Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(S)C.[CH3:6][N:7]([CH3:33])[CH2:8][CH2:9][N:10]1[C:26](=[O:27])[C:25]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:28]C)[CH:22]=4)[NH:17][C:16]=3[C:15]([CH2:30][O:31][CH3:32])=[CH:14][C:13]=2[C:11]1=[O:12]>CN(C)C=O>[CH3:6][N:7]([CH3:33])[CH2:8][CH2:9][N:10]1[C:26](=[O:27])[C:25]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:28])[CH:22]=4)[NH:17][C:16]=3[C:15]([CH2:30][O:31][CH3:32])=[CH:14][C:13]=2[C:11]1=[O:12]
Reactant: COCc1cc2c(c3c1[nH]c1ccc(OC)cc13)C(=O)N(CCN(C)C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: COCc1cc2c(c3c1[nH]c1ccc(O)cc13)C(=O)N(CCN(C)C)C2=O
Temperature: 25 °C
Yield: 34.6 %

Procedure:
520 mg of 60% sodium hydride was suspended in 10 ml of N,N-dimethylformamide. Thereto was dropwise added a solution of 0.87 ml of ethanethiol dissolved in 5 ml of N,N-dimethylformamide, in 5 minutes with stirring at room temperature. Then, thereto was added 90 mg of N-(2-dimethylaminoethyl)-6-methoxy-1-methoxymethylcarbazole-3,4-dicarboximide. The mixture was stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 20 ml of water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=40/1 to 20/1), followed by recrystallization from n-propanol to obtain 30 mg (yield: 35%) of N-(2-dimethylaminoethyl)-6-hydroxy-1-methoxymethylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH2:39])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:30]1([CH2:29][CH2:28][CH2:27][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH:39][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@@H](Cc2cccnc2)C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.66 g; 2.89 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 3-(3-Pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (85) (1.00 g; 2.41 mmol), N,N-diisopropylethylamine (0.68 g; 5.29 mmol) and PyBOP (1.50 g; 2.89 mmol) are added sequentially. The reaction is stirred for 5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (80%→100% ethyl acetate in hexanes) affording the desired product (86) as a white solid. ESMS:MH+ 627.6
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][CH3:16])=[C:5](C(O)=O)[NH:6]2.[H-].[Na+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][CH3:16])=[CH:5][N:6]2[CH2:19][C@H:20]([OH:21])[CH3:22]
Reactant: CCc1c(C(=O)O)[nH]c2ccc(F)c(Cl)c12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cn(C[C@@H](C)O)c2ccc(F)c(Cl)c12
Reaction time: 4 h
Yield: 80 %

Procedure:
A suspension of 1.2 g of 4-chloro-5-fluoro-3-ethyl-indole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 24 ml of tetrahydrofuran. 186 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.5 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 114 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium surfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:2) and subsequently with toluene-ethyl acetate (9:!). 102 g (80%) of (R)-1-(4-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol were obtained as pale brown crystals with m.p. 87°-88°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-:15])=[O:14])=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc([N+](=O)[O-])c1C
Product: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To cooled (0° C.) fuming nitric acid (100 mL) was added slowly 2-methyl-3-nitroanisole (13.0 g, 77.8 mmol) in ten times. After the addition, the mixture was warmed to r.t. and stirred for 4 h, then poured into ice-water (500 g). The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water, saturated NaHCO3, brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by silica column chromatography (petroleum ether/EtOAc=20:1) to obtain the pure product 1-methoxy-2-methyl-3,4-dinitrobenzene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=O)[CH2:14][O:13][CH-]2)=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18].[OH-].[Na+]>C(O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:15][CH2:14][OH:13])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCNc1ccc(N2[CH-]OCC2=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCCNc1ccc(NCCO)cc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 9 %

Procedure:
0.4 mole (10.64 g) of N-[4-(β-aminoethyl)amino-3-nitrophenyl]oxazolidone, prepared according to Example 10, is added to 27 ml of 3N sodium hydroxide and 11 ml of 96° strength ethanol. After being heated for 45 minutes at 95° C., the solution is poured onto ice, and the precipitate obtained is drained and then washed with iced water. After being dried under vacuum, 0.036 mole (8.7 g) of the expected product is obtained. It melts at 112° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:21])=O)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:28][C:29]([O-:31])=[O:30].[Na+]>C(OC(=O)C)(=O)C>[CH2:25]([O:24][C:22]([C:5]1[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][CH2:21][O:31][C:29](=[O:30])[CH3:28])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:27])=[O:23])[CH3:26]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1S(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1SCOC(C)=O
Yield: 43.7 %

Procedure:
A suspension of 3.31 g (8.46 mm) of sulfoxide 34 and NaOAc (anhydrous, 1.10 g) in 9.1 mL of acetic-anhydride was stirred at reflux for 40 minutes. The acetic anhydride was removed at reduced pressure, and the residue diluted with 250 mL of CH2CL2 and 50 mL of H2O. The organic portion was washed with 10% aqueous HCl, 5% aqueous NaHCO3, and brine, dried (anhydrous MgSO4), filtered, evaporated, and flash chromatographed (silica gel, 30% EtOAc in hexane) to give acetate 35 (1.60 g, 44%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[N:34]=[CH:33][C:32]=2[CH3:42])=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[NH:43]1[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44]1>CC(O)C.CCOC(C)=O>[OH:48][C@@H:45]1[CH2:46][CH2:47][N:43]([C:11]2[C:30]([C:31]3[N:35]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:34]=[CH:33][C:32]=3[CH3:42])=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[O:16])=[CH:13][N:12]=2)[CH2:44]1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 140 °C

Procedure:
DIPEA (43.9 μL, 0.252 mmol) was added to a solution of 6-chloro-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 4.1, 55 mg, 0114 mmol) and (R)-pyrrolidin-3-ol (11.96 mg, 0.137 mmol) in iPrOH (114 μL) in a vial, which was sealed and heated at 140° C. for 18 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH 98:2) to afford 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide as an off-white foam. This intermediate (39 mg, 0.073 mmol) was dissolved in DCM (0.8 mL), treated with TFA (0.262 mL, 3.4 mmol) and stirred at RT for 3 h. The RM was poured into 25 mL Na2CO3 10% and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as an off-white powder. HPLC (Condition 4) tR=4.46 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=448.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.81 (m, 2H) 1.86 (s, 3H) 2.78-2.97 (m, 1H) 3.07-3.41 (m, 3H) 4.18 (br. s, 1H) 4.81 (br. s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.58 (br. s, 1H) 7.85 (d, J=9.38 Hz, 2H) 7.93 (br. s, 1H) 8.73 (br. s, 1H) 10.14 (s, 1H) 12.63 (br. s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=1>CC(N(C)C)=O>[C:3]1(=[O:13])[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:18][CH:17]=2)[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C

Procedure:
A suspension of 22.4 g. (0.447 mole) of sodium hydride (50% in mineral oil) in 200 ml. dimethylacetamide is treated dropwise by the addition of 59.6 g. (0.406 mole) phthalimide in 500 ml. dimethylacetamide. The mixture is stirred for 2 more hours at room temperature and then treated dropwise with 100 g. (0.406 mole) α-bromo-p-pivaloyl toluene in 300 ml. dimethylacetamide. The resulting mixture is stirred at room temperature for 18 hours and then the solvent is removed in vacuo. The residue is taken up in methylene chloride/water and the layers separated. The water layer is washed twice with methylene chloride and the combined methylene chloride layers washed twice with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting solid is triturated with ether to give 4'-(phthalimidomethyl)pivalophenone; m.p. 138°-140.5° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([CH3:37])[CH:23]=[CH:22][C:21]([S:24][CH2:25][C:26]([C:28]2[S:32][C:31]([CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=2)=[O:27])=[CH:20][CH:19]=1>>[CH3:37][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][C:26]([C:28]2[S:32][C:31]([CH2:33][C:34]([NH:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[N:9][N:8]4[CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)=[O:35])=[CH:30][CH:29]=2)=[O:27])=[CH:20][CH:19]=1
Reactant: Cc1ccc(SCC(=O)c2ccc(CC(=O)O)s2)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: Cc1ccc(SCC(=O)c2ccc(CC(=O)Nc3ccc4cnn(CCN5CCCC5)c4c3)s2)cc1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and [5-(2-p-tolylsulfanyl-acetyl)-thiophen-2-yl]-acetic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.82 (m, 2 H), 1.98 (m, 2 H), 2.25 (s, 3 H), 3.02 (m, 2 H), 3.52 (m, 2 H), 3.70 (q, J=5.80 Hz, 2 H), 4.05 (s, 2 H), 4.41 (s, 2 H), 4.68 (t, J=6.26 Hz, 2 H), 7.12 (m, 4 H), 7.26 (m, 2 H), 7.74 (m, 1 H), 7.94 (m, 1 H), 8.11 (s, 1 H), 8.27 (s, 1 H), 9.56 (br s, N H); MS (DCI/NH3) m/z 519 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.ClCCl.Cl[C:30]([O:32][CH3:33])=[O:31].C(N(CC)CC)C>C(Cl)Cl.CO>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:30](=[O:31])[O:32][CH3:33])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: COC(=O)Cl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3), 7 mL of dichloromethane, 23 μL of methyl chloroformate and 41 μL of triethylamine were added. The mixture was magnetically stirred at 20° C. during 4 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 102 mg (yield: 87%) of the desired product (formula below) as an orange powder
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.[CH3:11][O:12][C:13]1[C:18]2[O:19][C:20]([C:22](OC)=O)=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O>O1CCCC1.O>[CH3:11][O:12][C:13]1[C:18]2[O:19][C:20]([C:22]3[O:5][N:4]=[C:2]([CH3:3])[CH:1]=3)=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)=NO
Reactant: COC(=O)c1cc2cccc(OC)c2o1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2cc(-c3cc(C)no3)oc12
Temperature: 0 °C
Yield: 16.9 %

Procedure:
Thionyl chloride (10 ml) was added dropwise to methanol (100 ml) with stirring under ice-cooling. 7-Methoxybenzo(b)furan-2-carboxylic acid (10 g) was successively added, and the mixture was refluxed under heating for 1 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g). This was used in the next reaction without purification. Acetone oxime (4.8 g) was dissolved in tetrahydrofuran (100 ml), and butyllithium (1.6M hexane solution) (80 ml) was added dropwise to this solution at −5° C. with stirring. Thereafter, the mixture was stirred under ice-cooling for 1 hr, and a solution (50 ml) of methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g) in tetrahydrofuran was added. The mixture was stirred at room temperature for 20 hr. A solution of sulfuric acid (28 g) dissolved in tetrahydrofuran (120 ml)-water (30 ml) was prepared, into which the reaction mixture was poured. The mixture was refluxed under heating for 2 hr. After cooling, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.1 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:48]([CH3:51])[CH2:49][CH3:50])[C@H:19]([O:46][CH3:47])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:44][CH3:45])[C@@H:29]([CH3:43])[C:30]([NH:32][C@H:33]([CH3:42])[C@@H:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:53][CH2:54][CH2:55][C:56]([OH:58])=[O:57].C([BH3-])#N.[Na+]>>[C:56]([CH2:55][CH2:54][CH2:53][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:48]([CH3:51])[CH2:49][CH3:50])[C@H:19]([O:46][CH3:47])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:44][CH3:45])[C@@H:29]([CH3:43])[C:30]([NH:32][C@H:33]([CH3:42])[C@@H:34]([OH:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:6])[CH3:5])([OH:58])=[O:57]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
100 mg (0.139 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 40) were used, in analogy to the preparation of Intermediate 61, by reaction with 4-oxobutanoic acid in the presence of sodium cyanoborohydride, to obtain 94 mg (84% of theory) of the title compound. The title compound was purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:23]2[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16]C(=O)C(F)(F)F)[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].CC(OC)(C)C>CO.CCOC(C)=O>[NH2:16][CH2:15][C@@H:14]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[N:9]1[C:7]([C:5]1[N:6]=[C:2]([NH2:1])[S:3][C:4]=1[C:23]1[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=1)=[O:8]
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: COC(C)(C)C
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of N-[(1S,3S,5S)-2-(2-amino-5-m-tolyl-thiazole-4-carbonyl)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide (2.33 mmol) in MeOH (7.7 mL) is treated with a sat. aqueous K2CO3 solution (0.62 mL) and stirred at 60° C. for 5 h. After stirring for additional 16 h at RT the mixture is made basic by slow addition of aqueous NaOH solution (32%). Equal volumes of TBME and EtOAc are added and the mixture is stirred vigorously for 1 h. The layers are separated, the aqueous layer is extracted with a mixture of TBME and EtOAc and the combined organic layers are dried over Na2SO4. The solvents are removed in vacuo to give the desired product which is used without further purification. LC-MS (basic): tR=0.67 min; [M+H]+=329.0.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]([NH:9][C:10](=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])SC)#[N:8]>>[C:7]([NH:9][C:10]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])#[N:8]
Reactant: CN(C)CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN(C)C

Procedure:
By the procedure of Example 4, 2-(dimethylamino)ethylamine is reacted with N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.O.C(#N)C>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(S(C)(=O)=O)CC4)c3F)s2)c1
Reaction time: 8 h
Yield: 31.9 %

Procedure:
3-Fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (crude from deprotection of 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide, 0.042 g, 0.066 mmol) was diluted in NMP (1 mL) and treated with methanesulfonyl chloride (0.010 g, 0.086 mmol) and diisopropylethylamine (0.059 mL, 0.331 mmol) at 23° C. The reaction was stirred overnight, then diluted in 10% water in acetonitrile+0.05% TFA and purified on preparative HPLC (acetonitrile/water/trifluoroacetic acid). The fractions containing the desired product were evaporated and the residue was diluted with DMF and applied on a SCX SPE cartridge. This was washed with methanol and eluted with 2M ammonia/methanol/THF. The fractions containing the desired product were concentrated to give a solid (0.0129 g, 32%) which was triturated with ethyl ether, suspended in acetonitrile and treated with a 0.1N hydrochloric acid/methanol solution (0.210 mL). The solution was diluted with water and concentrated on speedvac to give the HCl salt of the title material. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.92 (1H, ddd, J=13.58, 10.04 and 3.41 Hz), 2.25 (2H, dd, J=13.14 and 3.79 Hz), 2.31 (3H, s), 2.76-2.84 (4H, m), 2.86 (3H, s), 6.84-6.88 (1H, br d), 6.93 (1H, s), 7.03 (1H, t, J=5.31 Hz), 7.11-7.16 (2H, m), 7.23-7.29 (2H, m), 7.36-7.45 (3H, m), 7.81 (1H, s), 8.17 (1H, d, J=5.05 Hz), 8.22 (1H, d, J=5.05 Hz), 8.28 (1H, t, J=6.32 Hz), 11.84 (1H, s). LC/MS (M+H)+: 613. HPLC ret. time (Condition C): 5.588 min.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][C:5]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]([Br:32])=[CH:19][C:18]=2I)=[C:4](I)[CH:3]=1.CCCCCC.[Br-].[Mg+2].[Br-].[CH:44]([C:47]1[CH:52]=[C:51]([CH:53]([CH3:55])[CH3:54])[CH:50]=[C:49]([CH:56]([CH3:58])[CH3:57])[C:48]=1[B:59](OC)OC)([CH3:46])[CH3:45]>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][C:5]2[C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]([Br:32])=[CH:19][C:18]=3[B:59]([C:48]3[C:49]([CH:56]([CH3:57])[CH3:58])=[CH:50][C:51]([CH:53]([CH3:55])[CH3:54])=[CH:52][C:47]=3[CH:44]([CH3:46])[CH3:45])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCOc1cc(-c2cc(OCCCCCCCC)c(Br)cc2I)c(I)cc1Br
Reactant: COB(OC)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1cc2c(cc1Br)B(c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1cc(Br)c(OCCCCCCCC)cc1-2
Temperature: 25 °C

Procedure:
2.0 g of 4,4′-dibromo-2,2′-diiodo-5,5′-dioctyloxy-1,1′-biphenyl synthesized as above was put in a 100 ml flask in an atmosphere of nitrogen and 20 ml of tetrahydrofuran was added to dissolve the same. Then, the tetrahydrofuran solution was cooled to −90° C. and 3.4 ml of 1.6M hexane solution was added dropwise. After 1-hour stirring, a solution of 1.5 g of magnesium bromide in 20 ml of tetrahydrofuran was added, warmed to room temperature, and stirred for 1 hour. The mixture was cooled again to −90° C., and 1.01 g of (2,4,6-triisopropylphenyl)dimethoxyborane was added. After warming, the mixture was allowed to react under reflux for 12 hours.