Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=O)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].B>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](OCC(=O)N3CCOCC3)c3ccccc32)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](OCCN3CCOCC3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
To a solution of Intermediate 32d (50 mg, 62.3 μmol) in THF (1.7 mL) was added borane (1M in THF, 0.12 mL, 0.12 mmol) and the mixture stirred at 60° C. After 23 h, further borane (1M in THF, 0.31 mL, 0.31 mmol) was added. After 26 h, further borane (1M in THF, 0.31 mL, 0.31 mmol) was added. After 3 d, the cooled reaction mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by HPLC (Gemini C18 column, 20-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying (15 mg, 47%). LCMS (Method 5): Rt 3.64 min, m/z 532 [MH+]. 1H NMR (400 MHz, CDCl3): 1.32 (9H, s), 1.93-1.96 (3H, m), 2.02-2.07 (1H, m), 2.32 (4H, t, J 4.5), 2.38 (3H, s), 2.47 (1H, dt, J 13.0, 5.3), 2.61 (1H, ddd, J 13.0, 7.3, 5.4), 3.56-3.58 (5H, m), 3.67-3.68 (1H, m), 4.35-4.37 (1H, m), 4.98-5.02 (1H, m), 5.50 (1H, d, J 8.8), 6.27 (2H, s), 7.18-7.28 (5H, m), 7.30-7.32 (1H, m), 7.36 (2H, d, J 8.2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(O[B:24]([O:29][CH:30]([CH3:32])[CH3:31])[O:25][CH:26]([CH3:28])[CH3:27])(C)C.C([Li])CCC.OC(C(O)(C)C)(C)C>O1CCCC1.C1(C)C=CC=CC=1>[F:8][C:6]1[CH:7]=[C:2]([B:24]2[O:25][C:26]([CH3:27])([CH3:28])[C:30]([CH3:31])([CH3:32])[O:29]2)[CH:3]=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]=1[F:9]
Reactant: COc1ccc(COc2cc(Br)cc(F)c2F)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c2F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-1,2-difluoro-3-(4-methoxy-benzyloxy)-benzene (0.35 g) in tetrahydrofuran (10 ml) under nitrogen was added triisopropylborate (0.29 ml). The mixture was cooled to −78° C. and 2.5M n-butyllithium solution in hexanes was added. The reaction mixture was stirred at −40° C. for 1 hour, then warmed to 20° C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 using saturated sodium bicarbonate solution, then partitioned between ethyl acetate and water, dried (MgSO4) and the solvents removed in vacuo to yield a crude residue (0.31 g). A mixture of this crude residue and pinacol (0.25 g) in toluene (10 ml) were stirred under reflux overnight in a Dean-Stark apparatus. The solvents were removed in vacuo, the residue was then partitioned between ethyl acetate and water, the combined organics were washed with water then brine and dried (MgSO4), the solvents were removed in vacuo to yield 2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.28 g)
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=O.Cl>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:10]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:12][C:11]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: COC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
Methyl thioglycolate (19.62 mL, 0.216 mol) was added dropwise, via syringe pump, to a stirred suspension of 95% sodium hydride (5.99 g, 0.237 mol) in dry N,N-dimethyl-formamide (400 mL) at r.t. under nitrogen (CAUTION: hydrogen evolution). Upon complete addition, the reaction was stirred for 10 min and then a solution of 2-chloro-5-nitrobenzaldehyde (40.0 g, 0.216 mol) in DMF (120 mL) was added. The solution turned orange and a gentle exotherm was observed. After 1h, the now yellow mixture was heated to 100° C. for 5 h. The mixture turned amber in appearance. After cooling to r.t. the mixture was poured into 1 N aqueous hydrochloric acid (500 mL). The resulting yellow precipitate was filtered off and washed with water (250 mL). The solid was suspended in hot methanol/ethyl acetate (1:1) (1000 mL) and allowed to cool to r.t. The resulting solid was filtered off and air dried to yield methyl 5-nitrobenzo[b]thiophene-2-carboxylate (33.77 g, 66%) as a tan amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 3.92 (s, 3H), 8.32 (dd, J=9, 2 Hz, 1H), 8.37 (d, J=9 Hz, 1H), 8.45 (s, 1H), 9.00 (d, J=2 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+]>O1CCCC1.CO>[C:12]1([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[CH:7][CH:8]=2)[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)COc1ccc(-c2cccc3sc4ccccc4c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2cccc3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of [4-(dibenzothiophen-1-yl)-phenoxy]-acetic acid methyl ester (0.911 g, 2.61 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) was added an aqueous solution of potassium hydroxide (1N, 3.10 mL, 3.10 mmol, 1.2 eq) dropwise at room temperature. After stirring 1 hour at room temperature the solvents were removed. The residue was dissolved in water (125 mL) and was acidified with 10% aqueous hydrochloric acid. The water was removed and the solid was triturated in petroleum ether. Recrystallization from boiling acetic acid with hot filtration to give the title compound as a white crystalline solid (0.458 g, 52%): mp 169.5-170.5° C.; NMR (CDCl3): δ 7.88-7.81 (m, 2H), 7.48-7.39 (m, 3H), 7.37-7.32 (m, 1H), 7.26-7.17 (m, 2H), 7.13-7.08 (m, 3H), 4.83 (s, 2H); MS (El): [M+] 334; Anal. Calc. for C20H14O3S: C, 71.84, H, 4.22, N, 0.00. Found: C, 71.04, H, 3.90, N, 0.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:15][N:14]=[C:13]([N+:16]([O-])=O)[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[NH2:16][C:13]1[CH:12]=[C:11]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:10])[NH:15][N:14]=1
Reactant: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])n[nH]1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)Nc2cccc(F)c2)[nH]n1
Yield: 73.8 %

Procedure:
N-(3-fluorophenyl)-3-nitro-1H-pyrazole-5-carboxamide (100 mg, 0.4 mmol) in ethyl acetate:ethanol (10:4) was stirred with platinum dioxide (10 mg) under an atmosphere of hydrogen (70 psi) for 3 hours. The catalyst was filtered off and the solvent was evaporated in vacuo to yield 3-amino-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (65 mg, 73% yield):
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:7]=[CH:6][CH:5]=2.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1cccnc1
Reactant: Cc1cc2c(/C=C/C(=O)OCc3ccccc3)cccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2cccc(/C=C/C(=O)OCc3ccccc3)c2c1Cc1cccnc1
Reaction time: 0.75 h
Yield: 35.1 %

Procedure:
A solution of benzyl (E)-3-[2-methyl-1H-indol-4-yl]-2-propenoate (4.75 g) and pyridine-3-carboxaldehyde (2.10 g) in dry dichloromethane (45 ml) was added dropwise to a stirred solution of triethylsilane (7.82 ml) in trifluoroacetic acid (40 ml) at 0° C. The solution was stirred, allowing the temperature to rise to room temperature, for 45 minutes and then evaporated. The residue was partitioned between dichloromethane and dilute aqueous ammonia solution. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave impurity,and further elution with dichloromethane/methanol (19:1) gave pure product.The product fractions were evaporated and the residue was triturated with ether to give the title compound (2.19 g), m.p. 180°-182° C., Rf. 0.35(SS1).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13]C(=O)[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].C[Al](C)C.[C:26]([O:29][C:30](=[O:32])[CH3:31])(=O)[CH3:27].O>O1CCOCC1.C1(C)C=CC=CC=1.[Cu]Br>[C:30]([O:29][C:26]1[CH:11]=[C:10]2[C@:15]([CH3:16])([C@@H:14]([CH3:13])[CH:27]=1)[C@@H:17]1[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH2:8][CH2:9]2)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cu]Br
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
14.2 g (50 mmol) of androsta-1,4-diene-3,17-dione is dissolved in 100 ml of anhydrous dioxane under nitrogen atmosphere. 716 mg (5 mmol) of copper(I) bromide is added and the solution is heated to 25° C. Then 47 ml (55 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction so that the temperature does not rise above 35° C. Then it is stirred for 1.5 hours more at 35° C. 16.84 g (0.165 mol) of acetic anhydride is added at 35° C. and the reaction solution is stirred for 1 hour more at 30° C. For completion of the reaction it is then heated for 15 minutes to 60° C. After cooling of the solution to 20° C., 4 ml of water dissolved in 20 ml of dioxane is added to the reaction for the hydrolysis and the solution is stirred again for 15 minutes. The inorganic solid is suctioned off on diatomaceous earth and the solid is washed again with 50 ml of dioxane. After concentration by evaporation of the solution on a rotary evaporator, 18 g of crude product is obtained, that is chromatographed on silica gel with hexane and an increasing part of ethyl acetate as eluent. After concentration by evaporation of the fractions, 11.4 g of 3-acetoxy-1α-methyl-androsta-2,4-dien-17-one (70% of theory) is obtained as viscous material that can be recrystallized from diisopropylether.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13](=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]=[C:3]([O:10][CH3:13])[C:2]([F:11])([F:12])[F:1])[CH3:9]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(OC)C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of ethyl 4,4,4-trifluoroacetoacetate (12 mL, 82 mmol) in DMF (80 mL) is added cesium carbonate (26.4 g, 82 mmol). The reaction mixture is heated to 70° C. A solution of methyl p-toluenesulfonate (13.5 mL, 90 mmol) in DMF (30 mL) is then added dropwise during 30 min and the reaction mixture is stirred for an additional 1 hr. After cooling to room temperature, the reaction mixture is diluted with H2O (150 mL) and extracted with Et2O (2×150 mL). The organic extracts are combined and washed with H2O and brine, then dried (Na2SO4), filtered and concentrated to afford the title compound (9.0 g, 56%) as an oil which is used without further purification.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32]([NH:35][CH2:36][C:37]([OH:39])([CH3:40])[CH3:38])=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CNC(=O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carboxylic acid (0.205 g) in N,N-dimethylformamide (5 mL) were added 1-amino-2-methyl-propan-2-ol (76 mg), triethylamine (0.18 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (123 mg) and 1-hydroxybenzotriazole (98 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column 15 chromatography (ethyl acetate:hexane=40:60-100:0, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.126 g, yield 53%) as colorless crystals. MS: 552 (MH+). melting point 126-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:24])(=[O:23])=[O:22].Cl.[NH2:26][OH:27].C(N(CC)CC)C.O>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:26][OH:27])[NH2:20])[C:3]=1[S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: NO
Reactant: CS(=O)(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1c(C(N)=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfonylpyrazole (500 mg, 1.3 mmol) and hydroxylamine hydrochloride (87 mg, 1.3 mmol) were dissolved in 5 ml of dioxane, and then triethylamine (130 mg, 1.3 mmol) was added at room temperature. After the mixture was stirred at room temperature for 5 hours, the reaction mixture was poured into 100 ml of iced water and extracted with 100 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain 470 mg (1.1 mmol) of the title compound as a pale pink crystal. Yield 87%.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH:41]=[CH:42][N:43]=[CH:44]2)=[CH:39][CH:38]=1>>[CH:44]1[C:45]2[C:40](=[CH:39][CH:38]=[C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)[CH:46]=2)[CH:41]=[CH:42][N:43]=1
Reactant: BrCc1ccc2ccncc2c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccncc3c2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylate [Example 120(g) (a)] with 7-bromomethyl-isoquinoline (WO 9,319,059) there was obtained tert-butyl (3RS,4RS)-3-(isoquinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a light yellow resin; MS: 613 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O-]S([O-])(=O)=O.[Na+].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)([O-:15])=[O:14].O>ClCCl>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[S:2]([Cl:1])(=[O:5])=[O:3])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]cc(S(=O)(=O)Cl)c2c1
Yield: 51 %

Procedure:
A solution of chlorosulfonic acid (3 mL, 45 mmol) and Na2SO4 (700 mg, 4.9 mmol) in dichloromethane (30 mL) was treated dropwise with a solution of 5-nitroindole (800 mg, 4.9 mmol) in dichloromethane (20 mL) over 1 hour, stirred for another 30 minures, and decanted to provide a thick brown oil. The oil was slowly treated with water (20 mL), stirred for 10 minutes, filtered, and dried in a vacuum oven to provide 651 mg of the desired product.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][CH2:61][C:62]([NH:64][C:65]1[CH:79]=[CH:78][C:68]([CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:67][CH:66]=1)=[O:63]>C(Cl)Cl>[C:73]([O:72][C:71]([NH:70][CH2:69][C:68]1[CH:67]=[CH:66][C:65]([NH:64][C:62](=[O:63])[CH2:61][NH:60][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:79][CH:78]=1)=[O:77])([CH3:74])([CH3:75])[CH3:76]
Reactant: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid (2.66 g, 7.53 mmol, 1.0 eq.) in dry DCM (50 mL) at 0° C. was added N,N-diisopropylethylamine (1.93 g, 15.1 mmol, 2.0 eq) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2.86 g, 7.53 mmol, 1.0 eq.). The mixture was stirred at 0° C. for 30 min and #B119 (2.1 g, 7.53 mmol, 1.0 eq.) was added in one portion. The mixture was stirred at room temperature overnight. The mixture was filtered and solid was washed with DCM and dried in vacuo to afford #B120 (4 g, 86.4%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ 9.91 (s, 1H), 8.11 (br, 1H), 7.90 (d, 2H), 7.69 (d, 2H), 7.51 (d, 2H), 7.41 (m, 2H), 7.33 (m, 3H), 7.17 (d, 2H), 4.28 (m, 3H), 4.06 (d, 2H), 3.86 (br, 2H), 2.97 (m, 2H), 2.15 (m, 2H), 1.51 (m, 2H), 1.38 (m, 12H); LCMS (Protocol I): m/z 637.1 (M+Na]+, retention time=1.18 minutes.
Reaction SMILES: [NH2:1][C@@:2]1([C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(OC([NH:22][C@@H:23]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:24]([OH:39])[C@@H:25]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:26]([OH:28])=[O:27])=O)(C)(C)C.Cl>ClCCl.CO.C(OCC)C>[NH2:1][C@@:2]1([C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[NH2:22][C@@H:23]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:24]([OH:39])[C@@H:25]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:26]([OH:28])=[O:27]
Reactant: COc1ccc(CN[C@@H](C(=O)O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: NC(=O)[C@]1(N)c2ccccc2C[C@H]1O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN[C@@H](C(=O)O)[C@@H](O)[C@@H](N)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 g of 4(S)-tert-butoxycarbonylamino-3(S)-hydroxy-2(R)-(4-methoxybenzyl-amino)-5-phenyl-pentanoic acid 1(S)-amino-2(R)-hydroxyindan-amide (compound of Example 1) are dissolved in a mixture of 20 ml of dichloromethane and 4 ml of methanol. 300 ml of a 3 N solution of HCl in diethylether are added and the mixture is stirred for 3 hours at room temperature. The white precipitate is filtered off, washed with diethylether and dried in vacuo. The title compound is obtained in dihydrochloride salt form (m.p.: 147°-151°).
Reaction SMILES: C(CCN[C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36]>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6]([N:33]3[CH2:39][CH2:38][CH2:37][C@H:34]3[CH2:35][OH:36])=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Reactant: OC[C@@H]1CCCN1
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)N1CCC[C@H]1CO

Procedure:
Compound 109 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with L-prolinol. LCMS (+ESI) m/z=477.3 [M+H]+. 1H NMR (CDCl3) δ 7.88 (d, J=9.7 Hz, 1H), 7.45-7.51 (m, 1H), 7.30-7.32 (m, 1H), 7.19-7.26 (m, 1H), 4.82 (s, 2H), 4.64 (d, J=9.8 Hz, 1H), 4.45 (br, 1H), 4.29-4.33 (m, 1H), 3.91-3.97 (m, 3H), 3.55-3.74 (m, 3H), 3.18 (br, 2H), 1.86-2.11 (m, 3H), 1.59-1.66 (m, 1H), 1.11 (s, 9H).