Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)N.C(O)(=O)C>O>[F:7][C:8]([F:17])([F:16])[C:9]1[CH:15]=[C:14]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:13]=[CH:11][CH:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C/C(N)=C\C#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=CC#N)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Aminocrotonitrile (1.0 g, 12.2 mmol), 3-trifluoromethylaniline (2.0 g, 12.4 mmol), and acetic acid (1.23 g, 20.5 mmol) are dissolved in water (8 ml). The reaction mixture is stirred at room temperature for 30 minutes. The mixture is extracted with toluene three times and the organic phase is dried over sodium sulfate. The solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Ic1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
To a solution of iodobenzene (102 mg), 4-chlorophenylboronic acid (117 mg), and potassium carbonate (138 mg) in ethanol (3 ml) was added the plated mesh catalyst precursor (12 mm by 14 mm, wire diameter of 0.1 mm, opening of 0.154 mm) prepared in Example 6 and heated for 12 hours at 80° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was taken off from the mixture and washed with ethanol. The solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane) to give an intended product, 4-chlorobiphenyl quantitatively. The catalyst precursor taken off from the mixture could be recycled at least ten times with an average yield of not less than 90%. The wet-gilded type and the dry-gilded type provided the similar results.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCCl>[C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:4]([O:3][CH3:2])=[O:10])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 3.00 g (18.1 mmol) of L-proline methyl ester hydrochloride, 5.05 g (18.1 mmol) of trityl chloride and 10 mL of triethylamine in 40 mL of 1,2-dichloroethane is stirred at 22° C. After a few minutes, a thick precipitate began to form. An additional 20 mL of 1,2-dichloroethane is added and the mixture is heated to 60° C. and stirred for 3 hrs. The reaction mixture is partitioned between water (100 mL) and CH2Cl2 (100 mL). The organic layer is washed with satd. NaHCO3 (50 mL), dried (MgSO4) and evaporated. The residue is recrystallized from hexane/EtOAc to give 5.76 g of 1-trityl-pyrrolidine-2-carboxylic acid, methyl ester as a white crystalline solid which is used directly in the next step.
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.C(N(CC)CC)C.C[O:20]C1C=C(C)C(S)=CC=1.O>CO>[NH:7]1[C:6](=[O:20])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: COc1ccc(S)c(C)c1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
6-Chloroguanine derivative prepared in Preparation 6 (4.86 g) was dissolved in 85 ml of methanol and 1.4 g of triethylamine and 2.9 g of 4-methoxythiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20 ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methoxyphenylthio group.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:13][C:12]=12.N1CC(C2C=CC(C(NCC3C=CN4C=CN=C4C=3)=O)=CC=2)C1>>[CH:2]1([S:4]([N:28]2[CH2:29][CH2:30][CH:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][C:14]4[CH:15]=[CH:16][N:11]5[CH:10]=[CH:9][N:8]=[C:12]5[CH:13]=4)=[O:31])=[CH:21][CH:22]=3)[CH2:27]2)(=[O:6])=[O:5])[CH2:3][CH2:1]1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNC2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(S(=O)(=O)C3CC3)C2)cc1

Procedure:
The title compound was prepared as described in Example 557C, substituting cyclopropane sulfonyl chloride for propane-2-sulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(pyrrolidin-3-yl)benzamide for 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (t, J=5.9 Hz, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 7.88 (m, 3H), 7.51 (d, J=1.2 Hz, 1H), 7.45 (m, 2H), 7.38 (m, 1H), 6.85 (dd, J=6.9, 1.7 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H), 3.79 (dd, J=9.7, 7.5 Hz, 1H), 3.53 (m, 2H), 3.43 (m, 1H), 3.23 (m, 1H), 2.78 (m, 1H), 2.34 (m, 1H), 2.01 (m, 1H), 0.98 (m, 4H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)(=O)=O.C(N(CC)CC)C.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:9]1[CH:8]=[C:7]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:12]=[CH:11][CH:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1

Procedure:
Following General Procedure D and using trifluoromethanesulfonic acid, 3-tert-butyl-phenyl ester (Intermediate 101, 2.54 g, 9.0 mmol), triethyl amine (2 mL), copper(I)iodide (0.63 g, 3.33 mmol), trimethylsilyl acetylene (5 mL, 36 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.6 g, 2.25 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound was obtained as a brown oil that was used as such for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][C:39]([OH:44])=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][C:39]([O:44][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccc2c(c1)OCC(c1cccc(F)c1)C2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2cccc(F)c2)C3)nc1

Procedure:
2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 125 mg of 3-(3-fluorophenyl)-chroman-7-ol. The product was recrystallised from ethanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.0, 2.8 Hz), 7.33 (m, 1H), 7.16 (d, 1H J 8.9 Hz), 6.95-7.06 (m, 4H), 6.69-6.71 (m, 2H), 4.38 (dd, 1H, J 10.6, 4.3 Hz), 4.06 (t, 1H, 10.6 Hz), 3.30 (m, 1H), 3.06 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.[Na]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][CH:36]1[CH2:37][CH2:38][O:33][CH2:34][CH2:35]1
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1ccncc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3-amino-isonicotinic acid methyl ester (500 mg, 3.29 mmol), dry N,N-dimethylformamide (10 mL), trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 eq) was added tetrahydro-pyran-4-one (0.5 mL, 4.94 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 24 hours then poured into saturated sodium hydrogenocarbonate (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and evaporated to dryness affording the crude title compound as yellow syrup that was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:22][C:23]1[C:28](B(O)O)=[C:27]([CH3:32])[CH:26]=[CH:25][N:24]=1.[O:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1>>[O:33]1[CH2:34][CH:35]=[C:36]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:28]2[C:23]([F:22])=[N:24][CH:25]=[CH:26][C:27]=2[CH3:32])=[CH:7][CH:6]=4)[CH2:37][CH2:38]1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1ccnc(F)c1B(O)O
Product: Cc1ccnc(F)c1-c1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(C3=CCOCC3)ncc1O2

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA1 above, but using (S)-7-bromo-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described in Method BB41), 2-fluoro-4-methylpyridin-3-ylboronic acid and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH3:13][O:14][CH2:15][CH2:16]O.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:16][CH2:15][O:14][CH3:13])=[O:4]
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 72.5 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 25 g of 2-methoxyethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 8 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into ice water and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 23.9 g (yield 73%) of crude 2-methoxyethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].C(Cl)[Cl:56]>CO.C(Cl)(Cl)Cl>[ClH:56].[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH2:34][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)=[N:33][C:26]=2[NH:25]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: ClCCl
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cl
Product: O=C1CSc2ccc(CNC3CCN(C[C@@H]4Cn5c(=O)ccc6ncc(=O)n4c65)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R)-2-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (50 mg, 0.166 mmol) (for a preparation see Example 16(j)) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (29 mg, 0.90 eq.) (for a synthesis see WO2003087098, Example 301(d)) were stirred in 9:1 chloroform:methanol (1 ml) at room temperature for 3 hours, then sodium triacetoxyborohydride (105 mg, 3.00 eq.) was added. The mixture was stirred at room temperature for a further 30 minutes, then saturated aqueous sodium hydrogen carbonate (0.5 ml) was added, and the organic phase was diluted with DCM (10 ml). The mixture was stirred vigorously for 10 minutes, then the organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The residue was taken up in DCM (ca. 3 ml)+1 drop MeOH and purified by column chromatography on silica (eluted with 0-12% (2M NH3 in MeOH) in DCM). Appropriate fractions were combined and evaporated to give the free base of the title compound as a yellow amorphous solid.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][CH:14]1[CH2:15][CH2:16][CH:17]2[CH2:22][NH2:23])([OH:11])(=[O:10])=[O:9]>C(O)(C)C.O>[S:8]([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[CH2:22][NH2:23])([OH:11])(=[O:9])=[O:10]
Reactant: NCC1CCC2CN1C(=O)N2OS(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O

Procedure:
The compound of Formula (IX) was reacted with trifluoroacetic acid in a suitable solvent such as dichloromethane to provide trifluoroacetic acid and sodium salt of 6-sulfooxy-2-(amino methyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane (X). This trifluoroacetic acid and sodium salt (X) was further treated with water isopropyl alcohol mixture to obtain zwitterion form, (2S, 5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane (XI).
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C>CO>[OH:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH2:2][N:3]([CH2:15][CH2:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5]2
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCc2cc(O)ccc2C1
Yield: 79.8 %

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (345 mg, 1.5 mmol), tert-butyl acrylate (0.44 mL, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.6 mL, 15.0 mmol) in MeOH was irradiated in the microwave at 90° C. for 1800 s. Removal of the solvents gave the residue which was purified on ISCO column (2% to 5% MeOH/CH2Cl2) to provide the title compounds (332 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 6.85 (d, 1H), 6.55 (dd, 1H), 6.54 (s, 1H), 3.55 (s, 2H), 2.83 (m, 4H), 2.76 (m, 2H), 2.54 (dd, 2H), 1.45 (s, 9H). MS (ESI) m/z: Calculated: 277.17; Observed: 277.90 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:32][CH2:33][N:34]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:16][CH:15]=3)[CH2:35][CH2:36]1)(=[O:29])=[O:30])[CH:22]=[CH:21]2
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)ccn1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)ccn1
Yield: 68 %

Procedure:
4-(2-Methyl-4-pyridyl)benzoic acid (62 mg), 1-(6-bromonaphth-2-ylsulphonyl) piperazine (94 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg) were dissolved in DMF (2.5 ml) and the resultant solution stirred at ambient temperature for 16 hours. Excess DMF was removed in vacuo, water (10 ml) was added and the precipitate that formed was filtered, washed thoroughly with cold water and dried over P2O5. The solid thus obtained was purified by flash chromatography at 3 psi on silica (Merck ART 9385) eluting with 2.5% v/v methanol in dichloromethane. There was thus obtained the 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-methyl-4-pyridyl)benzoyl]piperazine (99 mg); mp 204-205° C.; 1H NMR (300 MHz, DMSO-d6) δ=2.48 (s,3H), 3.03 (s,4H), 3.57 (broad s, 4H), 7.46 (t,3H), 7.56 (s,1H), 7.77(d,2H), 7.83(d,2H), 8.17(q,2H), 8.42 (s,1H), 8.48 (d,2H), ppm; MS: m/z 550/552 (M+H)+ (1 Br pattern).
Reaction SMILES: Br.[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]=3Br)=[CH:8][CH:9]=[CH:10][C:3]1=2.C([Mg][Cl:23])C.[CH3:24][S:25]SC>O1CCCC1>[ClH:23].[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[S:25][CH3:24])=[CH:8][CH:9]=[CH:10][C:3]1=2
Reactant: CC[Mg]Cl
Reactant: CSSC
Reactant: BrC1=C(c2cccc3sccc23)N2CCN=C2S1
Agent: Br
Solvent: C1CCOC1
Product: CSC1=C(c2cccc3sccc23)N2CCN=C2S1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1.17 h

Procedure:
3-(Benzo[b]thiophen-4-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (2.3 g) was added in portions under nitrogen at 0-5° C. over 20 minutes to a stirred solution of ethylmagnesium chloride (2.0 M solution in ether; 6.9 ml) in tetrahydrofuran (35 ml), then the mixture was stirred at 0-5° C. for 20 minutes and at ambient temperature 70 minutes. The mixture was cooled to 0° C. and dimethyl disulphide (0.82 ml) was added, then the mixture was stirred at ambient temperature for 4 hours and quenched by the addition of saturated aqueous ammonium chloride solution (40 ml) and water (50 ml). The product was extracted into ethyl acetate (250 ml), then the extract was washed with saturated aqueous sodium chloride solution (2×100 ml), dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 96:4 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo. The residue was triturated with 2M ethereal hydrogen chloride solution (20 ml) and the resulting solid was collected by filtration, washed with ether (2×20 ml) and dried in vacuo to give 3-(benzo[b]thiophen-4-yl)-2-(methylthio)-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (0.219 g) as a cream solid, m.p. 95-105° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[O:7].[Cl:15][C:16]1[CH:31]=[C:30]([Sn:32]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:28][C:17]=1[C:18](ON1C(=O)CCC1=O)=[O:19]>CN(C)C=O>[Cl:15][C:16]1[CH:31]=[C:30]([Sn:32]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:28][C:17]=1[C:18]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][NH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])=[O:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Reactant: N[C@@H](CNC(=O)c1cccs1)C(=O)O
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Reaction time: 72 h

Procedure:
A mixture of 3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin (2.00 g) and 1-[[2-chloro-4-(tributylstannyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 374; 2.50 g, 4.6 mmol) in N,N-dimethylformamide was shaken for 72 h. The resin was washed with dichloromethane and methanol to give N-[2-chloro-4-(tri-n-butylstannyl)benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=2)[NH:22][CH:21]=1)=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=O)C>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=2)[NH:22][CH:21]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc2[nH]cc(C(=O)[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1

Procedure:
To a stirred mixture of lithium borohydride (0.092 g, 4.22 mmol, 2 eq) in anhydrous tetrahydrofuran (5 mL) at 0° C. was added a solution of the (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole (0.80 g, 2.11 mmol) in anhydrous tetrahydrofuran (8 mL). The resultant mixture was heated at reflux under nitrogen for 1 hour. The reaction mixture was cooled, and water (1 mL) was added carefully, followed by ethyl acetate (20 mL). The resultant mixture was stirred at room temperature for 30 minutes, dried (MgSO4), filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue was column chromatographed using silica gel (approximately 50 g) and elution with ethyl acetate/hexanes [1:1] afforded (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-methoxy-1H-indole as a colorless gum: 13C NMR [Note: due to slow nitrogen inversion two conformers of the products are seen by NMR spectroscopy] (CDCl3) δ162.5, 136.9, 136.2, 128.4, 127.8, 127.6, 124.5, 123.3, 120.8, 120.3, 111.5, 66.8, 57.4, 39.5, 36.5, 31.4, 29.8, 25.8, 25.5, 18.8; LRMS (m/z, relative intensity) 364 (30, M+), 204 (17), 160 (92), 145 (17), 117 (13), 91 (100). Anal. calcd for C22H24N2O3 ·0.5 H2O: C, 70.76; H, 6.75; N, 7.50. Found: C, 70.70; H, 6.94; N, 7.15.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O=C1CCC(=O)N1[O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:50])[CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[CH2:29]1)=O.C(N(CC)CC)C>CN(C=O)C.ClCCl>[Br:17][C:15]1[CH:16]=[C:11]([C@@H:2]([NH:1][C:26]([C@@H:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:50])[CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][CH2:38]3)[CH2:29]2)=[O:25])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1cncc(Br)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Yield: 72.9 %

Procedure:
To tert-butyl (3S)-3-amino-3-(5-bromopyridin-3-yl)propanoate (1.33 g, 4.42 mmol) in DMF (17 mL) was added tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 25c 2.54 g, 4.91 mmol) and triethylamine (1.85 mL, 13.2 mmol) in dichloromethane (17 mL) at 0° C. After 3 hours the mixture was quenched by addition of saturated aqueous ammonium chloride solution, phases were separated and the aqueous phase was extracted with diethyl ether. Combined organic extracts were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 12 to 100% followed by methanol in ethyl acetate 0 to 15%) to yield 2.1 g of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate.