Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[NH2:15][C:16]1[N:42]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:41])=[C:29]([NH:31][C:32]([C:34]4[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=4)=[O:33])[CH:30]=3)=[CH:23][N:18]2[N:17]=1>O1CCCC1.CN(C)C=O.O>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:15][C:16]1[N:42]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:41])=[C:29]([NH:31][C:32]([C:34]4[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=4)=[O:33])[CH:30]=3)=[CH:23][N:18]2[N:17]=1)=[O:6]
Reactant: O=C(O)C1CC1(F)F
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2F)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5(F)F)nn4c3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 2,2-difluorocyclopropanecarboxylic acid (104 mg, 0.850 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (74.3 μL, 0.850 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-{5-[(2-Amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (65.0 mg, 0.170 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20→0/100) and recrystallized from ethyl acetate to give the title compound (22.0 mg, 27%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl>CO.ClCCl>[NH2:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](CNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC[C@H]1CC[C@@H](CNc2nccc(-c3cc4ccccc4s3)n2)CC1
Temperature: 110 °C
Yield: 90 %

Procedure:
A solution of cis-{4-[(4-benzo[b]thiophen-2-yl-pyrimidin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (20 mg, 0.044 mmol) in MeOH (2 mL) is treated at ambient temperature with 10% HCl (2 mL), and the mixture is heated at 110° C. for 15 hours. At ambient temperature the mixture is diluted with dichloromethane (10 mL), washed with 1N NaOH (2 mL), and dried (MgSO4). After concentration in vacuo, the title compound is obtained (15.6 mg, 90% yield). ES+(m/z) 353 [M+H].
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)=[O:10].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH3:21][C:12]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:10])=[CH:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)CCCC1=O
Reactant: Sc1ccccc1
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Sc2ccccc2)CCCC1=O
Reaction time: 1.5 h

Procedure:
4.0 g (0.0134 mol) of 3-hydroxy-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-2-enone (compound A2-B1) are suspended in 25 ml of oxalyl chloride, and 0.1 ml of dimethylformamide is subsequently added dropwise. After the vigorous evolution of gas has ceased, the mixture is held for 1.5 hours at a bath temperature of 45° C. and subsequently concentrated, and the residue (3-chloro-2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-cyclohex-2-enone) is dissolved in 60 ml of methylene chloride. Triethylamine (3.7 ml, 0.0268 mol), dimethylaminopyridine (160 mg, 1.34 mmol) and 1.5 ml (0.0147 mol) of thiophenol are added at a temperature of 0-5° C. After 20 hours at a temperature of 22° C., the reaction mixture is concentrated and purified on silica gel (hexane/ethyl acetate 5:1). Trituration in hexane gives pure 2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-3-phenylsulfanylcyclohex-2-enone in the form of white crystals of melting point 124-125° C. 1H-NMR (CDCl3): 1.99, m, 2H; 2.41, m 4H; 2.80, s, 3H; 2.60: 7.40-7.60, m, 6H; 7.80 ppm, d(J, 8.2 Hz), 1H.
Reaction SMILES: [NH:1]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([O:55]CC1C=CC=CC=1)=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:66]([O:68][C:69]([CH3:70])([CH3:72])[CH3:71])=[O:67])[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([OH:55])=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:14])=[O:15])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
At 0° C. to the solution of 230 mg (0.221 mmol) of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14) in 6 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 180 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(C)([O-])C.[Na+].[CH3:27][S:28](Cl)(=[O:30])=[O:29].CN(C=O)C>C1COCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:28]([CH3:27])(=[O:30])=[O:29])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(C)(=O)=O)c23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.2 %

Procedure:
To a stirred solution of 2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (Description 17) (277 mg, 0.793 mmol) in THF (2.5 mL) at RT, was added sodium tert-butoxide (220 mg, 2.289 mmol). The reaction mixture was stirred at RT for 15 min, followed by the addition of methane sulfonyl chloride (0.14 mL, 1.797 mmol). The reaction mixture was stirred at 1 h at RT, followed by the addition of DMF (2.5 mL), another portion of sodium tert-butoxide (203 mg, 2.112 mmol) and methane sulfonyl chloride (0.14 mL, 1.797 mmol). The reaction mixture was stirred for another 1 h at RT before the addition of water (20 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with water (15 mL), dried (phase separating column) and concentrated to give a residue. Purification on silica (twice), eluting with a gradient of 0-75% ethyl acetate in cyclohexane afforded the title compound (109 mg) which was of sufficient purity for subsequent steps. In addition, some impure fractions were isolated and these were combined and further purified by MDAP (acidic conditions), to give an analytically pure sample of the title compound (9 mg). LCMS (A) m/z: 427/429 [M+1]+, Rt 1.33 min (acidic).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:24])[C:7]1[C:8]([Br:23])=[CH:9][CH:10]=[C:11]([NH:19][C:20](=[O:22])[CH3:21])[C:12]=1[C:13]2=[O:18])([O-:3])=[O:2].[OH-].[K+].[CH3:27]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:24])[C:7]1[C:8]([Br:23])=[CH:9][CH:10]=[C:11]([N:19]([CH3:27])[C:20](=[O:22])[CH3:21])[C:12]=1[C:13]2=[O:18])([O-:3])=[O:2]
Reactant: CI
Reactant: CC(=O)Nc1ccc(Br)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of 5-nitro-4-bromo-1-acetylaminoanthraquinone (purity 98%, 38.7 g), monochlorobenzene (460 g), tetra-n-butyl ammonium bromide (0.3 g) and 96% potassium hydroxide (12.0 g) was stirred for 1 hour at 30° C., and then methyl iodide (28.4 g) was added at 30° C. over 2 hours. The same after-treatment as in Example 3 was conducted to obtain 5-nitro-4-bromo-N-acetyl-1-methylaminoanthraquinone (39.3 g, purity 92.3%, yield 92.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][O:28][NH2:29])([CH3:22])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:29][O:28][CH2:27][CH2:26][NH:25][C:24](=[O:30])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCON
Product: CC(C)(C)OC(=O)NCCON=C(c1ccc(Cl)cc1)c1cc2ccncc2[nH]1

Procedure:
tert-Butyl 2-[[[(4-chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate was prepared from (4-chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 103) and tert-butyl[2-(aminooxy)ethyl]carbamate following the procedure described for Example 104. Purification by Biotage chromatography (silica, 2 to 15% methanol in methylene chloride) provided tert-butyl 2-[[[(4-chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (geometry of the oxime double bond undefined).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.S(Cl)([Cl:18])=O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:18])[CH:9]=2)=[N:6][CH:7]=1
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccc(-c2ncc(Br)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
80 g (302 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol are suspended in 300 ml of dichloromethane, and 33 ml (453 mmol) of thionyl chloride are slowly added with cooling. The reaction mixture is stirred at room temperature for 3 h. The solvent was distilled off, co-evaporated 3 times with toluene and stirred with diethyl ether:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]([F:34])[F:33])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.S(Cl)(C)(=O)=O.[NH2:49][CH:50]1[C:75](=[O:76])[N:52]2[C:53]([C:59]([O:61][CH:62]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[O:60])=[C:54]([CH2:57][Cl:58])[CH2:55][S:56][C@H:51]12.C[Si](C)(C)NC(=O)C>CN(C)C=O.C(Cl)Cl.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]([F:33])[F:34])[C:27]([NH:49][CH:50]2[C:75](=[O:76])[N:52]3[C:53]([C:59]([O:61][CH:62]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[O:60])=[C:54]([CH2:57][Cl:58])[CH2:55][S:56][C@H:51]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 105.8 %

Procedure:
A mixture of 2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetic acid (syn isomer) (2.4 g) and diisopropylethylamine (1.29 g) in N,N-dimethylformamide (35 ml) was cooled to -30° C. and mesyl chloride (1.15 g) was added dropwise thereto. The mixture was stirred at -20° to -30° C. for 30 minutes to give an activated acid solution. On the other hand, a mixture of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (2.18 g) and N-trimethylsilylacetamide (5.25 g) in methylene chloride (20 ml) was stirred to be a clear solution for 30 minutes at room temperature and then cooled to -20° C. To this solution was added the activated acid solution obtained above in one portion. The mixture was stirred for 30 minutes at -15° to -10° C., poured into water and extracted with ethyl acetate. The extract was washed with water three times, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)- 2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (4.64 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1.[O:27]1CCOCC1>Br.CC(O)=O>[NH2:1][C:2]1[C:3]([C:25]([NH2:26])=[O:27])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1
Reactant: C1COCCO1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2Br)ccc1=O
Agent: Br
Solvent: CC(=O)O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2Br)ccc1=O
Temperature: 22.5 °C
Reaction time: 5 h

Procedure:
A mixture of 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile (59 mg) in 25% hydrogen bromide in AcOH (0.36 ml) was stirred at 20-25° C. for 5 hours. Dioxane (3 ml) was added to the mixture to give a precipitate. The precipitate was collected by filtration and suspended in sat. aq. NaHCO3 to give a solid. The solid was collected by filtration and dried under reduced pressure to give 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (17 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29](=[O:32])[CH2:30][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=2)[CH:11]=[CH:12]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.4 %

Procedure:
To an ice cold solution of 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (13 g, 52.5 mmol) and cesium carbonate (18.8 g, 57.8 mmol) in DMF (130 ml) under an argon atmosphere was added bromo-acetic acid tert-butyl ester (8.5 ml, 57.8 mmol). The mixture was naturally warmed to room temperature, stirred for 14 h, poured onto 2 N HCl/ice water 1/1 and extracted two times with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 14.3 g (39.6 mmol, 75%) of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.OS(O)(=O)=O.[BrH:15].N(C(C)(C)C#N)=NC(C)(C)C#N.OO>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:15])=[C:4]([F:9])[CH:3]=1
Reactant: Br
Reactant: Cc1ccc(Cl)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: Clc1ccccc1
Product: Fc1cc(Cl)ccc1CBr

Procedure:
361.5 g of 4-chloro-2-fluorotoluene, 520 g of chlorobenzene, 6 g of conc. H2SO4, 467 g of 47% strength hydrobromic acid and 2.7 g of 2,2'-azobis(2-methylpropionitrile) were mixed at 70° C. in a 4 l stirred apparatus. 620.5 g of a 10% strength aqueous hydrogen peroxide solution and a solution of 16.5 g of 2,2'-azobis(2-methylpropionitrile) in 270 g of chlorobenzene were simultaneously added dropwise over the course of 1.5 hours. The mixture was then stirred at 70° C. for 1 hour. GC analysis of the org. phase:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2Cl.Cl.[NH:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[N:16]=[CH:15]1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu-]=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[N:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[N:16]=[CH:15]1
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Reactant: Clc1ccnc2c(Br)cccc12
Agent: O=[Cu-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cn1cc(-c2cn(-c3ccnc4c(Br)cccc34)cn2)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in 2-propanol (240 ml) was heated to reflux for 1 hour. The reaction solution was cooled to 0° C., and the deposit was then filtrated to obtain a pale yellow solid (35.0 g). A suspension of the obtained pale yellow solid (10.0 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). Thionyl chloride (5.9 ml) was added to 8-bromoquinolin-4(1H)-one (9.0 g), and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-bromo-4-chloroquinoline (8.3 g) as a white solid. The obtained 8-bromo-4-chloroquinoline (0.050 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.045 g), 8-quinolinol (0.0045 g), copper(I) oxide (0.0015 g), PEG (Mn=3400) (0.010 g), and cesium carbonate (0.17 g) were suspended in DMSO (2.1 ml). The suspension was purged with nitrogen, then sealed in the tube, and stirred at 110° C. for 2 hours. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate to obtain 8-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline as a pale yellow solid (0.073 g). Compound (119) was obtained as a pale yellow solid (yield based on 6 steps: 17%) according to Example 1(5) using the obtained 8-bromo-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline instead of compound (1d).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[CH:14]=[C:9]2[C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7]1)(C)(C)C.Br[C:40]1[C:44]([CH3:45])=[CH:43][S:42][CH:41]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.CCOC(C)=O.CC#N.CC#N.Cl[Pd]Cl>[CH3:23][N:21]([CH3:22])[C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:14]=[C:9]3[C:8]([C:40]4[C:44]([CH3:45])=[CH:43][S:42][CH:41]=4)=[CH:7][NH:6][C:10]3=[N:11][CH:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1cscc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn([Si](C)(C)C(C)(C)C)c2ncc(-c3ccc(N(C)C)cc3)cc12
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cscc1-c1c[nH]c2ncc(-c3ccc(N(C)C)cc3)cc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A mixture of 7 (129.7 mg, 0.186 mmol), 3-bromo-4-methylthiophene (30 μL, 0.30 mmol), PdCl2(MeCN)2 (4.8 mg, 18.6 μmol), tri-o-tolylphosphine (11.4 mg, 37.5 μmol) in toluene (1.7 mL) was stirred under N2 at 85° C. overnight. The reaction mixture was cooled to r.t., diluted with AcOEt (3 mL), and extracted with 10% aqueous HCl ((4×0.5 mL). combined aqueous solutions were washed with CH2Cl2 (2 mL), and basified with 10% aqueous NaOH (2.5 mL). The mixture was extracted with CH2Cl2:MeOH=19:1 (4×3 mL). Combined extracts were washed with brine, dried (MgSO4), and concentrated in vacuum. The residue was purified by preparative TLC using CH2Cl2:MeOH=19:1 as eluent to afford 8 (12.9 mg, 21%) as tan solid. 1H NMR (400 MHz, CDCl3) δ 2.34 (d, J=1.0 Hz, 3H), 3.01 (s, 6H), 6.85 (d, J=8.9 Hz, 2H), 7.10 (dq, J=3.3, 1.0 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 7.41 (d, J=1.2 Hz, 1H), 7.53 (d, J=8.9 Hz, 2H), 8.14 (d, J=2.1 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H), 10.00 (bs, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][N:9]=1)([OH:7])[CH3:6].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C1COCC1.O>[F:19][C:4]([F:3])([F:18])[C:5]([O:7][S:21]([CH3:20])(=[O:23])=[O:22])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][N:9]=1)[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C(C)(O)C(F)(F)F)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(OS(C)(=O)=O)C(F)(F)F)nc1
Reaction time: 3 h

Procedure:
To a stirred mixture of 0.213 g (8.44 mmol) sodium hydride in 6 ml dry THF, 1.06 g (4.22 mmol) 1,1,1-trifluoro-2-(5-methoxymethoxy-pyridin-2-yl)-propan-2-ol (dissolved in 4.9 ml dry THF) was added dropwise at 0° C. After completion of the addition, stirring was continued for 3 h at room temperature. Then methanesulfonyl chloride (dissolved in 7.3 ml dry THF) was added at room temperature and stirring was continued for another 2 h. Then water and sat. NaHCO3 soln. were added. This mixture was extracted 2 times with EtOAc. The combinded organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 1.7 g of the title compound, which was used directly in the next step. LCMS (method L): tR=0.96 min, M+H=330.