Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1([CH2:50][C:49]2[CH:52]=[CH:53][C:46]([F:45])=[CH:47][CH:48]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(Cc2ccc(F)cc2)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (10.5 g, 27.8 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (200 mL) under a nitrogen atmosphere was added N,N-dimethylformamide (30 mL). The reaction was cooled to about −78° C., and a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (83 mL, 42 mmol) was added. The reaction was stirred at about −78° C. for about 1 hour, and then 4-fluorobenzyl bromide (5.2 mL, 42 mmol) was added. The reaction was stirred for about 1 hour more at about −78° C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as a yellow oil. Purification by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded the title compound of part 1-A (8.54 g, 63%) as a colorless oil: +APcI MS (M−Boc+H)+ 387; 1H NMR=400 MHz (CDCL3) δ: 7.45-7.30 (arom, br s, 5H), 7.00-6.80 (arom, br m, 4H), 5.35-5.05 (br m, 2H), 2.53 (br t, 1H), 1.40 (Boc, s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([C@@H:8]([NH:19][C:20]([C:22]2[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:24][CH:23]=2)=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C@@H:8]([NH:19][C:20]([C:22]2[N:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the (S)-tert-butyl 2-((6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)pyridin-3-yl)oxy)acetate from above in DCM (0.5 mL), was added TFA (0.550 mL, 7.40 mmol). The resulting mixture was then stirred at rt for 1 h. The mixture was then concentrated and MeOH (1 mL) was added. The mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.55 (d, J=4.7 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.59-7.72 (m, 5H), 7.42-7.55 (m, 2H), 6.68 (d, J=1.6 Hz, 1H), 4.89 (s, 2H). MS (ESI pos. ion) m/z: 450.2 (M+H).
Reaction SMILES: [F-].[K+:2].C1COS(=O)(=O)CC1.[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([OH:32])(=[O:31])=[O:30])([C:14]([C:17]([C:20]([F:23])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12].[NH4+]>>[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([O:32][K:2])(=[O:31])=[O:30])([C:14]([C:17]([C:20]([F:23])([F:21])[F:22])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12]
Reactant: O=S(=O)(O)CCCCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [K+]
Agent: O=S1(=O)CCCCO1
Agent: [F-]
Agent: [NH4+]
Product: O=S(=O)(CCCCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)O[K]

Procedure:
n-C4F9OC4H8SO3K was prepared from normal-perfluorobutyl acid fluoride, KF and 1,4-butane sultone and isolated in 92% purity as described in U.S. Pat. No. 6,890,452, as FC-11. The sulfonic acid salt was converted to the corresponding acid through an ion-exchange column packaged with acidified Amberlite IR-120 ion-exchange resin. The corresponding ammonium salt was prepared by adjusting the pH of C4F9O(CH2)4SO3H aqueous solution to ˜10 with 10% aqueous ammonium solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:24](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:24][C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)[nH]1)cn2C
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 0.11 mmol) in DMF (4 mL) was treated with ethylenediamine (0.22 mL, 3.3 mmol) and heated to about 85° C. for about 5 min. The solution was cooled and TBAF (1 M in THF, 0.11 mL, 0.11 mmol) was added. The solution was re-heated to about 85° C. for about 30 min. The mixture was cooled to ambient temperature and another portion of the TBAF (1 M in THF, 0.054 mL, 0.054 mmol) was added and heating was continued for about 1.5 h. The solution was cooled and the material was purified by preparative RP-HPLC (Table 2, Method 1). The product-containing fractions were concentrated to remove MeCN then basified with saturated aqueous NaHCO3 and extracted with EtOAc (2×10 mL). The combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated. Trituration of the solid with heptane (5 mL) then collection by filtration gave 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.028 g, 8%): LC/MS (Table 2, Method a) Rt=1.91 min; MS m/z: 318.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6 δ 12.18 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.90, 2.36 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])(=O)=O.CCN(CC)CC>C(Cl)(Cl)Cl>[Cl:24][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:9]=[CH:8][C:7]=1[N:10]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:11]1=[O:20]
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1N(c2ccc(C3CC3)cc2Cl)CCC12CCNCC2
Yield: 30.8 %

Procedure:
A mixture of 0.275 g (1 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one. 1.57 g (11.3 mmol) sulfuryl chloride and 0.154 g (1.52 mmol) NEt3 in 50 mL CHCl3 was stirred at room temperature. After evaporation of the volatiles the residue was taken up in DMF and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 94 mg (30%) of the title compound as light yellow gum. MS m/e: 305.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:13].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][CH2:25][CH2:24][CH2:23][CH2:22][S:21][C:18]1[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][CH:19]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: O=C1Nc2ccc(O)c(Cl)c2CO1
Product: Cc1ccc(SCCCCOc2ccc3c(c2Cl)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 5-chloro-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)O1.[Cl:19][C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[CH:22][C:21]=1I.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C>[Cl:19][C:20]1[C:21]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:22][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)=[O:25])=[CH:37][CH:38]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(I)c1
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(-c2cccc([N+](=O)[O-])c2)c1
Yield: 146.6 %

Procedure:
4,4,5,5-Tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborolane (0.40 g, 0.0016 mol) was mixed with 4-chloro-3-iodo-N-[3-(trifluoromethyl)phenyl]benzamide (0.600 g, 0.00141 mol), potassium carbonate (0.39 g, 0.0028 mol), toluene (10 mL), ethanol (1.7 mL), and water (1.1 mL). The mixture was degassed by bubbling nitrogen through it. To the reaction was added tetrakis(triphenyl-phosphine)palladium(0) (0.078 g, 0.000068 mol). The reaction was heated to reflux for 16 hours. LCMS showed about 80% conversion to M+H 421/423 (3:1). The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, then dried (Na2SO4). Solvent was removed under vacuum to give 0.87 g oil. The product was purified by automatic flash chromatography on silica gel. Used a 40 g column; flow 40 mL/min; [A=hexane] [B=EtOAc]. A, 4 min; Gradient to 20% B in 30 min. The product eluted in 23-28 min (starting material at 16-18 min). Removal of solvent under vacuum gave 0.46 g white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13](C3C=CC(C4C=NC=CC=4)=CC=3)[CH:12]=[C:11]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)[N:10]=2)[CH:5]=[C:6](Cl)[CH:7]=1.[C:39]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:40](B(O)O)=[CH:41][CH:42]=[CH:43][CH:44]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:11]3[CH:12]=[C:13]([C:27]4[CH:28]=[CH:29][C:30]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:31][CH:32]=4)[N:14]=[C:9]([C:4]4[CH:3]=[C:2]([C:41]5[CH:42]=[CH:43][CH:44]=[C:39]([C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=6)[CH:40]=5)[CH:7]=[C:6]([C:43]5[CH:44]=[C:39]([C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)[CH:40]=[CH:41][CH:42]=5)[CH:5]=4)[N:10]=3)=[CH:28][CH:29]=2)[CH:34]=1
Reactant: Clc1cc(Cl)cc(-c2nc(-c3ccc(-c4cccnc4)cc3)cc(-c3ccc(-c4cccnc4)cc3)n2)c1
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: c1ccc(-c2cccc(-c3cc(-c4cccc(-c5ccccc5)c4)cc(-c4nc(-c5ccc(-c6cccnc6)cc5)cc(-c5ccc(-c6cccnc6)cc5)n4)c3)c2)cc1
Temperature: 25 °C

Procedure:
In a stream of argon, 0.45 g (0.85 mmol) of 2-(3,5-dichlorophenyl)-4,6-bis[4-(3-pyridyl)phenyl]pyrimidine, 0.37 g (1.87 mmol) of m-biphenylboronic acid, 0.39 g (1.86 mmol) of potassium phosphate, 8 mg (0.034 mmol) of palladium acetate and 32 mg (0.068 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisipropylbiphenyl were suspended in 20 mL of tetrahydrofuran, and the obtained suspension was heated under reflux for 66 hours. The reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was purified by silica gel chromatography using chloroform as an eluent to give 0.42 g of the target 4,6-bis[4-(3-pyridyl)phenyl]-2-(1,1′:3′,1″:3″,1″′:3″′,1″″-quinquephenyl-5″-yl)pyrimidine as a white solid (yield: 640).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cccc(CBr)c1
Yield: 101.8 %

Procedure:
To 1-methyl-3-tert-butyl-benzene (551 mg, 3.72 mmol), NBS (730 mg, 1.1 eq) and AIBN (14 mg, catalytic amount) was added CCl4 (8 mL), which was then refluxed for 2 h. The suspended particles were removed by filtration, and washed with CCl4. The organic layers were combined and concentrated under reduced pressure to give 860 mg of a yellow liquid (which was identified by NMR to contain about 15% dibromo derivative).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].O.[Cl:29][Si](C)(C)C>C(Cl)Cl>[ClH:29].[C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Agent: CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccn3)s2)nc2ccccn12
Solvent: O
Solvent: ClCCl
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6.93 g (18.6 mmol) of N-tert-butyl-2-(5-(pyridin-2-ylethynyl)thiophen-2-yl)imidazo[1,2-a]pyridin-3-amine (Example 94) in DCM (180 ml) was combined with 335 μl (18.6 mmol) of water and 2.35 ml (18.6 mmol) of chlorotrimethylsilane and stirred at RT for 16 h. The resultant precipitate was filtered out and dried under a vacuum at 40° C., 6.09 g (14.8 mmol, 80%) of N-tert-butyl-2-(5-(pyridin-2-ylethynyl)thiophen-2-yl)imidazo[1,2-a]pyridin-3-amine hydrochloride being obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:23]([F:24])=[C:22]([F:25])[C:21](Cl)=[CH:20][C:11]=1[C:12]([NH:14][O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)=[O:13].IC1C=CC(NC2C(F)=C(F)C(Cl)=CC=2C(NOCC2CC2)=O)=CC=1.IC1C=CC(NC2C(F)=C(F)C(Cl)=CC=2C(O)=O)=CC=1.ClC1C=C(I)C=CC=1NC1C(F)=C(F)C(Cl)=CC=1C(O)=O.ClC1C(F)=C(F)C(NC2C=CC(I)=CC=2C)=C(C=1)C(O)=O.ClC1C(F)=C(F)C(NC2C=CC(I)=CC=2C)=C(C=1)C(NOCC1CC1)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:11]=1[C:12]([NH:14][O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)=[O:13]
Reactant: O=C(NOCC1CC1)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Agent: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc(Cl)c(F)c1F
Agent: Cc1cc(I)ccc1Nc1c(C(=O)O)cc(Cl)c(F)c1F
Agent: O=C(NOCC1CC1)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1
Product: O=C(NOCC1CC1)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl

Procedure:
Additional preferred compounds include 2-(2-chloro4-iodophenylamino)-5-chloro-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 297189), 2-(4-iodophenylamino)-N-cyclopropylmethoxy-5-chloro-3,4-difluorobenzamide (PD 297190), 2-(4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296771), 2-(2-chloro4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296770), 5-chloro-3,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzoic acid (PD 296767); and 5-chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzamide (PD 298127).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:32]([C:27]5[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][N:28]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1cccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccnc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 46.9 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), 3-methylpyridine-2-carboxylic acid (126 mg, 0.917 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (187 mg, 0.978 mmol), 1-hydroxybenzotriazole (133 mg, 0.988 mmol), triethylamine (0.14 mL, 1.039 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (128 mg, 47%) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([Sn:4]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8])CC1.FC=C[Sn](CCCC)(CCCC)CCCC.FC([Sn](CCCC)(CCCC)CCCC)=C(F)F.C([Sn](CCCC)(CCCC)CCCC)C=C.C([Sn](CCCC)(CCCC)CCCC)#C.C([Sn](CCCC)(CCCC)CCCC)C#CCC.COC1C=CC(COC[Sn](CCCC)(CCCC)CCCC)=CC=1>>[CH3:1][Sn:4]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Agent: C#C[Sn](CCCC)(CCCC)CCCC
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: CCC#CC[Sn](CCCC)(CCCC)CCCC
Product: CCCC[Sn](C)(CCCC)CCCC

Procedure:
cyclopropyltributyltin; fluorovinyltributyltin; trifluorovinyltributyltin; prop-2-enyltributyltin; ethynyltributyltin; pent-2-ynyltributyltin; allyltributyltin; and 4-methoxybenzyloxymethyltributyltin; there are obtained:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH2:20]([NH:24][C:25]([C:27]1[C:31]2[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=2[O:29][C:28]=1[CH3:37])=[O:26])[CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:20]([NH:24][C:25]([C:27]1[C:31]2[CH:32]=[CH:33][C:34]([O:36][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:35][C:30]=2[O:29][C:28]=1[CH3:37])=[O:26])[CH:21]([CH3:23])[CH3:22]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1oc2cc(O)ccc2c1C(=O)NCC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCC(C)C)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b with 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 83b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ 8.53 (1H,d, J=5.5 Hz), 7.88 (1H, d, J=3.0 Hz), 7.82 (1H, d, J=8.5 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd, J=8.5, 2.3 Hz), 6.70 (2H, d, J=5.5 Hz), 4.10–3.83 (3H, m), 3.73–3.58 (2H, m), 3.33, 3.29 (3H, 25), 3.23 (2H, t, J=6.8 Hz), 2.65 (3H, s), 2.10–1.95 (2H,m), 0.98 (6H, d, J=6.6 Hz).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:9]([NH:12][S:13]([CH2:16][CH2:17][S:18][CH3:19])(=[O:15])=[O:14])([CH3:11])[CH3:10])#[N:8]>O.CO>[C:7]([C:9]([NH:12][S:13]([CH2:16][CH2:17][S:18]([CH3:19])=[O:2])(=[O:14])=[O:15])([CH3:11])[CH3:10])#[N:8]
Reactant: CSCCS(=O)(=O)NC(C)(C)C#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)CCS(=O)(=O)NC(C)(C)C#N
Yield: 36.5 %

Procedure:
To a stirred solution of 4.27 g (0.020 moles) sodium metaperiodate in 40 ml water which had been cooled to about 0° C. in an ice bath, 4.10 g (0.0184 mole) N-(2-cyano-2-propyl)-2-methylthioethylsulfonamide (the product of Example 27) in about 10 ml methanol was added slowly. Initially, the mixture was homogeneous, but after the addition was complete (after about three minutes), a thick precipitate formed. Additional methanol (15 ml) and water (60 ml) was added, thinning the precipitate to allow stirring. The mixture was stirred overnight in a slowly melting ice bath and then filtered. The solid was washed with methylene chloride. The filtrate was washed three times with 50 ml methylene chloride. The methylene chloride fractions were combined and evaporated to dryness to give 2.2 g of crude product, as a white solid. Recrystallization from ethanol gave 1.6 g of the above-identified product as a solid, melting point 142°-144° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:41])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9][C:8]1=[O:42])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl>[OH:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:41])[C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[CH:23][CH:24]=2)[CH2:10][CH2:9][C:8]1=[O:42]
Reactant: CC(=O)OCCN1C(=O)CCN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc(C)cc3)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CCO)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A mixture of 1-(2-acetoxyethyl)-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (450 mg) and potassium carbonate (117 mg) in methanol (15 ml) was stirred at ambient temperature for 3 hours. The mixture was diluted with chloroform and the solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 1-(2-hydroxyethyl)-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro -1,5-benzodiazepin-2(2H)-one (430 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.CCN(C(C)C)C(C)C.CN(C(O[N:40]1N=[N:47][C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=NC=1CN>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:47][CH2:42][C:41]2[N:40]=[CH:43][CH:44]=[CH:45][N:46]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 15.8 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (300 mg, 0.88 mmol), DIEA (0.5 mL, 2.88 mmol) were dissolved in 30 mL of THF, HATU (405 mg, 1.06 mmol) and pyrimidin-2-ylmethylamine (115 mg, 1.06 mmol) were added under ice-water-bath, reacted at room temperature overnight, to the reaction solution was added 100 mL of water, then extracted with dichloromethane, dried with anhydrous sodium sulfate, dried by rotation, then solid was separated with silica gel column (dichloromethane:methanol=40:1) to obtain a white solid 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide 60 mg, yield 16%.