Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[S:28]([CH2:26][CH3:27])(=[O:30])=[O:29]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), ethanesulfonyl chloride (5 μL, 1.5 eq), triethylamine (15 μL, 3.0 eq) and dichloromethane (1 mL) was stirred at room temperature overnight. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12.5 mg, 82% yield)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:33]([O-:35])=[O:34])=[C:15]([CH:32]=1)[C:16]([NH:18][C:19]1[CH:24]=[C:23]([C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])[CH:22]=[CH:21][C:20]=1[CH3:31])=[O:17]>>[CH:28]1([NH:27][C:25]([C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]3[CH:32]=[C:11]([N:4]4[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]4)[CH:12]=[CH:13][C:14]=3[N+:33]([O-:35])=[O:34])[CH:24]=2)=[O:26])[CH2:30][CH2:29]1
Reactant: OCCN1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting materials, N-piperazine ethanol was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[4-(2-hydroxyethyl)piperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.30 (s, 3H), 2.44 (t, 2H), 2.54 (m, 4H), 2.83 (m, 1H), 3.50 (m, 6H), 4.46 (s, 1H), 7.05 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.04 (d, 1H), 8.35 (d, 1H), 9.90 (s, 1H); Mass Spectrum: M+H+ 468.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:45])[C:41](=[O:44])[CH:42]=[CH2:43].[H-].[Na+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:43][CH2:42][C:41]([N:40]([CH3:45])[CH3:39])=[O:44])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N(C)C
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](OCCC(=O)N(C)C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (316 mg, 0.57 mmol) was treated with N,N-dimethylacrylamide (175 mg, 1.77 mmol) and sodium hydride (60% in oil, 36 mg, 0.91 mmol) in tetrahydrofuran (5.7 ml) in the same manner as shown in Example 4(1) (at 0° C. for 1.5 hours and then at room temperature for 1.5 hours), followed by work up and purification using column chromatography (hexane:ethyl acetate=2:1) to give the titled compound (352 mg, 93.9%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:3])[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:35][CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCNCC3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCN(S(C)(=O)=O)CC3)ncnc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of (2R,3R,4R,5S)-4-(Acetyloxy)-5-[3-(tert-butyl)isoxazol-5-yl]-2-[6-(piperidin-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (40 mg) in tetrahydrofuran (4 ml) was added methanesulfonyl chloride (0.0088 ml) and triethylamine (0.0212 ml). The reaction mixture was stirred for 16 h at 20° C., and partitioned between ethyl acetate (2×100 ml) and water (100 ml). The organic layers were washed with water (100 ml), dried (MgSO4), and evaporated in vacuo to afford the title compound (36.7 mg) as a colourless gum.
Reaction SMILES: C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.[C:14]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:34])[CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH3:33].CCN(CC)CC.[CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH:60]([CH3:62])[CH3:61])[C:55]=1[N:63]=[C:64]=[O:65])([CH3:53])[CH3:52]>C1COCC1>[C:14]([NH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:64]([NH:63][C:55]2[C:54]([CH:51]([CH3:52])[CH3:53])=[CH:59][CH:58]=[CH:57][C:56]=2[CH:60]([CH3:62])[CH3:61])=[O:65])=[CH:38][CH:37]=1)(=[O:34])[CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH3:33]
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Nc1ccc(CN)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)Nc1ccc(CNC(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 87.7 %

Procedure:
This compound was subjected to TLC analysis [silica gel plate, developing solvent:CHCl3 -MeOH-H2O (90:10:1)]. As a result, a single spot was obtained by the detection with iodine and a 0.2% ninhydrin reagent. The obtained 4-(N-5,8,11,14,17-eicosapentaenoylamino)benzylamine (813 mg, 2 mmol) and Et3N (204 mg, 2 mmol) were dissolved in anhydrous THF (10 ml), and 2,6-diisopropylphenyl isocyanate (406 mg, 2 mmol) was added. The mixture was reacted for about 2 hours under cooling in a nitrogen stream, and concentrated under reduced pressure. The obtained concentrate was dissolved in a small amount of CHCl3 and applied to an SiO2 (800 g) column activated with CHCl3 in advance, which was followed by elution with CHCl3 (600 ml) and CHCl3 -MeOH (98:2, 800 ml) in this order. The objective fractions were recovered from the obtained eluate fractions based on TLC analysis as an index, and concentrated to give the objective compound (1.07 g, yield 88%).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O1CCCC1.O>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: Fc1cccc(CCl)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (125 mL), and N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent), are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Sodium bromide (1.3 g) is added and 3-fluoro-benzyl chloride (1.05 equivalents) is added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 mL) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product, 3-[2-( 3-fluoro-phenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide, may crystallize.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccnc4Cl)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.054 mMol 2-chloro-3-pyridinecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C@H:8]([CH3:12])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:32]C(OCC)=O>ClCCl>[C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C@H:8]([CH3:12])[C:9]([Cl:32])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)Cl
Reaction time: 1 h

Procedure:
(S)-(+)-3-(tert-Butyl-diphenyl-silanyloxy)-2-methylpropionic acid (0.44 g; 1.20 mmol) (from Example 13a supra) was dissolved in dichloromethane (3 mL, dried over molecular sieves). Triethylamine (0.36 mL; 2.58 mmol) (Aldrich) was added and the solution was cooled in an ice-water bath. Ethyl chloroformate (0.16 mL; 1.63 mmol) (Aldrich) was added dropwise and the mixture was stirred in the cold for 1 hour. The mixture was then diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield (S)-(+)-3-(tert-butyl-diphenyl-silanyloxy)-2-methylpropionic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][Cl:12]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccncc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCc1ccncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a mixture of 0.70 g of (3-chloropyridin-4-yl)methanol and 8 ml of chloroform was added dropwise 0.70 g of thionyl chloride at room temperature, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layers were combined and dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure to obtain 0.78 g of 3-chloro-4-(chloromethyl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]4[CH2:23][O:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O1CCCC1>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]([OH:22])[CH2:23][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26]
Reactant: CCNCC
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@@H]1CO1
Solvent: C1CCOC1
Product: CCN(CC)C[C@H](O)COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 120 h
Yield: 91.1 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2S)-oxiran-2-yl)methoxyquinoline (72 mg, 0.196 mmol) in tetrahydrofuran (2.0 ml) under a nitrogen atmosphere, diethylamine (0.4 ml) was added and the mixture was stirred at 50° C. for 5 days. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (78.6 mg, 0.178 mmol, 91.1%) as light yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1.[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>[Na]>[CH:21]1([NH:27][C:28]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]3[O:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[O:13][CH2:12]3)[OH:10])[CH2:4][CH2:3]2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCN(CC(O)C2COc3ccccc3O2)CC1
Reactant: O=C=NC1CCCCC1
Agent: [Na]
Product: O=C(NC1CCCCC1)NC1CCN(CC(O)C2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]piperidine (2.0 g, 0.0072 m) prepared according to Example 3(c) in sodium dried benzene was treated with cyclohexyl isocyanate (0.99 g 0.008m) in sodium dried benzene (25 mls). The mixture was stirred at room temperature for 18 hours. The solid was filtered off and washed with benzene. The white solid was suspended in ethyl acetate and acidified with ethanolic hydrogen chloride until the solution was acidic. The title compound was filtered off, washed with ether and dried (1.47 g 46.5%)
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[C:7]([CH3:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:45])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:19][Br:45])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2]
Reactant: COc1cc2cc(OC(C)=O)nc(C)c2cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2cc(OC(C)=O)nc(CBr)c2cc1OC
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-yl acetate SIL 32158 (261 mg, 1.00 mmol) in dry CCl4 (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added benzoyl peroxide (12 mg, 0.05 mmol) followed by NBS (178 mg, 1.00 mmol) and the mixture was stirred for 15 min at 130° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (20 mL), washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave 1-(bromomethyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32162 as a yellow solid (140 mg, 41% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(S(C)(=O)=O)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 36.6 %

Procedure:
Using a procedure analogous to Example 26, the product from Example 14 (120 mg, 0.150 mmol) was treated with methanesulfonyl chloride (24.0 mg, 1.4 eq) to provide the title barbituric acid (42.0 mg, 37%). MS found: (M+H)+=538.
Reaction SMILES: FC(F)(F)C1C=CC(C2C=C(CO)C=CC=2)=NC=1.C[O:20][C:21](=[O:51])[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=3)[CH:36]=2)=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2>>[F:50][C:47]([F:48])([F:49])[C:44]1[CH:45]=[CH:46][C:41]([C:37]2[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=2)[CH2:34][S:33][C:30]2[CH:31]=[CH:32][C:24]([O:23][CH2:22][C:21]([OH:51])=[O:20])=[C:25]3[C:29]=2[CH2:28][CH2:27][CH2:26]3)=[N:42][CH:43]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cn3)c2)c2c1CCC2
Agent: OCc1cccc(-c2ccc(C(F)(F)F)cn2)c1
Product: O=C(O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cn3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 53A. MS m/z 237 (M+1-Cl). Step 3. Preparation of {7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (Compound 53C)
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[C:15]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][C:7]1[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:15]=2[NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1-c1ccccc1NC(=O)OC(C)(C)C
Yield: 132.3 %

Procedure:
2-Bromo-3-methylpyridine (0.65 g, 3.8 mmol) and N-(tert-butoxycarbonyl)-2-amino-1-phenylboronic acid (0.90 g, 3.8 mmol), prepared according to the method described by J. J. S. Lambda and J. M. Tour in J. Am. Chem. SDC., 1994,116,11723-11736, were coupled as in Example 70 (also see J. Org. Chem., 1995, 60, 292), to give 1.43 g of crude tert-butyl 2-(3-methyl-2-pyridinyl)phenylcarbamate, which was deprotected as in Example 75 to give 0.45 g of 2-(3-methyl-2-pyridinyl)aniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(Br)cc1C1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 4-bromo-2-cyclopentyl-phenol (2.0 g, 8.29 mmol) and Cs2CO3 (3.24 g, 9.95 mmol) in DMF (13.0 mL) was added benzyl bromide (1.6 g, 1.09 mL, 9.12 mmol) dropwise. The reaction was stirred at room temperature under inert atmosphere for 2 h. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexane) provided 1-benzyloxy-4-bromo-2-cyclopentyl-benzene (1.8 g, 64% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.43-7.40 (m, 4H), 7.35-7.28 (m, 3H), 6.99 (d, J=9.4 Hz, 1H), 5.12 (s, 2H), 3.28-3.24 (m, 1H), 1.94-1.92 (m, 2H), 1.70-1.69 (m, 2H), 1.61-1.52 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCCN(CCC)c1c(SC)nc2c(Br)cc(C)cn12
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCCN(CCC)c1c(SC)nc2c(-c3ccc(Cl)cc3Cl)cc(C)cn12
Yield: 72.5 %

Procedure:
N-[8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (50 mg) was dissolved in a mixed solvent of 1,2-dimethoxyethane (6 mL) and water (1 mL). 2,4-Dichlorobenzeneboronic acid (53 mg), barium hydroxide octahydrate (88 mg) and tetrakistriphenylphosphine palladium complex (16 mg) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give N-[8-(2,4-dichlorophenyl)-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (43 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12](=[S:14])=[S:13]>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[S:13])[SH:14]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: S=C=S
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNC(=S)S
Reaction time: 8 h

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (10.2 g.) in ethanol (75 ml.) was added slowly, with stirring, to carbon disulphide (200 ml.). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallised from aqueous isopropyl alcohol to afford N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]dithiocarbamic acid (9.8 g.) m.p. 127°-129°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH3:42])/[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH3:42])/[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Yield: 52.2 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylate (1.65 g, 2.65 mmoles) and anisole (0.5 ml) was treated with TFA (5 ml) at room temperature for 1 hour. The mixture was diluted with IPE. The resulting precipitate*1 was collected by filtration and chromatographed on a column of the packing (50 ml) of a PrepPAK cartridge (Waters) with 20-30% methanol to yield 605 mg (52%) of the title compound. Estimated purity 90% (by HPLC). Mp.>160° C. (grad. dec.).