, 27.36, 25.77, and 14.45; 19F NMR (376 MHZ, CDCl3) δ −174.49.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]3)[NH:13][CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]3)[N:13]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(CC1)NC2
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2CC3)c1

Procedure:
Reaction of Intermediate 26 with 3-methoxybenzaldehyde affords the title compound.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 90.4 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (10.0 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid (10.1 g) in a yield of 90.4%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.24 (s, 1H), 4.53 (m, 1H), 1.34 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[BH4-].[Na+].Cl>CCO.C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of (1S,2R,5R,6S)-2-azido-3-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (IX-1) (100 mg, 0.29 mmol) in EtOH (1.7 mL) and THF (0.5 mL) was added NaBH4 (22 mg, 0.58 mmol) at -50° C. and stirring was continued at -50° C. for 4 h. The reaction mixture was poured on ice, acidified with 1 N HCl and extracted with ether. After washing with sat. NaHCO3 -sol., brine and drying over MgSO4 the crude product was purified by silica gel column chromatography with hexane/EtOAc 5:1 to give (1 S,2R,3S,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (X-1) (51 mg, 51%) as a colorless oil. 1H-NMR (250 MHz, CDCl3) □1.26 (3H, t, J=7.2 Hz), 2.03-2.18 (3H, m),2.31-2.48 (2H, m),2.53 (1H, t,J=4 Hz),4.13 (2H, q,J=7.2 Hz), 4.21 (1H,bs), 5.26 (2H, s), 7.36-7.40 (5H, m); MS [EI]300 [(M--OEt)+ ];
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1>C(Cl)Cl>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH2:27])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1
Reactant: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)C(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmol) was added to a stirring solution of 3-(1H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 3-(1H-indol-3-yl)-2-amino-N-(2-methoxybenzyl)propanamide (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[N:4]=1)#[N:2].C(O)(C(F)(F)F)=[O:21]>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([OH:15])=[O:14])[N:4]=1)(=[O:21])[NH2:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2ccncc21
Product: NC(=O)c1nn(CC(=O)O)c2cnccc12

Procedure:
To a solution of tert-butyl 2-(3-cyano-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (663 mg, 2.40 mmol) in TFA (6 mL) was subjected to microwave irradiation at 140° C. for 90 min. The reaction mixture was concentrated in vacuo, the residual solid was suspended in MeOH and volatiles were removed again in vacuo. MS: 221.0 [M+H]+; tR (HPLC conditions d): 0.23 min.
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[C:7]([CH3:21])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:22]C1C=C(C2C=CC=C(C(F)(F)F)C=2)NC(=O)C=1C(O)=O.OS(O)(=O)=O>CO>[CH3:22][N:10]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[CH:8][C:7]([CH3:21])=[C:3]([C:4]([OH:6])=[O:5])[C:2]1=[O:1]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(O)c1C(=O)O
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)n(C)c(=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
A solution of 0.30 g (1.0 mmol) of 2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid/4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid in 15 ml of MeOH was treated with 0.06 ml=0.01 g (0.1 mmol) of H2SO4 (98%) and the reaction mixture was heated up to reflux. After 4 hours, it was cooled down to RT, poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.24 g (77%) of the title compound as off-white solid. MS: 312.0 (MH+).