Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[NH:12]2)=[CH:8][CH:7]=1.Cl[Sn](Cl)(Cl)Cl.C(Cl)Cl.[CH3:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].[O-]S([O-])(=O)=O.[Mg+2]>ClCCl.[N+](C)([O-])=O.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:36]([N+:37]([O-:39])=[O:38])[C:28]=3[CH3:27])=[C:11]([C:15]([O:17][CH3:18])=[O:16])[NH:12]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2cc(C(=O)OC)[nH]c2c1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCOc1ccc2c(C(=O)c3cccc([N+](=O)[O-])c3C)c(C(=O)OC)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104 %

Procedure:
To a homogeneous, colorless solution of methyl 6-(2-methoxyethoxy)-1H-indole-2-carboxylate (0.934 g, 3.75 mmol) in dichloromethane (18.74 mL) at 0° C. under nitrogen was added 1M perchlorostannane/CH2Cl2 (4.87 mL, 4.87 mmol) over 10 min. After 5 min, the cold bath was removed, and the yellow, heterogeneous solution was stirred to room temperature for 30 min. A solution of 2-methyl-3-nitrobenzoyl chloride (0.897 g, 4.50 mmol) in nitromethane (18.74 mL, previously dried over MgSO4 overnight) was added over 20 min. After 3.25 hr, additional acid chloride (0.350 g) in nitromethane (3 mL) was added to the reaction. Thirty minutes later, the reaction was poured into ice water (50 mL) and stirred for 15 min. It was diluted with EtOAc (150 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (25 mL). The organic solution was dried over MgSO4 and concentrated in vacuo to give the desired product (1.6103 g, 3.90 mmol, 104% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[N:3][CH:4]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Yield: 98.7 %

Procedure:
To a solution of 2-amino-5-bromopyridine (89.87 g, 0.5194 mol) in toluene (500 mL) was added 2,5-hexanedione (85.0 mL, 0.724 mol). The reaction flask was equipped with a Dean-Stark apparatus and the solution heated to reflux for 14 h. The cooled reaction solution was extracted with H2O (2×200 mL). The organic layer was added directly to a plug of SiO23″l×2″w and eluted with toluene (250 mL). This treatment removes a significant amount of color from the crude product. The resulting eluent was concentrated to a light amber oil, which solidified upon cooling to provide 128.76 g (99%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+]>[Br-].[Zn+2].[Br-]>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:13][N:12]=[N:11][N:6]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Br)cc(Br)c1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Brc1cc(Br)cc(-c2nnn[nH]2)c1
Temperature: 120 °C
Yield: 95 %

Procedure:
A round-bottomed flask was charged with 3,5-dibromobenzonitrile (15.65 g, 60.00 mmol), sodium azide (7.80 g, 120.00 mmol) and zinc bromide (27.00 g, 120.00 mmol). After degassed, DMF (100 mL) was added. The reaction mixture was heated to 120° C. and stirred at this temperature until complete. The reaction was cooled to rt and then in an ice-water bath. 300 mL of 1N aqueous HCl was added. The white precipitate formed was collected by suction filtration, washed with water, and dried together with phosphorous pentoxide under vacuum to afford 17.32 g (95%) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:20]4[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=3.[CH2:36]([Sn](CCCC)(CCCC)CCCC)[CH:37]=[CH2:38].[Li+].[Cl-]>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.C1COCC1>[CH2:38]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:20]4[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:9][CH:8]=3)[CH:37]=[CH2:36]
Reactant: CC(C)Cn1c2ccccc2c2cc(-c3ccc4c(c3)c3cc(Br)ccc3n4CC(C)C)ccc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1ccc2c(c1)c1cc(-c3ccc4c(c3)c3ccccc3n4CC(C)C)ccc1n2CC(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
THF (20 ml) was added into a mixture of 5 (0.62 g, 1.18 mmol), allyltributyltin (0.78 g, 2.36 mmol), Pd(PPh3)4 (0.068 g, 0.06 mmol) and LiCl (0.092 g, 3.54 mmol). The reaction mixture was stirred at 90° C. for 24 hours. After evaporating off the solvent, the crude product was purified by gradient column chromatography on silica gel with hexane/methylene chloride 9:1 to 4:1 (v/v) as the eluent to yield 6 (0.35 g, 61%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.40-8.38 (dd, 2H), 8.19-8.17 (d, 1H), 8.00 (s, 1H), 7.93-7.79 (m, 2H), 7.50-7.41 (m, 4H), 7.34-7.22 (m, 3H), 6.18-6.08 (m, 1H), 5.20-5.10 (m, 2H), 4.15-4.11 (m, 4H), 3.61-3.59 (d, 2H), 2.50-2.39 (m, 2H), 1.03-1.01 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH2:16][CH:15]3[CH2:18][CH:13]2[C:14]3([CH3:20])[CH3:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:19][C:14]1([CH3:20])[CH:13]2[CH2:18][CH:15]1[CH2:16][CH2:17][CH:12]2[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][CH2:22][CH2:21][OH:25])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C#CCCO
Reactant: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of the product of Step A (0.37 g, 0.5 mmol) and but-3-yn-1-ol (0.12 ml, excess) in a mixture of DMF (5 ml) and DIPEA (0.5 ml) was degassed with N2 and Cl2Pd(PPh3)2 (0.07 g) was added, followed by catalytic amount of CuI and the mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NH4Cl solution and diluted with H2O followed by the extraction with EtOAc (100 ml). The organic layer was separated, dried over MgSO4, filtered and the filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the product (0.11 g, 60%), as creamy paste. 1H-NMR (CDCl3) 7.66 (d, 2H, J=8.43 Hz); 7.51 (d, 2H, J=8.43 Hz); 3.81 (b, 2H); 3.01-2.86 (m, 2H); 2.71-2.67 (m, 4H); 2.50-2.10 (m, 2H); 1.94-1.82 (m, 5H); 1.52-1.48 (m, 1H); 1.18 (s, 3H); 1.02 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:15](=[O:17])[C:16]=3[N:8]2[CH2:7][CH2:6]1)[CH3:2].C(O[C@@H](C)CCCCCl)(=O)C>>[CH2:1]([O:3][CH2:4][N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[C:15](=[O:17])[C:16]=3[N:8]2[CH2:7][CH2:6]1)[CH3:2]
Reactant: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O)c(=O)n1C
Agent: CC(=O)O[C@@H](C)CCCCCl
Product: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@H](C)O)c(=O)n1C

Procedure:
(S)-7,8-dihydro-8-ethoxymethyl-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione was prepared according to the method described for the synthesis of (R)-7,8-dihydro-8-ethoxymethyl-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione but using (S)-5-acetoxy-1-chlorohexane in place of (R)-5-acetoxy-1-chlorohexane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[CH2:9][CH2:8][C:7]1=[O:18].[CH2:19]1[NH:24][CH2:23][CH2:22][N:21]2[CH2:25][CH2:26][CH2:27][CH:20]12>>[CH2:19]1[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[CH2:9][CH2:8][C:7]2=[O:18])[CH2:23][CH2:22][N:21]2[CH2:25][CH2:26][CH2:27][CH:20]12
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Reactant: C1CC2CNCCN2C1
Product: O=C1CCC(=O)N(CCCCN2CCN3CCCC3C2)c2ccccc21
Yield: 35.2 %

Procedure:
Analogously to the method for Example 12b, reaction of 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.40 mmol, 0.11 g) and octahydropyrrolo[1,2-a]pyrazine (0.40 mmol, 0.05 g) afforded 0.05 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH:17]=[O:18])=[CH:12][CH:11]=1>C(O)(=O)C>[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])=[CH:12][CH:11]=1
Reactant: CNN=CC(C)=O
Reactant: O=CC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 8.6 %

Procedure:
2-Oxopropanal methylhydrazone (8.540 mmol, 855 mg) synthesized in Reference Synthetic Example 1 and (4-trifluoromethylphenyl)(oxo)acetaldehyde (6.432 mmol, 1.3 g) synthesized in Reference Synthetic Example 7 were dissolved in acetic acid (30 mL) and stirred at 100° C. for about 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/AcOEt=2/1, and 4/1) to give the desired product as an orange solid (157.3 mg, yield 8.6%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].[F:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:3]=[CH:2][CH2:1][N:4]2[C:12]3[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=3[C:6]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]2=3)=[CH:22][CH:21]=1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC=Cc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 0.76 mmol, 1 equiv.) and 4-fluorobromobenzene (134 mg, 0.76 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (5 mg, 0.023 mmol), triphenyl phosphine (12 mg, 0.046 mmol) and triethyl amine (0.22 mL, 2 equiv.) in THF (5 mL) for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (20 mL) and washed with water (5 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (DMSO-d6) δ (ppm): 10.0 (bs, 1H), 7.61-7.58 (d, 2H), 7.44-7.40 (dd, 2H), 7.20-7.11 (m, 3H), 6.4 (d, 1H), 6.3 (m, 1H), 5.0 (m, 2H), 4.62 (d, 1H), 4.29-4.25 (m, 1H), 3.78 (m, 1H), 3.5 (m, 1H), 3.18 (m, 2H), 2.98 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][C:9]([O:23]C)=[C:10]([NH:19][CH:20]([CH3:22])[CH3:21])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2].C1(S)C=CC=CC=1.[H-].[Na+].OS([O-])(=O)=O.[Na+]>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[C:12]2[C:7](=[CH:8][C:9]([OH:23])=[C:10]([NH:19][CH:20]([CH3:22])[CH3:21])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2nc(OC(C)C)cc(C(F)(F)F)c2cc1NC(C)C
Agent: O=S(=O)([O-])O
Agent: Sc1ccccc1
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)Nc1cc2c(C(F)(F)F)cc(OC(C)C)nc2cc1O
Yield: 91.4 %

Procedure:
A solution of 2-isopropyloxy-6-isopropylamino-7-methoxy-4-(trifluoromethyl)quinoline (0.10 g, 0.30 mmol), thiophenol (0.24 g, 2.2 mmol), and NaH (60% dispersion in mineral oil, 78 mg, 2.0 mmol) in 2 mL DMF was heated at 110° C. for 5 h, whereupon the mixture was poured over ice, and adjusted to pH 5 with 2M NaHSO4. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed sequentially with water (2×) and brine, dried over MgSO4, filtered and concentrated. Flash chromatography (4:1 hexanes:EtOAc) afforded 90 mg (95%) of 2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline, a yellow oil. Data for 2-isopropyloxy-7-hydroxy-6-isopropylamino-4-(trifluoromethyl)quinoline: 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 6.98 (s, 1H), 6.92 (s, 1H), 5.37 (sept, 1H, J=6.2), 3.70 (sept, 1H, J=6.3), 1.35 (d, 6H, J=6.2), 1.29 (d, 6H, J=6.3).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO>[CH3:1][O:2][CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[CH:11]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(NC(=O)Cc2ccc(C(F)(F)F)cc2)c1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(OC)C(=O)O)cc1NC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
Ethyl 2-methoxy-3-[4-methoxy-3-[2-[4-(trifluoromethyl)phenyl]acetylamino]phenyl]propanoate (442 mg, 0.986 mmol), methanol (9 mL) and 1 mol/L aqueous solution of sodium hydroxide (5 mL) were mixed. After stirring for 5 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, washed with ether, and then made acidic with diluted hydrochloric acid. The precipitates produced were filtered and dried to afford 379 mg (93%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([Mg]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([C:10]1([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
1-Boc-3-azetidinone (1) (2.0 gm, 11.68 mmol) was dissolved in dry THF (20 ml) under nitrogen and cooled to 0° C. Then the solution was added 2.0 M solution of Benzyl magnesium bromide (2) in THF (8.76 ml, 17.52 mmol) under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred for 1 h. The reaction completion was monitored by TLC. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Crude product was then purified by column chromatography to give compound 3 (2.15 gm, 70%). 1H NMR (400 MHz, DMSOd6) δ: 1.40 (s, 9H), 2.25 (s, 2H), 4.00 (d, 2H), 4.35 (d, 2H), 6.05 (s, 1H), 7.18 (m, 3H), 7.25 (d, 2H); MS: m/z 263.90 (M+1)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[C:16]1[S:25][C:19]2[S:20][C:21](Br)=[C:22]([CH3:23])[C:18]=2[C:17]=1[CH3:26]>C1COCC1.[Zn]>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:16]1[S:25][C:19]2[S:20][C:21]([C:2]3[S:3][CH:4]=[CH:5][C:6]=3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:22]([CH3:23])[C:18]=2[C:17]=1[CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1ccsc1Br
Reactant: Cc1c(Br)sc2sc(Br)c(C)c12
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccsc1-c1sc2sc(-c3sccc3CCCCCCCC)c(C)c2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 2-bromo-3-octylthiophene (4.0 g, 14.5 mmol) in dry THF (20 ml) under nitrogen was added a solution of Rieke zinc (Aldrich, 1.1 g 20 ml of THF, 17 mmol) at −78° C. The solution was allowed to warm to RT and stirred for 16 h. Stirring was stopped and the solution allowed to settle for 2 h. The resultant solution was transferred by cannula into a flask containing 2,5-dibromo-3,4-dimethylthieno[2,3-b]thiophene (1.28 g, 3.9 mmol), degassed THF (50 ml) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (64 mg, 2 mol %) at 0° C. The reaction was warmed to RT over 30 min, and then refluxed for 24 h. The reaction was cooled and quenched with 5% HCL. The resultant mixture was extracted with ethyl acetate (3×50 ml), and the combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica (eluent: petrol), followed by reverse phase chromatography (eluent: CH3CN/THF 2:1) to afford the product as a colourless oil (1.56 g, 72%). M/Z 556 (M+). Found C, 69.1%, H, 7.6%. Calc. for C32H44S4 C, 69.0; H 8.0. NMR gave the expected signals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([CH:23]=O)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:23][C:17]1[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNCCCCN(C)C(=O)OC(C)(C)C)c(C)c1

Procedure:
Using General Procedure B: Reaction of (4-Amino-butyl)-methyl-carbamic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][C:26]=1[CH2:27][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (622 mg) in DMF (7 mL) was added potassium carbonate powder (958 mg) and 2,4-bis(trifluoromethyl)-benzyl bromide (2.13 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-40% EtOAc/hexanes), followed by recrystallization with hexanes to yield the title compound as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:21][C:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:3][CH:4]=2)[O:8][C:9]2[N:26]=[C:25]([C:27]3[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:10]1=2)([CH3:22])[C:13](=[O:20])[NH:14][C:15]1[S:16][CH:17]=[N:18][N:19]=1
Reactant: OB(O)c1ccccc1
Reactant: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(Cl)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(-c4ccccc4)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1

Procedure:
Using a two-step sequence for the synthesis of Example 64, Example 65 was synthesized from the acid from Step 4 of Example 54 and phenylboronic acid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.90 (1H, s), 8.13 (2H, d, J=8.31 Hz), 8.08 (2H, d, J=6.80 Hz), 7.43-7.67 (9H, m), 4.64 (1H, s), 3.18 (3H, s), 3.05 (3H, s), 1.29 (3H, br. s), 1.28 (3H, br. s); MS (ES+) m/z: 577 (M+H); LC retention time: 3.96 min (analytical HPLC Method A).
Reaction SMILES: CN1CCOCC1.[NH:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:9]([C:11]([N:13]([CH3:22])[C@H:14]([C:19]([OH:21])=O)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH3:10].C(Cl)(=O)C(C)(C)C.[NH:37]([CH3:52])[C@H:38]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41]>C(Cl)(Cl)Cl.O>[NH:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:9]([C:11]([N:13]([CH3:22])[C@H:14]([C:19]([N:37]([CH3:52])[C@H:38]([C:43]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[O:21])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH3:10]
Reactant: CN[C@@H](CC(C)C)C(=O)Cc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
17.9 ml (16.4 g=162.4 m mol) N-methylmorpholine are added to a solution of 24.5 g (77.3 m mol) BOC-(D)-Ala-MeLeu-OH dissolved in 200 ml chloroform and the whole is cooled to -20° C. 9.5 ml (9.27 g=77.3 m mol) pivaloyl chloride are then added over 5 minutes and the reaction mixture stirred for 90 minutes, still at -20° C. Anhyride formation is followed by means of IR control and when complete a solution of 18.2 g (77.3 m mol) H-MeLeu-Bzl in 50 ml chloroform is added dropwise at -20° within 5 minutes. A reaction period of 18 hours at -20° C. is required until no more anhydride is present. The obtained solution is poured onto 300 ml water and is extracted in a separating funnel after first diluting with a further 300 ml chloroform. The aqueous phase is extracted with 300 ml chloroform, the combined organic phases dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on 1 kg silica gel (0.063-0.24 mm) using 2% methanol in methylene chloride as eluant to yield the title compound: rotation, [α]D25 =-101.3° (c=0.9 in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1C1CCCCC1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCCC1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-cyclohexyl-1,3-dihydro-indol-2-one (0.11 g, 0.44 mmol) (from Example 19b supra), 3-chlorobenzyl bromide (0.11 g, 0.53 mmol) (Aldrich), potassium iodide (87 mg, 0.53 mmol) and potassium carbonate (0.13 g, 0.95 mmol) in acetone (3 mL) was heated at 60° C. for 2 days in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 5:95, V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexyl-1,3-dihydro-indol-2-one as a white solid. (Yield 30 mg, 18%).