Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[C:11]([C:25]([C:31]([F:34])([F:33])[F:32])([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[H-].[CH:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)([CH3:42])[CH3:41]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:35])([F:36])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:16]([F:18])([F:17])[F:19])([O:20][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:51])=[O:50])[C:21]([F:22])([F:23])[F:24])[CH:12]=[C:11]([C:25]([C:31]([F:32])([F:33])[F:34])([O:30][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:51])=[O:50])[C:26]([F:29])([F:28])[F:27])[CH:10]=1)([O:8][S:49]([C:46]1[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=1)(=[O:51])=[O:50])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(c1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)(=O)OC(c2cc(C(OS(=O)(=O)c3ccc(C(C)C)cc3)(C(F)(F)F)C(F)(F)F)cc(C(OS(=O)(=O)c3ccc(C(C)C)cc3)(C(F)(F)F)C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 76.8 %

Procedure:
4.5 g (7.88 mmol) of 1,3,5-tris-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 40 ml of dry DMF, and 0.95 g (31.5 mmol) of sodium hydride was added while flushing with nitrogen. After dissolution of the hydride, 6.56 g (30 mmol) of 4-isopropylbenzenesulfonyl chloride were added at 0 to 5° C. Slight evolution of heat was observed. The mixture was stirred for 20 hours at 5° C., ethyl acetate was added and the mixture was washed with water, dried, filtered and evaporated down. 9.6 g of crude product were obtained, and said crude product was eluted over a silica gel column with a 1:1 mixture of methylene chloride/hexane. The third fraction obtained was freed from the solvent and gave 6.8 g of 1,3,5-tris-[2,2,2-trifluoro-1-(4-isopropylbenzenesulfonyloxy)-1-trifluoromethylethyl]-benzene. M.p. 105° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:33]([CH3:32])[CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CNCCS(C)(=O)=O
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)CCS(C)(=O)=O)c4)cc23)CC1
Yield: 31 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (42.0 mg, 0.096 mmol), N-methyl-2-(methylsulfonyl)ethanamine (12.0 mg, 0.087 mmol) and NaBH(OAc)3 (58.0 mg, 0.261 mmol) were reacted to give the title compound (15.1 mg, 28.0%).
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[N:17]1([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: C1CNCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Temperature: 25 °C

Procedure:
To a stirred solution of 10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one in dry toluene at room temperature was added piperazine (Aldrich) followed by the dropwise addition of TiCl4. The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution. The resulting mixture was extracted with dichloromethane, and the combined organic phases were then dried (K2 CO3) and concentrated. Purification of the product was conducted on silica gel using ethyl acetate:hexane (5:1→4:1) as the eluant to give 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl>CN(C=O)C.O>[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30][N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COS(C)(=O)=O)CC[C@H]2C1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3ccc4cc(F)ccc43)CC[C@H]2C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
A solution of 8.41 g (62 mmol) of 5-fluoroindole in 250 mL of DMF was treated with 2.46 g (62 mmol) of sodium hydride (60% oil dispersion) and the mixture stirred at 50° C. for 1.5 h. Heating was stopped temporarily, 7.73 g (22.2 mmol) of (7R,9aS)-2-BOC-7-(methanesulfonyloxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 250 mL of DMF was added, and the mixture stirred at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with water, acidified to pH 2 with 6M hydrochloric acid, and washed with ethyl acetate. The aqueous phase was basified to pH 12 with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 3.09 g (36%) of (7R,9aS)-2-BOC-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCBr
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.2 %

Procedure:
A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.50 g, 4.22 mmol), 1-bromoundecane (1.31 ml, 6.33 mmol) and potassium carbonate (874 mg, 6.33 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.78 g (yield: 85.2%)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](C#C)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:12](SC1C=CC(I)=CC=1)[CH2:13][CH2:14][CH2:15][CH3:16]>C(NCC)C.[Cu]I>[C:4]1([C:1]#[C:2][C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CCCCCSc1ccc(I)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The product from step 2.4 (2.82 g) and the product from step 2.2 (6.0 g) were mixed in diethylamine (44 ml). Copper (I) iodide (0.026 g) and dichloro di(triphenylphosphine) palladium (0) (0.193 g) were then added and the mixture was then stirred at 20° C. under argon for 16 hrs. Purification by chromatography gave 4.3 g or tolane product, rapt. 43° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1nc(-c2ccc(N)cc2)cs1
Yield: 72.4 %

Procedure:
In 500 ml of ethyl acetate, was dissolved 4 g of ethyl N-(4-p-nitrophenyl-2-thiazolyl)carbamate, followed by an addition of 3 g of a 10% palladium/carbon catalyst. The mixture was then subjected under normal pressure to reduction with hydrogen gas. The catalyst was filtered off. The filtrate was concentrated and subjected to column chromatography on silica gel. The reaction product was eluted with a chloroform/ethylacetate mixed solvent. The resulting product was then recrystallized from methanol to obtain 2.6 g of ethyl N-(4-p-aminophenyl-2-thiazolyl)carbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[F:14][C:15]1[C:20]([O:21][CH3:22])=[C:19]([CH3:23])[CH:18]=[CH:17][C:16]=1B(O)O.[F-].[Cs+]>C(COC)OC.O>[NH2:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([O:21][CH3:22])[C:15]=2[F:14])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Reactant: COc1c(C)ccc(B(O)O)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C)c(OC)c2F)cc(N)c1Cl
Temperature: 85 °C
Yield: 18.2 %

Procedure:
A solution of 4-amino-3,6-dichloropyridine-2-carboxylic acid, methyl ester (0.24 g, 1.1 mmol), 2-fluoro-3-methoxy-4-methylphenyl boronic acid (0.30 g, 1.63 mmol) and cesium fluoride (3.0 g, 3.26 mmole) in dimethoxyethane (2 mL) and water (2 mL) was purged with a stream of nitrogen for 15 minutes before adding dichlorobis(triphenylphosphine) palladium (0.07 g, 0.1 mmol) and then heated to 85° C. for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×15 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (33% ethyl acetate in hexanes) to give 4-amino-3-chloro-6-(2-fluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylic acid, methyl ester (0.08 g, 0.2 mmol): mp 95-96° C.
Reaction SMILES: [C:1]1([C:14]([O:16]C)=[O:15])[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12]C)=[O:11])[C:5]=12.CO.[OH-].[K+]>O>[C:1]1([C:14]([OH:16])=[O:15])[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([OH:12])=[O:11])[C:5]=12
Reactant: COC(=O)c1ccn2c1C(C(=O)OC)CCC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn2c1C(C(=O)O)CCC2

Procedure:
A solution of 8.6 g. of dimethyl 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-1,8-dicarboxylate in 100 ml. of methanol is treated with a solution of 9.0 g. of potassium hydroxide in 100 ml. of water, and the reaction mixture is refluxed for 24 hours. The cooled solution is evaporated to dryness at a temperature of 30° C. and the residue is dissolved in the minimum amount of saturated sodium chloride solution. The resultant solution is acidified with concentrated hydrochloric acid and the precipitated solid is collected by filtration, washed with water and dried in vacuo. The mother liquor is extracted with ethyl acetate 3 times and the combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure and recrystallization of the combined residues from methanol yields 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-1,8-dicarboxylic acid (VIII, R=H, n=1), m.p. 236°-237° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 88 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 88% of theory. Colourless crystals, m.p. 165° C. (acetonitrile).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[C:11]([O:14][C:15](=O)[CH3:16])(=O)[CH3:12].C(OCC)(OCC)(OCC)C>C(OCC)(=O)C.O>[CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([C:5](=[C:11]([O:14][CH2:15][CH3:16])[CH3:12])[C:6]#[N:7])=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)C(=O)CC#N
Agent: CCOC(C)(OCC)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(C)=C(C#N)C(=O)C(CC)CC

Procedure:
A mixture of 4-ethyl-3-oxo-hexanenitrile (1.013 g, 7.28 mmol), acetic anhydride (1.5 ml) and triethyl orthoacetate (1.240 g, 7.64 mmol) was heated to reflux overnight. The reaction mixture was taken up in ethyl acetate and water. The brine and the ethyl acetate layer were separated. The organic layer was dried and concentrated to give 1.262 g of dry oil which was used directly for the next reaction. 1H NMR (CDCl3): 0.8-1.0(m,6H), 1.44(t,3H), 1.4-1.8(m,4H), 2.61(s,3H), 3.03(m,1H), 4.28(q, 2H)ppm.
Reaction SMILES: C([N:8]1[CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([N+:15]([O-])=O)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCOC(C)=O>CO.[Pd]>[CH2:18]([C:13]1([NH2:15])[CH2:14][NH:8][CH2:9][CH2:10][NH:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])C1(Cc2ccccc2)CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1(Cc2ccccc2)CNCCNC1
Yield: 75.7 %

Procedure:
In a 500 ml flask, compound 5 (16.0 g, 38.5 mmol) was dissolved in methanol (100 mL); Pd/C (10%, 3.0 g, moistened with 0.5 ml water) was added at once followed by ammonium formate (24.0 g, 0.385 mol). The mixture was stirred and heated to reflux for 3 h. When the reaction is complete (TLC PET/AcOEt 9/1), the catalyst was removed by filtration on Celite®, and the filtrate evaporated in vacuo. The residue is redissolved in dichloromethane and washed with 5% aq. NaOH. The organic phase was then dried (Na2SO4) obtaining 6 (5.98 g, 76%) as light yellow oil. M.p.: ESI-MS: 206 (MH+); (Calc. for C12H19N3: 205 u.m.a.).
Reaction SMILES: [O:1]1[C:5]2([C@@H:9]([NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH:27][C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(CC)CC>C1COCC1>[OH:27][C:28]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:29][CH2:30][CH:31]([N:7]2[CH2:8][C@H:9]([NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)[C:5]3([O:1][CH2:2][CH2:3][CH2:4]3)[CH2:6]2)[CH2:32][CH2:33]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CNCC12CCCO2
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCC(O)(c3ccccc3)CC2)CC12CCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the amine of step H (90 mg, 0.243 mmol) and 4-hydroxy-4-phenyl-cyclohexanone (43 mg, 0.226 mmol) in THF (5 mL) was added sodium triacetoxyborohydride (129 mg, 0.61 mmol) followed by Et3N (0.29 ml, 2 mmol). The mixture was stirred at room temperature overnight. Solvent was removed under vacuum. The residue was taken up in EtOAc/NaHCO3 aqueous solution. The two phases were separated and the water layer was extracted with EtOAc twice. The combined organic phase was dried (Na2SO4) and concentrated. Purification by prep-HPLC provided two isomers. MS: 546.4 (M+1)+.
Reaction SMILES: C(CC(O)=O)C.[C:7]([N:14](C(OC(C)(C)C)=O)[C@H:15]([C:22]([OH:24])=O)[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[N:33]1CCOCC1.ClC(OCC(C)C)=O.N[C@@H](CC(C)C)CSCC>C(OCC)(=O)C>[C:7]([NH:14][C@H:15]([C:22]([NH2:33])=[O:24])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCSC[C@@H](N)CC(C)C
Solvent: CCCC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Reaction time: 0.25 h

Procedure:
A mixture of NαNim -bis BOC-(S)-histidine ethyl acetate solvate (0.96 g, 2.50 mmol), 4 methyl-morpholine (0.28 mL, 2.50 mmol) and isobutyl chloroformate (0.33 mL, 2.50 mmol) in ethyl acetate (35 mL) is stirred in an ice bath under N2 for 15 minutes. A solution of (S)-2-amino-1-ethylthio-4-methyl pentane (0.40 g, 2.50 mmol) in ethyl acetate (2 mL) is then added and the reaction stirred at room temperature for 18 hours. After washing with 10% citric acid, brine, saturated NaHCO3 solution and brine, the ethyl acetate extract is dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is flash chromatographed over silica gel. Elution with a mixture of 2% methanol- 98% chloroform affords pure BOC-protected histidineamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[S:15][C:16]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:12][C:11]([C:25]([C:31]([F:34])([F:33])[F:32])([C:27]([F:30])([F:29])[F:28])[OH:26])=[N:10]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[S:15][C:16]([C:19]3[CH2:20][CH2:21][N:22]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:12][C:11]([C:25]([C:27]([F:30])([F:28])[F:29])([C:31]([F:32])([F:34])[F:33])[OH:26])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)s2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
1-(2-Chloro-phenyl)-5-[5-(1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 417, methanesulfonyl chloride (6.0 uL, 0.08 mmol), and triethylamine (38.0 uL, 0.28 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.C(OC([NH:29][CH:30]([CH2:34][NH:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1[Cl:46])(=[O:38])=[O:37])[C:31]([OH:33])=O)=O)C1C=CC=CC=1.[NH2:47][CH:48]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1)[C:49]([N:51]([CH2:55][CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH:52]([CH3:54])[CH3:53])=[O:50]>CN(C=O)C.C(Cl)CCl>[Cl:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][CH:48]([NH:47][C:31](=[O:33])[CH:30]([NH:29][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:34][NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[Cl:46])(=[O:37])=[O:38])[C:49](=[O:50])[N:51]([CH2:55][CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH:52]([CH3:54])[CH3:53])=[CH:69][CH:68]=1
Reactant: O=C(NC(CNS(=O)(=O)c1ccc(Cl)cc1Cl)C(=O)O)OCc1ccccc1
Reactant: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NS(C)(=O)=O)C(C)C)OCC
Reaction time: 12 h

Procedure:
52 mg of EDC, 45 mg of HOBt and 100 μl of N-ethylmorpholine are added to a solution of 124 mg of 2-benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)propionic acid in 1 ml of DMF. A solution of 100 mg of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide in 1 ml of DMF is added dropwise thereto, and the solution is left to stir for 12 h. The reaction solution is filtered, mixed with ethyl acetate and then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying of the organic phase over sodium sulfate is followed by concentration under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=784.186 (calculated); measured value (M−CO2+H)+: 741.10.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:18]1[C:19]([F:35])=[C:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl.O1CCOCC1>CC1C=CC(C)=CC=1.[Pd]>[CH2:27]([O:26][C:25]([NH:24][C:20]1[C:19]([F:35])=[C:18]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:1][CH:2]=2)[CH:23]=[CH:22][CH:21]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COCCOc1ccc2c(C(CN)c3cccc(NC(=O)OCc4ccccc4)c3F)c[nH]c2c1
Reactant: CCOC(=O)C=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2F)c2c1[nH]c1cc(OCCOC)ccc12
Temperature: 125 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a light homogeneous, orange solution of benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)ethyl)-2-fluorophenylcarbamate (3.5215 g, 7.37 mmol) and ethyl 2-oxoacetate (2.92 mL, 14.75 mmol) (50% in toluene) under nitrogen was added 4N HCl/1,4-dioxane (2.212 mL, 8.85 mmol); reaction turned dark burgundy. The reaction was stirred overnight, concentrated in vacuo, dissolved in EtOAc (50 mL) and saturated aqueous NaHCO3 (20 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (1.569 g, 1.474 mmol) in p-xylene (211 mL), and the solution was heated at 125° C. After 3.5 hr, the reaction was cooled to room temperature, filtered through a pad of CELITE®, and the insolubles were rinsed with EtOAc (250 mL). The filtrate was washed with brine (75 mL), and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 220 g column eluting with 5-40% EtOAc/CH2Cl2. Appropriate fractions (20-25% elution) were collected and concentrated in vacuo to give the desired product (0.811 g, 1.381 mmol, 18.7% yield) as a light orange solid.