Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[B-](F)(F)(F)[CH:26]=[CH2:27].[K+].C(N(CC)CC)C>C(O)CCC>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH:26]=[CH2:27])=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (2.00 g, 5.18 mmol), potassium trifluoro(vinyl)borate (1.51 g, 11.3 mmol), butan-1-ol (20 ml), triethylamine (1.05 ml, 7.53 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.31 g, 0.38 mmol) were combined and heated at 100° C. for 20 hours. The mixture was cooled, concentrated under vacuum and taken up in dichloromethane (120 mL). It was washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under vacuum. The residue was triturated with ethyl acetate (15 mL) for 20 hours, filtered, washed with cold ethyl acetate and suction dried to afford 1.09 g (63%) of the title compound as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 5.52 (d, J=10.92 Hz, 1H), 5.75 (s, 2H), 5.98 (d, J=17.57 Hz, 1H), 6.75-6.88 (m, 3H), 7.60 (d, J=8.66 Hz, 2H), 8.36 (s, 1H), 8.66 (d, J=2.13 Hz, 1H), 8.79 (d, J=2.26 Hz, 1H). LCMS (MH+, 334.1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]2[N:13]=[C:14]3[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:18][CH:17]=[C:16]([C:26]4[CH:27]=[CH:28][C:29]([N:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)=[O:39])[CH2:34][CH2:33]5)=[N:30][CH:31]=4)[N:15]3[CH:48]=2)[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].ClC1[CH:65]=[CH:64][C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[N:57]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[O:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[N:15]([CH:48]=[C:12]([CH:10]4[CH2:9][N:8]([C:6]5[CH:65]=[CH:64][C:63]6[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=6)[N:57]=5)[CH2:11]4)[N:13]=3)[C:16]([C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[O:39])[CH2:34][CH2:33]4)=[N:30][CH:31]=3)=[CH:17][N:18]=2)[CH2:21][CH2:22]1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3c(-c4ccc(N5CCN(C(=O)OCc6ccccc6)CC5)nc4)cnc(N4CCOCC4)c3n2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(C5CN(c6ccc7ccccc7n6)C5)cn34)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 29c (275 mg, 0.420 mmol) in DCM (3 mL), TFA (2 mL) was added. The resulting mixture was stirred at rt for 2 h and concentrated. The residue obtained was dried under reduced pressure overnight and re-dissolved in EtOH (5 mL). Na2CO3 (1.00 g, 9.50 mmol) and 2-chloroquinoline (234 mg, 1.43 mmol) were then added and the resulting mixture was heated at reflux for 5 h. The reaction mixture was allowed to cool to rt, diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtOA/heptane) to obtain compound 29d. Mass Spectrum (LCMS, ESI pos.) Calcd. for C39H39N9O3: 682.3 (M+H). Found 682.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29](O)=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH2:72].Cl>CN(C=O)C.O>[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH:72][C:29]([C:26]1[S:27][CH:28]=[C:24]([C:20]2[CH:19]=[C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])=[O:11])=[CH:33][CH:32]=3)[CH:23]=[CH:22][N:21]=2)[CH:25]=1)=[O:30]
Reactant: COC(=O)CN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)O)c4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic acid (100 mg, 0.22 mmol), HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of glycine methyl ester hydrochloride (41 mg, 0.33 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give methyl{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate as white solid. Yield: 90 mg, 78%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][N:7]1[CH2:12][C:11]2[CH:13]=[C:14](Br)[CH:15]=[N:16][C:10]=2[NH:9][C:8]1=[O:18])[CH3:2].BrC1C=N[C:24]2NC(=O)N(CCN(C)C)[CH2:28][C:23]=2[CH:22]=1>>[C:23]([O:19][C:4](=[O:3])/[CH:5]=[CH:6]/[C:14]1[CH:15]=[N:16][C:10]2[NH:9][C:8](=[O:18])[N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH2:12][C:11]=2[CH:13]=1)([CH3:22])([CH3:24])[CH3:28]
Reactant: CCOC(=O)CCN1Cc2cc(Br)cnc2NC1=O
Reactant: CN(C)CCN1Cc2cc(Br)cnc2NC1=O
Product: CCOC(=O)CCN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Yield: 21 %

Procedure:
According to the procedure of Preparation 130(d), except substituting 3-(6-bromo-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)propionic acid ethyl ester for the 6-bromo-3-(2-dimethylamino-ethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one, the title compound (0.39 g, 21%) was prepared as a white solid: MS (ESI) m/e 376 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Cl:42].O>C(OC(OCC)C)C.C(OCC)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:42])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)OCC
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 90 %

Procedure:
A 200 mg quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 4.3 ml of diethoxyethane. The solution was cooled in an ice bath with stirring. Thereto was added dropwise over 3 minutes 1.73 ml of a 0.3M solution of HOCl in diethyl ether. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 191 mg of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 90% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc([N+](=O)[O-])ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-nitro-biphenyl-3-yl)-acetic acid ethyl ester and benzyl chloroformate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C-:16]#[N:17].[Na+].[Cl-].[Na+]>>[C:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:17]
Reactant: ClCc1ccc(Sc2ccccc2)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Product: N#CCc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.7 %

Procedure:
The 1-chloromethyl-4-phenylthiobenzene (3.0 g) is dissolved in N,N-dimemthylformamide (15 ml), and thereto is added finely divided sodium cyanide (1.0 g), and the mixture is stirred at room temperature for 17 hours. To the reaction mixture are added saturated aqueous sodium chloride solution (50 ml) and ice water (50 ml), and the mixture is extracted with ethyl acetate (100 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (50 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-cyanomethyl-4-phenylthiobenzene (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][N:16]=1>C1COCC1.O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: Clc1ccc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)nc2)c(Cl)c1

Procedure:
2-Chloro-4-nitrophenol (17.4 mmol) in 15 ml of THF is slowly added to a stirring suspension of sodium hydride (17.4 mmol) in 25 ml of THF. After gas evolution has ceased, 2-chloro-5-bromomethylpyridine is added and the mixture is heated under reflux overnight. The reaction is diluted with water, extracted with chloroform, washed with water, dried and stripped to give 2-chloro-5-(2-chloro-4-nitrophenoxy)methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:19]([NH:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)c1ccc(N)s1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)s1
Reaction time: 20 h

Procedure:
To a solution of 8.6 g. of ethyl 5-amino-2-thiophenecarboxylate and 25 ml. of triethylamine in 100 ml. of methylene chloride is added dropwise 16.5 g. of palmitoyl chloride. The reaction mixture is stirred for 20 hours. Evaporation affords an oil. A methylene chloride solution of the oil is filtered and the filtrate passed through Magnesol. Removal of the solvent by evaporation yields a solid which is recrystallized from hexane. A second recrystallization from carbon tetrachloride affords the product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[N:6][N:5]=1.I[CH2:16][CH3:17]>CN(C=O)C>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[N:6]([CH2:16][CH3:17])[N:5]=1
Reactant: CCI
Reactant: Oc1nnc(Cl)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(Cl)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil, (0.480 g, 12.00 mmol) in DMF (50 mL) was added 4-chlorophthalazin-1-ol (1.806 g, 10 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of iodoethane (2.339 g, 15.00 mmol) in DMF (50 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The formed light yellow solid was filtered off and washed the cake with THF. The filtrate was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by silica gel chromatography eluting with 20% EtOAc in hexanes to afford 1.8 g of the desired product 4-chloro-2-ethylphthalazin-1(2H)-one as an oil. MS: MS m/z 209.06 (M++1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52-8.42 (m, 1H), 8.04-7.98 (m, 1H), 7.88 (dtd, J=18.5, 7.5, 1.5 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl-:1].[Cl-].[NH3+:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:24]=[CH:23][C:14]([NH:15][C:16]3[CH:21]=[CH:20][N+:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl>CO>[Cl-:27].[Cl-:1].[CH3:22][N+:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[CH:23]=[CH:24][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:25]=[CH:26][C:4]([NH:3][C:28]4[C:37]5[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[CH:5][CH:6]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1.[CH3:22][N+:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[CH:23]=[CH:24][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:25]=[CH:26][C:4]([NH:3][C:28]4[C:37]5[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[CH:5][CH:6]=3)=[CH:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ccnc2c1
Reactant: C[n+]1ccc(Nc2ccc(NC(=O)c3ccc([NH3+])cc3)cc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: C[n+]1ccc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5cc([N+](=O)[O-])ccc45)cc3)cc2)cc1
Reaction time: 65 h

Procedure:
To a solution of amine B7 (1.46 g, 3.73 mmol) in dry MeOH (20 mL) were sequentially added 4-chloro-7-nitroquinoline (S1) (0.78 g, 3.73 mmol) and two drops of c.HCl, and the resulting mixture was refluxed for 4 h. After this time, the temperature was reduced to ˜40° C. and heating was continued for a further 65 h. After this time, solvent was removed under reduced pressure. The residue was re-dissolved in MeOH, and solvent was again removed under reduced pressure. This latter process was repeated once more, and the residue was then re-precipitated twice from MeOH:Et2O. Finally, a portion of the solid thus obtained was re-precipitated from MeOH:EtOAc to afford Cpd. S as an amorphous yellow-orange solid (0.070 g, 3%). 1H NMR [(CD3)2SO]: 3.96 [S, 3H, R2N+CH3], 7.14 [m, 3H, ArH], 7.35 [d, J=8.85 Hz, 2H, ArH], 7.68 [d, J=8.57 Hz, 2H, ArH], 7.96 [d, J=8.85 Hz, 2H, ArH], 8.18 [d, J=8.57 Hz, 2H, ArH], 8.26 [d, J=7.37 Hz, 2H, ArH], 8.50 [dd, J=9.28, 2.23 Hz, 1H, ArH], 8.77 [d, J=6.65 Hz, 1H, ArH], 8.94 [d, J=2.23 Hz, 1H, ArH], 9.08 [d, J=9.28 Hz, 1H, ArH], 10.55 [s, 1H, ArNHAr], 10.71 [s, 1H, ArNHAr], 11.21 [br s, 1H, ArC(O)NHAr], 11.21 [v v br s, 1H, quinoline-N+H]; LCMS (APCl+): 492 (100%), 493 (30%). HPLC: 98.1%.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]1([N:22]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27](C(O)=O)=[CH:28]3)=[N:23]2)[CH2:21][CH2:20][CH2:19]1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(N(CC)CC)C>[CH:18]1([N:22]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27]([NH2:15])=[CH:28]3)=[N:23]2)[CH2:21][CH2:20][CH2:19]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2nn(C3CCC3)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1ccc2nn(C3CCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Diphenylphosphoryl azide (4.15 mL) and triethylamine (3.76 mL) were added to a solution of 2-cyclobutyl-2H-indazole-5-carboxylic acid obtained in the above-described Step 1 (3.26 g) in 1,4-dioxane (50 mL), and the reaction solution was stirred at room temperature for 2 hours and 20 minutes. Thereafter, 1 N hydrochloric acid (100 mL) was added to the reaction solution, and then the reaction solution was stirred at 100° C. for 30 minutes. The reaction solution was cooled to room temperature, and potassium carbonate (14 g) was slowly added. The reaction solution was extracted with ethyl acetate, and then the organic layer was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-cyclobutyl-2H-indazol-5-amine as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>>[Cl:8][C:5]1[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:3][C:2]([C:34]2[CH:35]=[CH:36][C:30]3[O:29][CH2:28][CH2:27][N:26]([C:20]4[C:19]5[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=5)[N:23]=[CH:22][N:21]=4)[CH2:32][C:31]=3[CH:33]=2)=[CH:7][N:6]=1
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(Cl)c(NS(C)(=O)=O)c5)cc4C3)ncnc2c1

Procedure:
Synthesized according to the method of example 5 using N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (reagent preparation 25) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.92 (br s, 1H), 8.75 (s, 1H), 8.62 (d, 1H), 8.19 (d, 1H), 8.10 (d, 1H), 7.89 (s, 1H), 7.62 (dd, 1H), 7.33 (dd, 1H), 7.25 (d, 1H), 7.04 (d, 1H), 5.41 (s, 2H), 4.65 (s, 2H), 4.47 (s, 2H), 3.96 (s, 3H), 3.19 (s, 3H); MS (EI) for C24H22ClN5O4S: 514 (MH+).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1.Cl>C1COCC1.CO.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 0 °C
Yield: 32.3 %

Procedure:
Lithium hydroxide (3.29 g, 78.5 mmol) was added to a stirred solution of (+/−)-ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.50 g, 78.5 mmol) in THF:MeOH:water (2:2:1, 225 mL) at 0° C. The reaction was warmed to room temperature as the ice bath expired. After 18 hours the reaction was acidified to pH 4 with 1N HCl (aq) and extracted with ethyl acetate (2×). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give a white solid (8.5 g, 97%). LCMS m/z 333.1 (M−1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3H) 1.95-2.05 (m, 1H) 2.30-2.48 (m, 2H) 2.67-2.79 (m, 1H) 3.10 (s, 3H) 3.26 (br. s., 1H) 7.17-7.24 (m, 2H) 7.43-7.52 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)=[N:5][N:6]=1.Br[CH2:13][CH2:14][C:15]([F:19])=[C:16]([F:18])[F:17]>O1CCOCC1.CN(C)C=O>[F:19][C:15](=[C:16]([F:18])[F:17])[CH2:14][CH2:13][S:1][C:2]1[O:3][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)=[N:5][N:6]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1nnc(C2CCCO2)o1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: FC(F)=C(F)CCSc1nnc(C2CCCO2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1594.3 %

Procedure:
2.1 g (0.019 mol) of potassium t-butylate are introduced into a solution of 3.2 g (0.018 mol) of 2-mercapto-5-(tetrahydrofuran-2-yl)-1,3,4-oxadiazole in a mixture of 80 ml of 1,4-dioxane and 10 ml of dimethylformamide. 4.9 g (0.026 mol) of 1-bromo-3,4,4-trifluoro-3-butene are then added dropwise at 25° C. and the reaction mixture is stirred at room temperature for 16 hours. The solvent mixture is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. This solution is extracted with water, ice-cold 1 N sodium hydroxide solution and water in succession, dried with sodium sulfate and filtered and the solvent is distilled off under reduced pressure. 80.43 g of the desired product are obtained as a yellow oil (nD27 =1.4904).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.F[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1S(C)(=O)=O>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: COC(=O)c1ccc(F)c(S(C)(=O)=O)c1
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(Oc2ccc(C(=O)OC)cc2)cc1
Reaction time: 336 h

Procedure:
By reacting ethyl 4-hydroxybenzoate with methyl 4-fluoro-3-methylsulfonylbenzoate in analogy with the protocol given under 14 d) methyl 4-(4-ethoxycarbonylphenoxy)-benzoate was obtained as a colorless to pale-yellow oil which was hydrolyzed, without any further purification steps, in analogy with the manner indicated in protocol 16 c), to give 4-(4-carboxyphenoxy)-3-methylsulfonyl-benzoic acid.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[CH3:8][N:9]1[CH2:14]COCC1.[NH2:15][C@H](C(NC1C=CC=CC=1)=O)CC(C)C>CN(C=O)C.CCOC(C)=O>[CH3:8][N:9]([CH3:14])[C:1]1[CH:6]=[CH:5][N:15]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccccc1
Reactant: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)c1ccncc1
Reaction time: 0.17 h
Yield: 83 %

Procedure:
The crude carboxylic acid (45 mg, 0.11 mmol) was dried by evaporation of a toluene solution and then dissolved in DMF (0.40 mL). Molecular sieves (4 Å, 0.16 g) and N-methylmorpholine (0.027 mL, 25 mg, 0.25 mmol) were added. After 10 min., benzotfiazol-1-yloxytris(dimethylamino)phosphonium hexafiuorophosphate (60 mg, 0.14 mmol) was added and the solution was stirred for 40 min. before the addition of L-leucine anilide (28 mg, 0.14 mmol). After 1.5 h at room temperature, the solution was diluted with 20 mL of EtOAc and washed with 2 N aq. HCl (10 mL), saturated aq. NaHCO3 (10 mL), and saturated aq. NaCl (10 mL). The organic layer was dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel (4.7 g) eluting with 100 mL of 3% EtOAc/dichloromethane gave 55 mg (83% yield) of the title compound as a colorless film. NMR (400 MHz, CDCl3) indicated a 1:1 mixture of diastereomers: δ8.50 (s, 1 H), 7.47 (d, 2H, J=7 Hz), 7.38-7.29 (m, 5H), 7.25 (t, 2H, J=7 Hz), 7.06 (t, 1H, J=7 Hz), 7.04 (d, 1H, J=8 Hz), 7.02 (d, 1H, J=8 Hz), 6.96 (d, 1H, J=8 Hz), 6.93 (d, 1H, J=8 Hz), 6.21 (d, 0.5H, J=8 Hz), 6.16 (d, 0.5H, J=8 Hz), 5.11 (s, 2H), 4.66 (bq, 1H, J=7 Hz), 2.95 (quintet, 0.5 H, J=8 Hz), 2.92 (quintet, 0.5H, J=8 Hz), 2.60-2.37 (m, 5H), 2.16-2.06 (m, 1H), 2.00-1.54 (m, 11H), 0.99 (d, 3H, J=6 Hz), 0.97 (d, 1.5H, J=6 Hz), 0.96 (d, 1.5 H, J=6 Hz), 0.93 (t, 1.5H, J=7 Hz), 0.92 (t, 1.5H, J=7 Hz).