Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Reactant: COc1ccnc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccnc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) yellow solution of commercially available 3-bromo-2,4-dimethoxypyridine (1.490 g; 6.83 mmol) in anh. THF (42 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (4.3 ml; 6.88 mmol). The resulting orange solution was further stirred at −78° C. for 10 min. A yellow solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (1.450 g; 6.21 mmol) in anh. THF (5 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 65 min. The resulting orange reaction mixture was treated successively with aq. sat. NH4Cl (22 ml), Et2O (75 ml) and water (20 ml). The separated orange organic layer was then washed with brine (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded methyl 5-(2,4-dimethoxypyridin-3-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow oil. LC-MS (conditions B): tR=0.75 min.; [M+H]+: 372.82 g/mol.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24])([O-:15])=[O:14].S(=O)(=O)(O)[OH:26]>C(O)(=O)C>[CH3:1][C:2]([NH:24][C:23](=[O:26])[CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14])([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Reactant: CC(C)CC=Cc1cccnc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(CCCc1cccnc1)NC(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 22.7 g of 3-(4-methyl-pentenyl)pyridine and 22.8 g of 2-nitrobenzeneacetonitrile in 80 mL of acetic acid was cooled to 12°-13° C. and then 16 mL of sulfuric acid was added dropwise over 6 minutes. The reaction was stirred for 2 hours at ambient temperature, then after the acetic acid was removed in vacuo, 1L of water was added and the mixture was extracted with dichloromethane to remove neutral impurities. The aqueous layer was basified with 10N sodium hydroxide, and extracted with dichloromethane (4×200 mL). The dried (K2CO3) extracts were evaporated to give 35.6 g of N-[1,1-dimethyl(3-pyridyl)butyl]-2-nitrobenzeneacetamide. A portion was crystallized from ethyl acetate-hexane to yield the analytical sample, mp 117°-118.5° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-:27])=O)=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1.C(N(CC)CC)C>[N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)=[O:27])=[CH:28][CH:29]=4)[CH:15]=3)[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccccn1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
Triethylamine (0.11 ml) was added to THF suspension (6 ml) of 4-[[2-(2-piperidinoethyl)-6-tetraliny]oxymethyl]benzoate (300 mg). Trimethylacetyl chloride (0.095 ml) was added dropwise to the obtained suspension under ice-cooling, which was stirred for 30 minutes. The temperature of the reaction mixture was raised to room temperature, which was stirred for 1 hour. THF solution (1.0 ml) of 2-aminopyridine (110 mg) was added dropwise to the reaction mixture under ice-cooling, which was stirred for 1 hour. Then the reaction mixture was stirred at room temperature for 6 hours, and at 60° C. for 12 hours, which was refluxed with heating for 6 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: THF), and recrystallized (ethyl acetate-IPE) to give the titled compound (30 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH:7]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8]1=[O:13])[OH:6])[CH3:2].C.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([OH:6])[CH:7]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]1=[O:13])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(O)C1CC(C)=CC1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)C1CC(C)CC1=O

Procedure:
99.1 g of crude alpha-hydroxy-(4-methyl-2-oxo-3-cyclopenten-1-yl)-acetic acid ethyl ester (as prepared in Example 1) in 882 ml of toluene was hydrogenated over 9.91 g of 10% by weight of palladium and 90% by weight of charcoal at room temperature and 25-50 psi. After hydrogen uptake had ceased, the catalyst and solvent were removed by filtration and evaporation to give 101 g of a viscous, amber-colored oil. This oil is distilled to provide the product alpha-hydroxy-4-methyl-2-oxo-cyclopentane acetic acid ethyl ester, bp 96°-111°/0.05 mmHg, for use in Example 5.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Cl:13][C:14]1[N:23]=[C:22](Cl)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>O1CCCC1>[Cl:13][C:14]1[N:23]=[C:22]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Clc1nc(-n2ccnc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a suspension of 60% sodium hydride (426 mg) in tetrahydrofuran (4 mL)-N,N-dimethylformamide (24 mL) was added imidazole (725 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise a tetrahydrofuran solution (35 mL) of 2,4-dichloroquinazoline (2.12 g) synthesized according to the method of H. C. Scarborough et al. (Journal of Organic Chemistry, 1962, pp. 957-961), in ice-acetone bath, and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water, and precipitated powder was collected by filtration, washed with water and dried. The obtained powder was purified by silica gel column chromatography, (ethyl acetate), to give 1.88 g of 2-chloro-4-(1-imidazolyl)-quinazoline as colorless crystals (yield 77%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1.Cl>ClCCl>[CH3:11][S:12]([O:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH2:5][CH2:6][O:7][S:12]([CH3:11])(=[O:14])=[O:13])(=[O:14])=[O:13]
Reactant: OCCC(CCO)CCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an stirred ice-cooled solution of tris(2-hydroxyethyl)methane (10 g, 0.0676 mol) in dichloromethane (50 ml) was slowly dripped a solution of methanesulfonyl chloride (40 g, 0.349 mol) in dichloromethane (50 ml) under nitrogen at such a rate that the temperature did not rise above 15° C. Pyridine (21.4 g, 0.27 mol, 4 eq) dissolved in dichloromethane (50 ml) was then added drop-wise at such a rate that the temperature did not rise above 15° C., exothermic reaction. The reaction was left to stir at room temperature for 24 h and then treated with 5N hydrochloric acid solution (80 ml) and the layers separated. The aqueous layer was extracted with further dichloromethane (50 ml) and the organic extracts combined, dried over sodium sulfate, filtered and concentrated in vacuo to give tris[2-(methylsulfonyloxy)ethyl]methane contaminated with excess methanesulfonyl chloride. The theoretical yield was 25.8 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:17]C(=O)OCC3C=CC=CC=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1)OCc1ccccc1
Agent: Cl
Product: Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
Benzyl 4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-ylcarbamate (2.7 g) prepared in a similar manner according to Step 4 of Production Example 24 and 6N hydrochloric acid (50 ml) were combined. The reaction mixture was refluxed for 3 hours. After cooled to room temperature, the precipitate was filtered in vacuo. The solid was washed with water and acetonitrile to give 4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-amine (1.34 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[NH:13][C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.Br[CH2:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1>CN(C=O)C>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Reactant: BrCC1CCOC1
Solvent: CN(C)C=O
Product: CSc1nc(C)c2cc(Br)c(=O)n(CC3CCOC3)c2n1
Temperature: 70 °C
Reaction time: 7 h
Yield: 61.3 %

Procedure:
To a mixture of 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (900 mg, 3.15 mmol) and 3-(bromomethyl)-tetrahydrofuran (571 mg, 3.46 mmol) in DMF was added CsCO3 (1.13 g, 3.46 mmol). After stirred at 70° C. for 7 h and the mixture was quenched with water and extracted with t-butyl ethyl ether (4 times) and concentrated. The crude mixture was purified by flash chromatography, using 0-2% MeOH/CHCl3, to give the title compound (715 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:19])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][C:32]([N+:35]#[N:36])=[C:31]([N+:37]([O-])=O)[CH:30]=1>>[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][C:32]2=[N:35][N:36]([C:11]3[CH:12]=[C:13]([C:15]([CH3:16])([CH3:18])[CH3:17])[CH:14]=[C:9]([C:6]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=4)([CH3:8])[CH3:7])[C:10]=3[OH:19])[N:37]=[C:31]2[CH:30]=1
Reactant: N#[N+]c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Agent: O=S(=O)([O-])O
Product: CC(C)(C)c1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
Following the general procedure of Example 13, starting with the substituted phenol prepared in Example 5 and the diazonium salt prepared in Example 8, the title compound is prepared as a light yellow solid melting at 129-132° C. The structure is confirmed by 1Hnmr, 19Fnmr and mass spectroscopy analyses.
Reaction SMILES: [Cl-:1].S(Cl)(Cl)=O.[C-]#N.[K+].FC(F)(F)[C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1>>[Cl:1][C:12]1[CH:13]=[C:14]([CH2:17][C:18]#[N:19])[CH:15]=[N:16][CH:11]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: [Cl-]
Agent: [C-]#N
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: N#CCc1cncc(Cl)c1

Procedure:
Conversion of the hydroxyl group to the chloride using thionyl chloride, followed by the displacement of the chloride by potassium cyanide was performed using the same procedures described for (6-trifluoromethyl-pyridin-3-yl)-acetonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (d, J=2.0 Hz, 1 H), 8.50 (d, J=1.1 Hz, 1 H), 7.73 (s, 1 H), 4.58 (s, 2 H). MS m/z 153.0
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: COc1cc(Br)cc(C=O)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(Br)cc(OC)c2)cc1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (6.1 g, 36.9 mmol) and 3-bromo-5-methoxy-benzaldehyde (8.0 g, 36.9 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-5-methoxy-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.5 g, 34%) as a white solid: LC/MS m/e calcd for C17H16BrNO3 M+: 362.2, observed: 362.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([CH3:15])[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1cc(Oc2cccc(Cl)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Oc2cccc(Cl)c2)ccc1N
Yield: 86.8 %

Procedure:
To a stirred solution of 4-(3-chloro-phenoxy)-2-methyl-1-nitro-benzene (0.56 g, 2.12 mmol) in ethanol and water, iron (594 mg, 10.6 mmol) and saturated ammonium chloride (569 mg, 10.6 mmol) were added. This reaction mixture was then heated to reflux for 12 h. This was then filtered through celite and then extracted with EtOAc (3×15 mL). The EtOAc layer was washed with brine, dried over sodium sulfate and concentrated. This was then purified by chromatography (11% EtOAc in hexanes) to afford 4-(3-chloro-phenoxy)-2-methyl-phenylamine (0.43 g, 87%). MS (M+H)+=234.1; 1H NMR (CDCl3) δ: 7.17 (t, J=6.0 Hz, 1H), 6.95 (d, J=2.8 Hz, 1H), 6.88-6.86 (m, 1H), 6.82-6.71 (m, 2H), 6.65 (d, J=6.27 Hz, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[Br-:21].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCCc1ccccc1
Solvent: CO
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 60.3 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0688 g, 0.225 mmol) and (3-bromopropyl)benzene (0.070 mL, 0.460 mmol) in 1 MeOH/1 CHCl3 (4.0 mL) were reacted to give the desired product (0.0685 g, 62.3%). EI-MS m/z 424(M+) Rt (1.97 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]([CH2:14][C:15]#[CH:16])[C:7]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][C:29](I)=[CH:28][C:25]=1[C:26]#[N:27]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:25]1[CH:28]=[C:29]([C:16]#[C:15][CH2:14][N:6]([CH2:5][C:4]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:3]=2[O:2][CH3:1])[C:7]([C:9]2[NH:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH:30]=[CH:31][C:24]=1[F:23])#[N:27]
Reactant: N#Cc1cc(I)ccc1F
Reactant: C#CCN(Cc1ccc(OC)cc1OC)C(=O)c1ccc[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(CC#Cc2ccc(F)c(C#N)c2)C(=O)c2ccc[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of A1 (1 eq) in a mixture of DMF and Et3N (1:1) was added 2-fluoro-5-iodobenzonitrile (2 eq), CuI (0.2 eq) and Pd(PPh3)4 (0.05 eq). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with 0.1N HCl (2×) and then with brine; dried (Na2SO4) and concentrated. The resulting crude was purified by on silica gel eluting with EtOAc/petrol ether to obtain the desired compound. MS (ES) C24H20FN3O3 requires: 417, found: 418 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 11.59 (1H, bs), 7.93 (1H, dd, J=6.3, 2.0 Hz), 7.78-7.73 (1H, m), 7.53 (1H, t, J=9.1 Hz), 7.13 (1H, d, J=8.3 Hz), 6.93 (1H, s), 6.60 (1H, d, J=2.3 Hz), 6.53 (1H, dd, J=8.3, 2.3 Hz), 6.50-6.38 (1H, m), 6.10 (1H, s), 4.77 (2H, s), 4.50 (2H, s), 3.78 (3H, s), 3.76 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][C:27](=[O:29])[CH:26]=[CH:25][C:24]=3[CH:30]=2)[C:11](=[O:31])[CH:10]([N:32]2C(=O)C3=CC=CC=C3C2=O)[N:9]=1.O.NN.C(Cl)(Cl)Cl>C1COCC1>[NH2:32][CH:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][C:27](=[O:29])[CH:26]=[CH:25][C:24]=3[CH:30]=2)[C:11]1=[O:31]
Reactant: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1ccc2oc(=O)ccc2c1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2ccc3oc(=O)ccc3c2)C1=O
Temperature: 25 °C
Yield: 30.1 %

Procedure:
To a suspension of (3RS)-2,3-dihydro-5-(2-flurophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.30 g) in THF (50 ml) was added dropwise hydrazine monohydrate (0.12 g) under stirring at ambient temperature. The mixture was stirred for 2 hours at the same temperature and refluxed under stirring for 2 hours. The reaction mixture was cooled in an ice-bath. The resultant precipitates were filtered off and washed with THF. The filtrate and washing were combined and concentrated in vacuo to afford a residue. The residue was dissolved into chloroform (100 ml) and extracted with 1N-HCl aqueous solution (2×25 ml). The aqueous layer was alkalined with sodium bicarbonate, extracted with chloroform (2×100 ml), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate to afford (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-1H-1,4-benzodiazepin-2-one as a colorless crystalline solid (0.30 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=1[S:28]([NH2:31])(=[O:30])=[O:29].Cl>O>[N+:22]([C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([S:28](=[O:30])(=[O:29])[NH2:31])[C:16]=1[O:13][C:12]1[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][CH:11]=1)[C:25]([OH:27])=[O:26])([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
124 g (0.9 mol) of potassium carbonate are dissolved in 800 ml of water. To this solution, there are added portionwise 1.6 mols of p-cresol and subsequently 112 g (0.4 mol) of 2-chloro-3-nitro-5-carboxy-benzenesulphonamide and the solution is heated to 85° C. The whole is stirred for 16 hours at this temperature, cooled to 25°-30° C and acidified with concentrated hydrochloric acid to pH 1. The oil which thereupon separates is isolated from the aqueous phase and subjected to steam distillation. Alternatively, it is also possible to adjust a pH-value of 8-9, to extract the excess phenol with ethyl acetate and then to acidify the aqueous phase. After having separated in this manner the excess p-cresol, the product crystallises upon cooling. By recrystallisation from acetone/H2O, the 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid melting at 236° C is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][S:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:32])[F:33])[CH:23]=4)(=[O:30])=[O:29])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=c1[nH]c2nccc(Oc3cccc(NS(=O)(=O)c4cccc(OC(F)(F)F)c4)c3)c2[nH]1
Yield: 84 %

Procedure:
Method K was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(trifluoromethoxy)benzenesulfonyl chloride to afford the title compound as an off-white solid (51 mg, 84%). 1H-NMR (δ, ppm, DMSO-d6): 6.20 (br s, 1H, HPy,5), 6.78 (s, 1H, Harom), 6.86 (d, 1H, Harom, J=7.5 Hz), 6.98 (d, 1H, Harom, J=7.4 Hz), 7.31-7.35 (m, 1H, Harom), 7.64-7.86 (m, 5H, Harom), 10.57 (s, 1H, NHSO2), 11.13 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.18, 110.92, 113.71, 115.35, 116.48, 118.88, 121.88, 125.77, 125.83, 130.96, 131.93, 138.77, 141.03, 141.15, 144.12, 147.19, 148.23, 154.15, 154.99. HRMS (EI): m/z [M+H] calcd for C19H14F3N4O5S: 467.0637; found: 467.0644.
Reaction SMILES: [CH:1]1([N:7]([CH3:16])[C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH:33]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)[N:34]2[CH2:35][CH2:36][N:37]([C:9](=[O:11])[C@@H:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH3:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:38][CH2:39]2)=[CH:45][CH:44]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCCCC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N(C)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (0.200 g, 0.880 mmol, Example 21, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.389 mL, 1.76 mmol) and solid O-benzotriazol-1-yl-N,N,N,′,N′-tetramethyluronium hexafluorophosphate (0.334 g, 0.880 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.254 g, 0.880 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 90 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (30% EtOAC in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.39 g (78%) of the pure titled compound as a white solid; mp 171-182° C. APCI-MS m/z 498.3 (MH+).