Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:15][S:16][CH3:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:37][C:38]([NH2:40])=[S:39].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[NH2:40][C:38]1[S:39][CH:2]=[C:3]([CH2:4][C:5]([NH:7][CH:8]2[C:34](=[O:35])[N:10]3[C:11]([C:18]([O:20][CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:19])=[C:12]([CH2:15][S:16][CH3:17])[CH2:13][S:14][C@H:9]23)=[O:6])[N:37]=1
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Yield: 69.3 %

Procedure:
To a solution of benzhydryl 7-[4-bromoacetoacetamido)-3-methylthiomethyl-3-cephem-4-carboxylate (6.0 g) in tetrahydrofuran (30 ml) was added dropwise a solution of thiourea (0.85 g) and sodium bicarbonate (0.94 g) in tetrahydrofuran (30 ml) and water (24 ml) at 25° C. with stirring, and the stirring was continued at 28° to 30° C. for an hour. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (100 ml), followed by separating out the organic layer, which was washed twice with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to give benzhydryl 7-[2-(2-aminothiazol-4-yl) acetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (4.0 g).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[N:9]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.[Cl-].[NH4+].[Mn]([O-])(=O)(=O)=O.[K+]>CCCCCC.CCOCC.CC(C)=O>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:24]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH:14]=2)[N:9]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: c1cncnc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1ccc2cc(-c3ccncn3)ccc2n1
Temperature: 25 °C

Procedure:
n-Butyl lithium (2.7 cm3 of a 1.5M solution in hexane) was added dropwise to a stirred suspension of 2-methoxy-6-bromoquinoline (0.95 g) in ether (5 cm3) at -70° under nitrogen. When all the solid material had dissolved a solution of pyrimidine (0.32 g) in ether (1 cm3) was added dropwise and the resulting solution was allowed to warm to room temperature. Saturated ammonium chloride solution (5 cm3) was added, the aqueous phase was extracted with chloroform (3×10 cm3) and the dried (MgSO4) extracts were concentrated in vacuo to give an oil. This residue was taken into acetone and treated dropwise with a solution of potassium permanganate (0.63 g) in acetone until the purple colour persisted. The mixture ws filtered through "Solkafloc" (Trademark) and concentrated in vacuo to give an oil which was chromatographed on silica (Merck "MK. 60.9385" [Trademark]) eluting with ethyl acetate:hexane, 1:1, to give a solid. Recrystallisation from ethyl acetate gave 2-methoxy-6-(4-pyrimidinyl)quinoline, m.p. 164°-165°, (0.54 g).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)[CH3:19]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:11][CH2:10][CH2:9][N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:2]=2[Cl:1])=[O:12])=[CH:22][CH:21]=1)[CH3:19]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CN(CCO)C(=O)NCc1cccc(Cl)c1Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)OCCN(C)C(=O)NCc2cccc(Cl)c2Cl)cc1
Reaction time: 8 h
Yield: 6.1 %

Procedure:
To a solution of 3-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (70 mg, 0.27 mmol) in DMF were added DMAP and 4-ethylphenylisocyanate (80 mg, 0.54 mmol). The reaction mixture was stirred overnight. The reaction mixture was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2,3-dichlorobenzyl)-1-methylureido)ethyl 4-ethylphenylcarbamate (7 mg, 6.5%). LRMS (M+H+) m/z 424.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][CH2:12][CH2:13][C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:21][CH:22]=[CH2:23])[CH2:15][C:16]([O:18]CC)=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:21]([C:14]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:13][CH2:12][N:11]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH3:10])[C:16](=[O:18])[CH2:15]1)[CH:22]=[CH2:23]
Reactant: C=CCC(CCN[C@@H](CC)c1ccc(Br)cc1)(CC(=O)OCC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: C=CCC1(c2ccccc2)CCN([C@@H](CC)c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of ethyl 3-(2-((S)-1-(4-bromophenyl)propylamino)ethyl)-3-phenylhex-5-enoate (0.5028 g, 1.10 mmol) and DBU (1.30 g, 8.54 mmol) in toluene (10 mL) was heated to reflux under nitrogen for 2 d. The reaction mixture was cooled to rt, quenched with 2 N aq HCl, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.3045 g (67%) of 4-allyl-1-((S)-1-(4-bromophenyl)propyl)-4-phenylpiperidin-2-one. LC-MS Method 3 tR=2.18, 2.22 min, m/z 412, 414 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][CH:12]([C:19](=[O:39])[N:20]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:11][CH:12]([C:19](=[O:39])[N:20]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:48])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCC(CS(=O)c1ccc(Cl)c(Cl)c1)C(=O)N(CCCc1ccccc1)CCCc1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCC(CS(=O)(=O)c1ccc(Cl)c(Cl)c1)C(=O)N(CCCc1ccccc1)CCCc1ccccc1
Temperature: 0 °C
Yield: 88.5 %

Procedure:
Into a solution of methyl 5-(3,4-dichlorophenylsulfinyl)-4-[N,N-bis(3-phenylpropyl)carbamoyl]pentanoate (220 mg) in dry dichloromethane (20 ml) were added portions of m-chloroperbenzoic acid (80%, 120 mg) with stirring at 0° C. After stirring at room temperature for 4 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (50:1) to give 200 mg of methyl 5-(3,4-dichlorophenylsulfonyl)-4-[N,N-bis(3-phenylpropyl)carbamoyl]pentanoate as an oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)(O)[O-].[Na+].Br[C:50]1[CH:51]=[C:52]([CH3:57])[CH:53]=[CH:54][C:55]=1[Cl:56]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:56][C:55]1[CH:54]=[CH:53][C:52]([CH3:57])=[CH:51][C:50]=1[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)c(Br)c1
Reactant: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCOC(c4ccccc4)C3)cc2)c1
Temperature: 120 °C
Yield: 2.8 %

Procedure:
109 mg of 4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 102 mg of bis(pinacolato)diboron, 97 mg of potassium acetate, 11 mg tetrakis(triphenylphosphine)palladium(0), and 1.9 mL DMF. The mixture was heated in a microwave reactor at 120° C. for 7 minutes and cooled. 0.8 mL of 2M aqueous sodium bicarbonate was added along with 101 mg of 3-Bromo-4-chlorotoluene in 0.15 mL DMF. The mixture was heated in the microwave reactor for an additional 5 minutes at 120° C. The reaction was cooled and filtered through Celite, washing with methylene chloride. The eluant was concentrated and purified by flash chromatography twice using an ethyl acetate/hexanes gradient to afford 3.5 mg of product. ES MS (+) m/z 378
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([C:18](Cl)=[O:19])[CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:21]=1)([O-:3])=[O:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:21]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1C=C2
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1C=C2
Temperature: 25 °C

Procedure:
Stir a mixture of the crude 8-nitrodibenzo[b,f]thiepin-3-carboxylic acid chloride in dry tetrahydrofuran at -78° C. under nitrogen, and add dropwise a filtered solution of 1.1 equivalents of lithium tri-tertiarybutoxy-aluminum hydride in tetrahydrofuran. Stir the mixture for 30 minutes at -78° C. and allow to warm to ambient temperature. Add the mixture to ice-cold dilute hydrochloric acid, and isolate the product by extraction with chloroform. Purify the title compound by chromatography on silica gel using a mixture of ethyl acetate and toluene for elution.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)O>>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:9](=[O:17])[C:10]3[C:11]([O:5][C:4]=2[CH:3]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)c1ccccc1O
Product: O=c1c2ccccc2oc2cc(O)ccc12
Yield: 12.3 %

Procedure:
Resorcinol (5.5 g, 50 mmol) and methyl salicylate (11.0 g, 72 mmol) were refluxed for 5 h using a Dean-Stark trap to remove H2O and MeOH. The resulting black oil was chromatographed over silica with 20% ethyl acetate-hexane as eluent. A yellow solid was isolated which was subsequently recrystallized from ethyl acetate to give 1.3 g (12.3%) of 3-hydroxy-9H-xanthen-9-one (lit. mp 242° C.). Literature references to the synthesis of this compound: R. J. Patolia and K. N. Trivedi, Indian J. Chem., 22B, 444 (1983); J. S. H. Davies, F. Scheinmann, and H. Suschitzky, J. Org. Chem., 23, 307 (1958). ##STR37##
Reaction SMILES: [C:1]([Si:5]([CH3:43])([CH3:42])[O:6][CH:7]([C:17]1[C:18]([CH3:41])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([CH2:37][C:38](O)=[O:39])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[C:1]([Si:5]([CH3:42])([CH3:43])[O:6][CH:7]([C:17]1[C:18]([CH3:41])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3([CH2:37][C:38]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:39])[CH2:35][CH2:36]3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(CC(=O)O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CS(N)(=O)=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(CC(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the procedure described in Example 315 using [1-(4′-{4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropyl]-acetic acid and methanesulfonamide.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([F:43])=[C:38]([F:44])[C:37]=1[CH2:45][CH2:46][OH:47].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:47][CH2:46][CH2:45][C:37]3[C:36]([F:35])=[C:41]([F:42])[CH:40]=[C:39]([F:43])[C:38]=3[F:44])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1c(F)c(F)cc(F)c1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2c(F)c(F)cc(F)c2F)cc1
Reaction time: 18 h
Yield: 22.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), 2-(2,3,5,6-tetrafluorophenyl)ethanol (51.8 mg, 0.267 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DIAD (0.052 mL, 0.267 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2,3,5,6-tetrafluorophenethoxy)phenyl)pyridin-3-yl)acetic acid (7.4 mg, 0.012 mmol, 22.49% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.48 (br. s., 1H), 7.21 (d, J=8.4 Hz, 1H), 7.08-6.88 (m, 3H), 5.81 (s, 1H), 4.34-4.20 (m, 2H), 3.29 (br. s., 1H), 3.13 (t, J=6.4 Hz, 2H), 2.82-2.76 (m, 1H), 2.43 (s, 3H), 2.16 (br. s., 1H), 2.04 (s, 3H), 1.94 (br. s., 1H), 1.48 (br. s., 1H), 1.29 (br. s., 1H), 1.17 (d, J=13.2 Hz, 1H), 1.12 (s, 9H), 1.00 (d, J=11.0 Hz, 1H), 0.84 (br. s., 3H), 0.59 (br. s., 3H). LCMS+H)=617.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][CH2:9][C:10](O)=[O:11])[CH:7]=1.O.O.[Sn](Cl)Cl>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[Cl:16])[NH:13][C:10](=[O:11])[CH2:9][NH:8]2
Reactant: O=C(O)CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: O=C1CNc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A solution of N-(5-bromo-4-chloro-2-nitrophenyl)glycine (0.255 g, 0.824 mmol) and tin (II) chloride dihydrate (0.560 g, 2.48 Aldrich, used as received) was refluxed for 3 h. It was then cooled to r.t. and allowed to stand overnight at r.t. The white solid was filtered and dried to yield 0.038 g (18%) of pure title compound as white flakes; m.p. 230°-232° C.; 1H NMR (DMSO-d6):3.732 (s, 2H), 6.371 (s, 1H), 6.830 (s, 1H), 6.912 (s, 1H), 10.437 (s, 1H). Extraction of the filtrate with ethyl acetate (30 mL) gave 0.136 g (68%) more product to get a combined yield of 81%.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[CH3:16])=[CH:8][CH:9]=[CH:10][C:3]1=2.[C:20](=O)([O-])O.[Na+]>ClCCl>[ClH:1].[CH3:16][C:15]1[S:14][C:13]2=[N:17][CH2:18][CH2:19][N:12]2[C:11]=1[C:7]1[C:4]2[CH:5]=[C:6]([CH3:20])[S:2][C:3]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: CC1=C(c2cccc3sccc23)N2CCN=C2S1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(c2cccc3sc(C)cc23)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (2 g; prepared in a manner similar to that described in Example 9 Method A), 5M aqueous sodium hydrogencarbonate solution (50 ml) and dichloromethane (50 ml) was stirred at ambient temperature for 30 minutes, then the free base was extracted into dichloromethane (2×50 ml). The combined extracts were dried (MgSO4) and the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (40 ml), then the stirred solution was cooled to −70° C. and n-butyllithium (2.5M solution in hexanes; 2.85 ml) was added dropwise under nitrogen. The mixture was stirred at −70° C. for 1 hour, then methyl iodide (0.45 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour then it was poured into saturated aqueous ammonium chloride solution (50 ml). The product was extracted into ethyl acetate (2×50 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified via flash chromatography over silica using a 9:1 mixture of dichloromethane and methanol as eluant. Appropriate fractions were combined and the solvents were removed in vacuo. The residue was dissolved in ethanol, concentrated hydrochloric acid (10 drops) was added, the solvent was removed in vacuo, and the residue was triturated with ether (30 ml). The mixture was allowed to stand at ambient temperature for 72 hours then the resulting solid was collected by filtration and dried in vacuo to give 2-methyl-3-(2-methylbenzo[b]thiophen-4-yl)-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (1.15 g) as a colourless solid, m.p. 271° C.
Reaction SMILES: [OH2:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][S:19][C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)[C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1.CC1C=CC(C2N3C=CC=C(CSC4NC5C=CC=CC=5N=4)C3=NC=2)=CC=1.N1C2C=CC=CC=2N=C1>>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][S:19]([C:20]4[NH:21][C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)=[O:1])[C:12]3=[N:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(-c2cnc3c(CSc4nc5ccccc5[nH]4)cccn23)cc1
Reactant: O
Agent: c1ccc2[nH]cnc2c1
Product: Cc1ccc(-c2cnc3c(CS(=O)c4nc5ccccc5[nH]4)cccn23)cc1
Yield: 56 %

Procedure:
The title compound (801 mg) was prepared by the method of Example 2 using 1.38 g (3.7 mmole) of 2-[[[3-(4-methylphenyl)imidazo[1,2-a]pyridin-8-yl]methyl]thio]-1H-benzimidazole hemihydrate (see Example 53) instead of 2-[(imidazo[1,2-a]pyridin-8-yl]methyl)thio]-1H-benzimidazole. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37](O)=[O:38].ON1C(=O)CCC1=O.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37]([NH:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Yield: 65.5 %

Procedure:
A mixture of p-toluenesulfonic acid salt of Phe-Gly-OBzl (3.06 g), Boc-Gly-OH (1.10 g), N-hydroxysuccinimide (941 mg), N-methylmorpholine (0.725 ml), and N,N-dimethylformamide (40 ml) was cooled to 4° C., and added with N,N′-dicyclohexyl-carbodiimide (1.56 g). The mixture was allowed to react overnight at room temperature with stirring, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=98:2 solution) to give Boc-Gly-Phe-Gly-OBzl (1.93 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:20]3[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=3[Cl:18])(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(N)c2c1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3c(Cl)cccc3Cl)cc12
Yield: 18.6 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-2,6-dichlorobenzenesulfonamide can be obtained as described in Example 39 from 0.8 g of 3,5-diamino-1H-indazole, 8 ml of pyridine, 8 ml of tetrahydrofuran and 1.29 g of 2,6-dichlorobenzenesulfonyl chloride. 350 mg of N-(3-amino-1H-indazol-5-yl)-2,6-dichlorobenzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 250° C. (analysis C13H10Cl2N4O2S % calculated C, 43.71; H, 2.82; Cl, 19.85; N, 15.68; O, 8.96; S, 8.98. % found C, 43.39; H, 2.92; Cl, 19.45; N, 15.31; S, 8.73).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.O[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
3 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 0.93 g of 4-hydroxybenzonitrile and 2.9 g of potassium carbonate are stirred for 17 hours at 40° C. in 30 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase yields 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-benzonitrile. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 4.14 (t, 2H), 4.32 (t, 2H), 4.58 (d, 2H), 6.10 (t, 1H), 6.83 (s, 2H), 7.00 (d, 2H), 7.60 (d, 2H)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1>C(O)(=O)C#CCCC>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:15](=[O:16])[C:14]#[C:13][CH2:12][CH2:11][CH3:10])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Agent: CCCC#CC(=O)O
Product: CCCC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 26.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and hex-2-ynoic acid, to afford the title compound (8.1 mg, 26.2%). Data: UPLC (C) Rt: 1.94 min; m/z 494.3 (M+H)+.