Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[F:23][C:24]([F:35])([F:34])[S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([S:25][C:24]([F:35])([F:23])[F:34])=[CH:27][CH:28]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: FC(F)(F)Sc1ccc(CCl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(SC(F)(F)F)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A mixture of 4-[[N-(2-amino-5-chlorobenzoyl)glycyl]aminomethyl]piperidine (16.2 mg, 0.050 mmol) with 4-(trifluoromethylthio)benzyl chloride (20.3 mg, 0.075 mmol), acetonitrile (1.0 mL) and chloroform (0.56 mL) was stirred at 60° C. for 15 hours, cooled, then loaded onto a VarianM SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-5-chlorobenzoyl) glycyl]aminomethyl]-1-[4-(trifluoromethylthio)benzyl]piperidine (Compd. No. 1616) (21.9 mg, 85%). The purity was determined by RPLC/MS (96%). ESI/MS m/e 545.2 (M++H, C23H26ClF3N4O2S).
Reaction SMILES: [NH2:1]C1C=CC(C2CCC(C(OC)=O)C2)=CC=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOC(C)=O>CCO>[NH2:1][C:20]1[CH:19]=[CH:18][C:17]([CH2:23][CH2:24][CH2:25][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:22][CH:21]=1
Reactant: COC(=O)C1CCC(c2ccc(N)cc2)C1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccc(N)cc1)C(=O)OCC
Yield: 10 %

Procedure:
Following the general procedure of Intermediate 84 except that diethyl (3-phenylpropyl)malonate (J. Med. Chem., 2004, 47(12), 3282) was used in place of methyl 3-phenylcyclopentanecarboxylate, nitration and reduction (using EtOAc as solvent in place of EtOH) gave the title compound (purified by chromatography, eluting with 10-50% EtOAc/Isohexane); 1H NMR δ 1.17 (t, 6H), 1.42-1.53 (m, 2H), 1.69-1.78 (m, 2H), 2.40 (t, 2H), 3.45 (t, 1H), 4.07-4.16 (m, 4H), 4.81 (s, 2H), 6.48 (d, 2H), 6.81 (d, 2H); MS m/e MH+ 294.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([Cl:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:3]=1.Br[CH2:23]CBr>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:23][O:10][C:6]=2[C:5]([Cl:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:20][CH2:21]3)=[CH:15][CH:14]=2)[CH:3]=1
Reactant: BrCCBr
Reactant: Clc1c(Cc2ccc(C3CC3)cc2)cc(Br)c2c1OCO2
Product: Clc1c(Cc2ccc(C3CC3)cc2)cc(Br)c2c1OCCO2

Procedure:
Similar procedure with preparation of 193 proceeded except for using 1,2-dibromoethane to obtain the compound 200.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:11]([CH3:21])([CH3:20])[N:10]=2)=[CH:5][CH:4]=1.C(#N)C>C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:11]([CH3:21])([CH3:20])[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=NC(C)(C)C(c3ccncc3)C2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NC(C)(C)[C@@H](c3ccncc3)C2)cc1

Procedure:
148 G. of racemic 4-[2-(p-methoxyphenyl)-5,5-dimethyl-1-pyrrolin-4-yl]-pyridine were dissolved in 280 ml. acetonitrile and 450 ml. ethylacetate. 150 G. of (+)-camphersulfonic acid are added and the reaction mixture is heated on a steam bath until all reactants are in solution. The resulting solution is cooled on an ice bath until crystallization begins, then it is allowed to crystallize at room temperature for 2.5 hours. The crystals are filtered and washed with ethyl acetate. The crystals are taken up in water and calcium carbonate is added until a pH 9 is reached and recrystallization occurs. The crystals are filtered, washed with water and taken up in methylene chloride. The organic phase which results is dried over sodium sulfate and evaporated under reduced pressure to obtain crystals of 4-[(4R)-2-(p-methoxyphenyl)-5,5-dimethyl-1-pyrrolin-4-yl]-pyridine: [α]D =-152° (CHCl3, c = 5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:13][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)=[C:2]([F:1])[CH:3]=2)[N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(-n2ccnc2)c(F)c1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3ccnc3)c(F)c2)n1

Procedure:
The title compound was prepared from 3-fluoro-4-imidazol-1-yl-phenylamine (81 mg, 0.46 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) in analogous manner to the procedure described in example 1e). Obtained as a light yellow wax (40 mg, 24%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: IC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(C4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([Cl:24])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: ClCCl
Product: CC(Cl)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To the solution of 1-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (50 mg, 0.158 mmol) in DCM (1.5 mL), was added thionyl chloride (0.1 mL, 1.378 mmol) dropwise. The mixture was stirred at room temperature for 1 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, and concentrated in vacuo to afford the title compound (50 mg, 95% yield). LCMS: rt=3.63 min, [M+H+]=299
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1([CH3:23])[CH2:16][NH:15][CH2:14][CH2:13][N:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:23])([CH3:10])[CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: CC1(C)CNCCN1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)CN(c2ccnc(Cl)c2Cl)CCN1c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of D10 (1.083 g, 3.955 mmol), 2,2-dimethyl-1-phenylpiperazine (0.903 g, 4.745 mmol) [C.A.S. 2946-75-0] and DIPEA (1.378 ml, 7.909 mmol) in CH3CN (15 ml) was heated in a sealed tube at 100° C. for 5 days. After cooling, the solvent was concentrated in vacuo. The residue was purified by column chromatography (silica gel; Heptane/EtOAc 100/10 to 80/20 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D55 (0.56 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][N:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][N:4]=1
Reactant: COc1cc(/C=C/c2ccccc2)cnc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CCc2ccccc2)cnc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
A flask containing a solution of 2,3-dimethoxy-5-[(E)-2-phenylethenyl]pyridine (Intermediate 5) (0.07 g, 0.29 mmol) in ethanol (10 ml) was evacuated and flushed with nitrogen. Palladium (10% on carbon) (0.03 g, 0.03 mmol) was added and the reaction vessel was evacuated and flushed with nitrogen before being filled with hydrogen gas from a balloon and stirred at room temperature for 45 minutes. The catalyst was removed by filtration through a pad of celite which was then washed with ethanol (20 ml). The combined organics were concentrated in vacuo to give 2,3-dimethoxy-5-(2-phenylethyl)pyridine as a colourless oil (70 mg, 99%).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[CH:20]=[CH:19][C:17]([NH2:18])=[N:16][C:14]1=[O:15])[CH2:2][CH3:3].[Cl-].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>O.N1C=CC=CC=1>[C:22]([NH:18][C:17]1[CH:19]=[CH:20][N:13]([C@@H:6]2[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]2[O:4][CH2:1][CH2:2][CH3:3])[C:14](=[O:15])[N:16]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.5 h

Procedure:
To the 2′-O-propylcytidine reaction mixture of Example 82 in an ice bath was added pyridine (60 ml) and trimethylsilIyl chloride (60 ml). The reaction was stirred for 30 mins followed by the addition of benzoyl chloride (55 ml). The resulting reaction mixture was stirred for 2.5 hr. and then cooled in an ice bath. H2O (100 ml) and conc. NH4OH (100 ml) were added. After stirring for 30 mins, the reaction mixture was evaporated and the residue partition between H2O and CH2Cl2. The organic phase was washed once with dil Na2CO3, once with dil HCl, dried over MgSO4 and evaporated. The resulting residue was loaded on a silica gel column (150 g) and eluted with first CH2Cl2 then 5 to 10% MeOH in CH2Cl2 as the elution solvent. The product containing fractions were evaporated to a foam. The foam was crystallized from EtOAc/Hexanes to give the product (6.5 g total) in several crystal batches.
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:57]2[CH:62]=[CH:61][C:60](Br)=[CH:59][N:58]=2)[CH3:56])[CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:57]2[CH:62]=[CH:61][C:60]([C:1]#[N:2])=[CH:59][N:58]=2)[CH3:56])[CH:38]=1)=[O:36])[CH3:33]
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Reactant: CCNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cn2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
Example 17 is prepared as described for Example 15, substituting preparation 15b with preparation 17b. ESI mass spectrum: [M+H]+=455; Retention time HPLC: 1.03 min (Z018_S04).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:21]=2)[CH:15]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 80 %

Procedure:
A mixture of methyl thiosalicylate (2.0 g, 11.7 mmol), 4-methoxy-2-cyanopyridine (1.5 g, 11.1 mmol), triethylamine (2.5 ml, 17.9 mmol) and toluene (5 ml) was refluxed for 12 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.4 g, 81%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.[OH-].[Na+]>C1COCC1>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccccc4)cc23)CC1
Yield: 75.7 %

Procedure:
By a method similar to Example 31, using benzenesulfonyl chloride (280 μL, 2.2 mmol), 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (418 mg, 1.8 mmol) in 0.2 N sodium hydroxide (10 mL, 2.0 mmol) and THF (6 mL) gave 650 mg of an off white solid. The crude product was recrystallized from ethyl acetate to give 505 mg (75%) of tan needles: mp=192-194° C.; MS(m/e): 370 (M+); Calculated for C20H22N2O3S: C, 64.84; H, 5.99; N, 7.56. Found: C, 64.92; H, 6.19; N, 7.67.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[C:15]([C:14]1[CH:23]=[CH:24][C:25]2[N:26]=[C:8]([C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])[NH:11][C:12]=2[CH:13]=1)(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(C)c(C(=O)O)[nH]1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C)c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
3,5-Dimethylpyrrole-2-carboxylic acid (99 mg, 0.71 mmol) was added to a pyridine (3 ml) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added, and the mixture was heated to 70° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2). The residue was dissolved in acetic acid (3 ml), and stirred for 8 hours at 100° C. The reaction mixture was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), to afford 5-benzoyl-2-(3,5-dimethylpyrrol-2-yl)-benzimidazole (34 mg, 15% in two steps) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[C:10]3([CH2:35][O:27][C:19]4[CH:20]=[C:21]5[C:22](=[CH:26][C:18]3=4)[CH2:23][CH2:24][O:25]5)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc(F)ccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: mp 228-229° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 7.39-7.25 (m, 10H), 7.06 (s, 1H), 6.90-6.87 (m, 1H), 6.72-6.65 (m, 1H), 6.42-6.38 (m, 3H), 4.83 (ABq, 2H), 4.53 (t, J=9.0 Hz, 2H), 3.02-2.97 (m, 2H); MS (ES+) m/z 464.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[CH:20]([Mg]Br)([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)([OH:8])[CH:20]([CH3:22])[CH3:21])=[N:4][CH:3]=1
Reactant: CC(C)[Mg]Br
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (800 mg, 2.31 mmol) in anhydrous THF (16 ml) was treated dropwise over 1 h with isopropylmagnesium bromide (2.31 mmol, 2 M, 1.15 mL) at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 15 min, the reaction was allowed to reach room temperature. After 1 h, the reaction mixture was quenched with saturated ammonium chloride and taken up in ethyl acetate, washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 20% EtOAc in hexanes) and then by preparative HPLC reverse phase (C-18) eluting with 55% to 100% water in acetonitrile (0.1% trifluoroacetic acid). The collected fractions were diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxy-2-methylpropyl]cyclohexanecarboxylate as a white solid. MS ESI calc'd. for C16H24BrNO3S [M+H]+ 390, 392. found 390, 392. 1H NMR (500 MHz, CDCl3) δ 7.60 (s, 1H), 4.10 (q, J=7.1, 2H), 2.30-2.20 (m, 1H), 2.17-2.06 (m, 1H), 2.05-1.79 (m, 2H), 1.93-1.81 (m, 1H), 1.62-1.50 (m, 1H), 1.48-1.20 (m, 5H), 1.22 (t, J=7.1, 3H), 0.88 (d, J=9.8, 3H), 0.87 (d, J=9.8, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][CH:26]=2)=[O:35])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1c[nH]c2ccccc12

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 106 mg (0.661 mmol) of indole-3-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR86## is obtained (92 mg, 33%) as oil. TLC: methylene chloride/methanol/conc. ammonia (350:50:1) Rf =0.61, FD-MS: M+ =505,507; IR: 3450, 3260, 1770, 1635 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.O>CN(C)C=O>[Si:25]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To methyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (Tetrahedron, 28, 4395, 1972) (10.0 g) in dimethylformamide (75 ml) was added t-butyldimethylsilyl chloride (4.97 g) and imidazole (2.24 g). The mixture was heated at 50° C. for 1 hour, then left at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The extract was washed twice with water, dried over magnesium sulfate and evaporated under vacuum to give methyl (E) 6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a beige solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([N:20]([CH3:35])[C@H:21]([CH2:33][OH:34])[CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[SH:36][C:37]1[S:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[S:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=[C:37]1[S:36][C:33](=[O:34])[C@H:21]([CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:20]([C:18](=[O:19])[C@H:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH3:35]
Reactant: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@H](CO)CCCNC(=O)OC(C)(C)C
Reactant: Sc1nc2ccccc2s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Sc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
This was prepared in a two step sequence. A solution of Boc-homophenylalanyl-Nδ-Boc-Nα-methylornithinol (D) (392 mg) and 2-mercaptobenzothiazole (267 mg) in dry tetrahydrofuran (9 ml) was cooled to 0° C. under nitrogen atmosphere. Then, a solution of triphenylphosphine (1.04 g), anhydrous tetrahydrofuran (1 ml), and diethyl azodicarboxylate (620 μl) was added. The reaction mixture was stirred for 1.5 h at 0° C., concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexane) to give Boc-homophenylalanyl-Nδ-Boc-Nα-methylornithinyl 2-benzo-thiazolyl thioether (270 mg). This intermediate was deprotected by Procedure E to afford titled product (75 mg): HPLC [20 to 40% gradient (acetonitrile/0.1% TFA) over 60 min, retention time=42.96 min]; 1H NMR (400 MHz, D2O) δ1.49 (m, 2H), 1.83 (m, 2H), 1.98 (m, 1H), 2.18 (m, 1H), 2.79 (m, 2H), 2.82 (s, 3H), 3.09 (m, 2H), 3.57 (dd, J=14.8; 11.2 Hz, 1H), 3.70 (dd, J=14.8; 4.0 Hz, 1H), 4.46 (m, 1H), 5.01 (m, 1H), 7.17 (m, 2H), 7.38 (m, 3H), 7.49 (t, J=8.0 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), and 7.94 (d, J=8.4 Hz, 1H).