Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17].Cl>O1CCCC1.O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:14])[C:16]([F:19])([F:18])[F:17])[C:10]([CH3:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1nn(Cc2ccccc2)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(Cc2ccccc2)cc1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde (compound 314.2, 1.20 g, 5.99 mmol) in tetrahydrofuran (15 mL) was added CF3SiMe3 (1.33 mL, 9.01 mmol) and TBAF (0.11 mL, 0.11 mmol, 1M solution in THF). The mixture was stirred for 10 min at room temperature under nitrogen. This was followed by the addition of aqueous HCl (6 M) (1 mL). The reaction mixture was stirred for another 10 min at room temperature, then diluted with 50 mL of H2O. The aqueous phase was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/5-1/2) as the eluent to furnish 1.15 g (71%) of the title compound as a light yellow solid.
Reaction SMILES: C(O)C.C(O[C:7](=[NH:37])[C:8]1[CH:36]=[CH:35][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:34]=[CH:33][C:29]([C:30](=[NH:32])[O-:31])=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1)C.Cl.[CH2:39]([O:41][NH2:42])[CH3:40].[OH-].[Na+]>O.C(Cl)(Cl)Cl.C(N(CC)CC)C>[NH2:37][C:7](=[N:42][O:41][CH2:39][CH3:40])[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)=[CH:35][CH:36]=1
Reactant: CCON
Reactant: CCOC(=N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)[O-])cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To an ethanol (8 mL) suspension of 0.20 g of ethyl=4-{3-[4-(3-{4-[ethoxy(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzimidate were sequentially added 0.39 g of O-ethylhydroxylamine hydrochloride and 0.84 mL of triethylamine under cooling with ice, which was then stirred at room temperature for 3.5 days. The reaction mixture was added to a mixture of chloroform and water, which was then adjusted to pH 9.7 using a 20% sodium hydroxide aqueous solution. The organic layer was separated, washed with water, and then dried with anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:ethanol=20:1) to provide 0.20 g of 4-{3-[4-(3-{4-[amino(ethoxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-ethyloxime as white solid form.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[CH:17][C:18]2[N:24]([CH3:25])[CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:43])[CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:31][CH:30]=3)=[O:27])=[CH:20][C:19]=2[CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:10]([S:9][C:6]1[CH:7]=[CH:8][C:3]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH3:25])[CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([CH2:35][N:36]([CH3:43])[CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:33][CH:34]=4)=[O:27])=[CH:20][C:19]=3[CH:44]=2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCSc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCSc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
In water/ethanol/toluene (1:1:10, 18.0 ml) were dissolved 4-ethylthiophenyl borate (264 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (439 mg), and to the mixture was added potassium carbonate (301 mg). Under argon atmosphere, the mixture was stirred for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (42 mg). Under argon atmosphere, the mixture was refluxed for 17.5 hours, and the mixture was dilute with ethyl acetate (200 ml). The mixture was washed with water (50 ml) and saturated brine (50 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, ethyl acetate→ethyl acetate/ethanol=9:1) and recrystallized from ethanol to give 7-(4-ethylthiophenyl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 320) (168 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH:11]2[CH2:13][CH2:12]2)[CH2:9][OH:10])[CH:7]=1.CC(C)([O-])C.[K+]>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH:11]3[CH2:13][CH2:12]3)[NH:14][C:15](=[O:18])[CH2:16][O:10][CH2:9]2)[CH:7]=1
Reactant: O=C(CCl)NC(CO)(c1cc(Br)ccc1F)C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=C1COCC(c2cc(Br)ccc2F)(C2CC2)N1

Procedure:
In an analogous manner to that described for the preparation of Building block A [e)], the cyclization of (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-1-cyclopropyl-2-hydroxy-ethyl]-2-chloro-acetamide with potassium tert-butoxide in tent-butanol at room temperature overnight yielded the (RS)-5-(5-bromo-2-fluoro-phenyl)-5-cyclopropyl-morpholin-3-one as a yellow oil (2.146 g, 88% of theory). Mass (calculated) C13H13BrFNO2 [314.153]; (found) [M+H]+=314, [M+2-H]+=316.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:19]1[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: CC1CNCC(C)C1
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CC(C)CC(C)C1

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 3,5-dimethylpiperidine. Yield: 0.4 g (48.1% of theory); C16H24N2O4 (M=308.38); calc.: molecular ion peak (M+H)+: 309; found: molecular ion peak (M+H)+: 309; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]=[C:15]3[C:10]([C:11]([C:18]([NH2:20])=[O:19])=[CH:12][C:13]([F:17])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].F[B-](F)(F)F>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[F:17][C:13]1[CH:12]=[C:11]([C:18]([NH2:20])=[O:19])[C:10]2[C:15](=[CH:16][N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)=[CH:3][CH:4]=3)[N:9]=2)[CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: NC(=O)c1cc(F)cc2cn(-c3ccc(Br)cc3)nc12
Agent: [Pd]
Agent: F[B-](F)(F)F
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)cc2cn(-c3ccc(-c4cccnc4)cc3)nc12
Temperature: 25 °C

Procedure:
A mixture of (D3) (1.0 eq) and pyridine-3-boronic acid (1.3 eq) in DMF (1.0 M) together with 2N Na2CO3 solution (2.0 eq) was degassed with a stream of Ar for 30 min. tBu3PH+BF4− (0.05 eq) and Pd2(dba)3 (0.05 eq) were added and the reaction mixture was heated at 90° for 48 h. The mixture was cooled to RT, DCM was added and the organic phase was washed with sat. aq. NaHCO3 solution, brine, dried (Na2SO4). The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 50-90% EtOAc/Petroleum ether then 10% MeOH/DCM to obtain the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.40 (1H, s), 9.01 (1H, d, J=1.6 Hz), 8.63 (1H, dd, J=4.8, 1.6 Hz), 8.57 (1H, br. s), 8.32 (2H, d, J=8.8 Hz), 8.20 (1H, d, J=7.8 Hz), 8.10 (1H, br. s), 8.01 (2H, d, J=8.8 Hz), 7.88-7.82 (2H, m), 7.54 (1H, dd, J=7.8, 4.8 Hz). MS (ES) C19H13FN4O requires: 332. Found: 333 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:23]([O-])=O)=[C:12]([C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3I)=[O:15])[CH:13]=2)=[CH:5][CH:4]=1.ClC1C=CC(CC2C=CC([N+]([O-])=O)=C(C(C3N(C)N=CC=3I)=O)C=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:23][C:17]4[CH:18]=[N:19][N:20]([CH3:21])[C:16]=4[C:14](=[O:15])[C:12]=3[CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2ccc([N+](=O)[O-])c(C(=O)c3c(I)cnn3C)c2)cc1
Agent: Cn1ncc(I)c1C(=O)c1cc(Cc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Product: COc1ccc(Cc2ccc3[nH]c4cnn(C)c4c(=O)c3c2)cc1

Procedure:
The title compound was prepared according to the procedure of step 5 in EXAMPLE 13 using [5-(4-methoxybenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone (EXAMPLE 16, step 3), instead of [5-(4-chlorobenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanone.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C(Cl)Cl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]2[C:17]3[N:16]=[C:15]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=4)[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=3[NH:5][C:23]=2[CH:22]=1)([O-:26])=[O:25]
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc(-c2ccc([N+](=O)[O-])cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCCC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 41.9 %

Procedure:
1,2-Dichloroethane (10 mL) was added to a mixture of methyl 3-azido-2-(4-nitrophenyl)-6-(3-(trifluoromethyl)phenyl)isonicotinate (1.0 g, 2.3 mmol), rhodium octanoate dimer (0.125 g, 0.161 mmol) and crushed 4A° molecular sieves (1.0 g). The reaction was heated at 80° C. for 20 hr. The crude mixture was diluted with DCM and silica gel chromatography (step gradient elution with DCM containing 0 to 20% MeOH) afforded methyl 7-nitro-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (400 mg, 0.963 mmol, 43% yield). MS (ESI) m/z 416.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.24 (1H, br s), 8.42-8.72 (5H, m), 8.16 (1H, dd, J=8.55, 1.83 Hz), 7.82 (2H, ddd, J=15.11, 7.78, 7.63 Hz), 4.10 (3H, s).
Reaction SMILES: C([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:36][CH2:35]4)=[C:26]([F:46])[CH:25]=3)=[O:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:47])C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[CH3:43][C:42]([CH3:45])([CH3:44])[CH2:41][CH2:40][N:37]1[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([C:22]([N:14]3[CH2:13][CH2:12][C:11]4[N:10]=[C:9]([CH3:47])[NH:8][C:17]=4[C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]3=4)=[O:23])=[CH:25][C:26]=2[F:46])[CH2:39][CH2:38]1
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(CCC(C)(C)C)CC3)c(F)c1)CC2
Yield: 51 %

Procedure:
(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-(4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-propoxy}-3-fluoro-phenyl)-methanone from Example E69.3 (90 mg, 0.14 mmol) was dissolved in methanol (5 ml) and acetic acid (1 ml) and hydrogenated over 20 wt. % palladium hydroxide catalyst (90 mg) for 8 h. The mixture was filtered through Celite® filter agent and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (39 mg, 51%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)=[C:11]([C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Li][Li].C(N(CC)CC)C.[C:43]1([C:49](Cl)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC(C)=O>[CH2:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29]([C:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[N:30]=3)=[CH:16][CH:15]=2)=[C:11]([C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li][Li]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1

Procedure:
A mixture of the title compound of Example 2, 2-ethyl-3-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-oxy]-4-quinolinecarboxylic acid, dilithium salt (700 mg, 1.6 mmol), triethyl amine (245 microliters, 1.76 mmol), triphenylmethyl chloride (468 mg, 1.68 mmol) and acetone (8 mL) was stirred at room temperature for 36 hours. The mixture was concentrated in vacuo to yield the crude product as a waxy solid (1.35 g, 100%).
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br/[C:18](=[CH:26]\[C:27]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[CH:33][C:34]=2[Cl:36])[N:29]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[C:28]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49])/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[S:53]1[CH:57]=[CH:56][CH:55]=[C:54]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1CCCCC1.C1CCCCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:53]1[CH:57]=[CH:56][CH:55]=[C:54]1/[C:18](=[CH:26]/[C:27]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[CH:33][C:34]=2[Cl:36])[N:29]([S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=2)(=[O:40])=[O:39])[C:28]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49])/[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: CCOC(=O)c1c(/C=C(\Br)C(=O)OC(C)(C)C)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)c1c(/C=C(\C(=O)OC(C)(C)C)c2cccs2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Combine tris(dibenzylideneacetone)dipalladium(0) (412 mg, 0.450 mmol) and tri-(fur-2-yl)phosphine (837 mg, 3.60 mmol) in tetrahydrofuran (60 mL). After 5 minutes, add (Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester (1.85 g, 3.0 mmol), thiophene-2-boronic acid (1.12 g, 9.20 mmol), and powdered potassium carbonate (1.27 g, 9.2 mmol). Heat to 60° C. After 8 days, dilute the reaction mixture with cyclohexane (120 mL) and chromatograph on silica gel eluting with 3/1 cyclohexane/ether to give the title compound. 1H NMR (CDCl3) δ 7.97 (d, 1H, J=1.7 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.64 (s, 1H), 7.27 (d, 2H, J=8.5 Hz), 7.23 (d, 1H, J=1.7 Hz), 7.16 (dd, 1H, J=5.1, 1.2 Hz), 6.83 (dd, 1H, J=3.7, 1.2 Hz), 6.75 (dd, 1H, J=5.1, 3.7 Hz), 4.24 (q, 2H, J=7.1 Hz), 2.39 (s, 3H), 1.57 (s, 9H), 1.26 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]2=[O:29])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[N:4][C:3]=1[N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]2=[O:29])[CH2:17][CH2:18]1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from 5,6-dichloronicotinic acid (2.2 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (3.0 g) using the method of example 115 step (ii). Yield 0.037 g
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]([CH3:16])[CH3:17]
Reactant: CN(C)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCc1c[nH]c2ccc(N)cc12
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A mixture of 5-nitro-3-[2-(dimethylamino) ethyl]indole (0.650 g, 2.79 mmol) and 10% palladium-on-charcoal (0.150 g) in 60 mL of ethanol was hydrogenated on a Parr shaker at 40 psi for 30 min. The mixture was then filtered through Celite and the catalyst was washed with additional ethanol. Evaporation of the filtrate gave the essentially pure title compound (0.510 g, 90%) as a light brown gum: IR (neat) 3410, 1630, 1588, 1464 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ7.84 (br s, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.66 (dd, J=8.5, 2.2 Hz, 1H), 3.44 (br s, 2H), 2.88 (m, 2H), 2.60 (m, 2H), 2.34 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH:17](OCC)=[CH2:18]>>[CH:17]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10])=[CH2:18]
Reactant: O=C1C=CC(=O)N1CCO
Reactant: C=COCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=COCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A quantity of 1.18 g of N-(2-hydroxyethyl)maleimide was suspended in 25 ml ethyl vinyl ether and refluxed with stirring under an argon atmosphere, 70 mg mercuric acetate was added, and the reaction was continued at reflux for 24 hours. After 24 hours, the reaction mixture was allowed to cool to room temperature, and 1.50 mg of anhydrous potassium carbonate was added. After stirring for a few more minutes, the mixture was filtered and the precipitate was washed thoroughly with ethyl acetate. The washings were combined with the filtrate and evaporated to dryness in vacuo to yield an oily residue. This oily residue was chromatographed over 50 grams of neutral alumina, activity III, using methylene chloride-hexane (1:1) for elution. The initial fractions were collected and combined to yield 200 mg of crude 2-maleimidoethyl vinyl ether. The product was suitable for use in the next step in preparation of the crosslinker, but for analytical purposes could be purified by rechromatography over alumina or kugelrohr distillation.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]([F:25])([F:24])[CH2:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:12]([F:11])([F:24])[F:25])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: OB(O)c1cccc(OCC(F)(F)F)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2cccc(OCC(F)(F)F)c2)cc1F
Yield: 77.2 %

Procedure:
The title compound (89 mg) was prepared from 4-bromo-2,6-difluoroaniline (80 mg, 0.38 mmol) and 3-(2,2,2-trifluoroethoxy)phenylboronic acid (108 mg, 0.5 mmol) as a colourless liquid.
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC(Cl)=CC=2)C(NO)=O)=CC=1)C#CC.[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28]>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])(=[O:5])=[O:37])=[CH:34][CH:35]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2ccc(Cl)cc2)cc1
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2ccc(Cl)cc2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2ccc(Cl)cc2)cc1
Yield: 29 %

Procedure:
Starting from a mixture of 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(4-chlorophenyl)-N-hydroxyacetamide (from example 80) and 2-{[4-(2-butynyloxy) phenyl]sulfinyl}-2-(4-chlorophenyl) N-hydroxyacetamide (750 mg, 1.99 mmol), and following the procedure as outlined in Example 75, 228 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(4-chlorophenyl)-N-hydroxyacetamide was isolated as a white solid. mp: 140° C.; Yield: 29%; MS: 394.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.85 (t, J=2.19 Hz, 3H), 4.86 (d, J=2.28 Hz, 2H), 5.05 (s, 1H), 7.1 (d, 2H), 7.4 (m, 4H), 7.5 (d, 2H), 9.33 (s, 1H), 10.8 (s, 1H).
Reaction SMILES: [Br-].[CH2:2]([CH:5]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[C:7](=[O:20])[CH2:6]1)[CH2:3][CH3:4].[Br:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([Si](C(C)C)(C(C)C)C(C)C)[CH:29]=[CH:30][C:23]=12.C([Si](C(C)C)(C(C)C)N1C2N=CC=C(C=O)C=2C=C1)(C)C.C(C1CN(CC2C=CN=C3N([Si](C(C)C)(C(C)C)C(C)C)C=CC=23)C(=O)C1)CC>>[Br:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12.[CH2:2]([CH:5]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[C:7](=[O:20])[CH2:6]1)[CH2:3][CH3:4]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)ccnc21
Agent: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C=O)ccnc21
Agent: CCCC1CC(=O)N(Cc2ccnc3[nH]ccc23)C1
Agent: CCCC1CC(=O)N(Cc2ccnc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)C1
Product: Brc1ccnc2[nH]ccc12

Procedure:
The further transformation of bromide x258 into the target product 240 is carried out in complete accordance with the transformation of bromide b191-1 into product ucb-108891-1 as described in examples 79.2 to 79.4. The yields are similar for intermediates 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine x259, 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde x260 and 4-propyl-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methyl}pyrrolidin-2-one x261. As a result, 1.0 g (5.1 mmol) of 4-bromo-1H-pyrrolo[2,3-b]pyridine x258 affords 0.45 g of 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one 240.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=O)[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH2:25](C1N(CCCC(OCC)=O)C2C3N=CC=CC=3N=CC=2N=1)CCC>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:25])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(C)=O

Procedure:
A modified version of the general methods described in Parts D-G of Example 4 was sequentially followed with ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate (6.0 g, 18.4 mmol) used in lieu of ethyl 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate as the starting substrate. Isolation after the last step of the sequence afforded 6.06 g of crude 5-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one.