Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C]=O.O=O.[C:17]([OH:20])(=[O:19])C>>[C:17]([C:5]12[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][C:3]([OH:11])([CH2:2]3)[CH2:4]1)[CH2:6]2)([OH:20])=[O:19]
Reactant: CC(=O)O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Agent: O=O
Agent: [C]=O
Product: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Yield: 80 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of 1,3-adamantanediol, 1 mmol of NHPI and 0.005 mmol of Co (AA)2, a gas pack containing a mixed gas (2 lit. of carbon monoxide and 0.5 lit. of oxygen; pressure:5 kg/cm2) was connected with the reactor, and the resultant mixture was stirred at a temperature of 60° C. for 6 hours. And, as a result, the 1,3-adamantanediol was converted into a 1-carboxy-3,5-adamantanediol (yield: 80%) with a conversion of 99%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][N:48]=1)[C:43](Cl)=[O:44]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:43]([C:42]5[CH:46]=[CH:47][N:48]=[C:40]([CH3:39])[CH:41]=5)=[O:44])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: Cc1cc(C(=O)Cl)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccnc(C)c3)CC4)nc12
Yield: 5007.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.5 ml tetrahydrofurane were added at 0–4° C. 0.37 ml N-ethyldiisopropylamine and 0.19 mg 2-methyl-isonicotinoyl chloride hydrochloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate/methanol 9:1 to yield 0.025 g (50%) [2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-(2-methyl-pyridin-4-yl)-methanone as yellow solid; MS (ISP): m/e=505 (M+H+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.[F:20][C:21]([F:32])([F:31])[C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:28]([C@H:25]2[CH2:24][CH2:23][C@H:22]([C:21]([F:20])([F:31])[F:32])[CH2:27][CH2:26]2)=[O:29])[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: NC(=O)c1ncc(Cl)cc1OC[C@H]1CCCN1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: NC(=O)c1ncc(Cl)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using (R)-5-chloro-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 29 Step 5) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[CH3:19][O-].[Na+].[N:22]1([C:33](=[O:34])[C:32]2[N:31]([CH2:35]C(Cl)=O)[CH:30]=[N:29][C:28]=2[N:26]([CH3:27])[C:24]1=[O:25])[CH3:23].C>CN(C)C=O>[N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][CH:15]3[N:16]=[C:35]([N:31]4[C:32]5[C:33](=[O:34])[N:22]([CH3:23])[C:24](=[O:25])[N:26]([CH3:27])[C:28]=5[N:29]=[CH:30]4)[O:18][N:17]3[CH3:19])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2]
Reactant: C[O-]
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: Cn1c(=O)c2c(ncn2CC(=O)Cl)n(C)c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1OC(n2cnc3c2c(=O)n(C)c(=O)n3C)=NC1Cn1cnc2c1c(=O)n(C)c(=O)n2C

Procedure:
5.04 g. of 2-(theophyllin-7-yl)-acetamidoxime and 1.08 g. of sodium methylate are suspended in 60 cm3 dimethylformamide whereafter a solution of 5.13 g. of theophyllin-7-yl-acetyl chloride in 25 cm3 of dimethyl-formamide is added dropwise within 15 minutes. The mixture is heated for 1 hour and after adding a small amount of activated charcoal it is filtered while hot and the filtrate is evaporated at reduced pressure. The residue is dissolved in 100 cm3 0.1N sodium hydrogen carbonate solution while hot and after cooling the crystals are filtered by suction, washed with water and crystallized from 50% aqueous ethanol. Thus 6.6 g. of 3-(theophyllin-7-yl-methyl)-5-(theophylline-7-yl)-methyl-1,2,4-oxadiazole are obtained, m.p.: 271°-272° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].COC1C=CC(C[N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][N:24]([C:28](=[O:37])[C@H:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH3+:30])[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=CC=1.[CH3:40][O:41][C:42]1[CH:78]=[CH:77][C:45]([CH2:46][N:47]2[C:51]3[N:52]=[CH:53][C:54]4[CH2:55][N:56]([C:60](=[O:76])[C@@H:61]([NH:68]C(=O)OC(C)(C)C)[C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)[CH2:57][CH2:58][C:59]=4[C:50]=3[CH:49]=[N:48]2)=[CH:44][CH:43]=1.[F:79][C:80]([F:85])([F:84])[C:81]([OH:83])=[O:82]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH:17]1[C:18]2[C:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:37])[C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH3+:30])[CH2:23][C:22]=3[CH:21]=[N:20][C:19]=2[NH:15][N:16]=1.[F:79][C:80]([F:85])([F:84])[C:81]([O-:83])=[O:82].[CH3:40][O:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[C:51]3[N:52]=[CH:53][C:54]4[CH2:55][N:56]([C:60](=[O:76])[C@H:61]([C:62]5[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=5)[NH3+:68])[CH2:57][CH2:58][C:59]=4[C:50]=3[CH:49]=[N:48]2)=[CH:77][CH:78]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)CC4)cc1
Reactant: O=C(O)C(F)(F)F
Agent: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)[C@@H]([NH3+])c2ccccc2)CC4)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: [NH3+][C@H](C(=O)N1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Synthesis of (S)-2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate. To a solution of (S)-tert-butyl 2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethylcarbamate (0.23 g, 0.43 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude product was purified using reverse phase HPLC to give the pure desired product (S)-2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate as a pale yellow solid (0.131 g, 50%). M.p.>115° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (brs, 2H), 8.45/8.15 (s, 1H, rotamers), 8.12/8.08 (s, 1H, rotamers), 7.55-7.33 (m, 5H), 7.17 (m, 2H), 6.82 (m, 2H), 5.75 (m, 1H), 5.55 (s, 2H), 4.97-4.35 (m, 2H), 4.02/3.74 (m, 2H, rotamers), 3.01/2.30 (m, 2H, rotamers); LC-Mass: m/e 428.57 (M+H). LCMS [M+H]: 428.
Reaction SMILES: Br[C:2]1[C:3]([NH2:24])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]3[CH2:21][O:20][CH2:19][CH2:18][O:17]3)=[C:10]([O:22][CH3:23])[CH:9]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)(Cl)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>[NH2:37][C:36]1[CH:38]=[CH:39][C:33]([C:2]2[C:3]([NH2:24])=[N:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C@H:16]4[CH2:21][O:20][CH2:19][CH2:18][O:17]4)=[C:10]([O:22][CH3:23])[CH:9]=3)[CH:7]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COc1cc(-c2cnc(N)c(Br)c2)ccc1OC[C@H]1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OC[C@H]1COCCO1
Yield: 60.1 %

Procedure:
The compound obtained in Step 2 of Example 41 (2.05 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.14 g), tetrakis(triphenylphosphine)palladium (0.3 g), and potassium carbonate (2.15 g) were suspended in dioxane (30 ml) and water (6 ml), and the suspension was stirred at 100° C. for two hours. After leaving to cool, the reaction solution was diluted with chloroform, followed by washing with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate:hexane=1:1->chloroform:ethanol=19:1 (v/v)] to give 1.27 g of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1[Cl:10].CNC([OH:15])C.[CH2:16]([N:18]([CH2:21]C)CC)[CH3:17]>>[CH3:21][N:18]([C:2]1[C:3]([Cl:10])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1)[CH2:16][CH2:17][OH:15]
Reactant: CNC(C)O
Reactant: Clc1nc(Cl)c(Cl)nc1Cl
Reactant: CCN(CC)CC
Product: CN(CCO)c1nc(Cl)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tetrachloropyrazine (10.8 g, 0.05 mol), methylaminoethanol (3.7 g, 0.05 mol), and triethylamine (10 g, 0.1 mol) was stirred overnight at room temperature. The white solid was filtered out and the filtrate concentrated on the rotary evaporator to leave a yellow oil. This was distilled on a Kugelrohr apparatus to give 10 g (78% of theoretical yield) of a yellow oil (b.p. 110° at 0.05 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[CH3:11][C:12]([CH3:14])=O.O>Br.C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:12]([CH3:14])[CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(C)=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(C(C)C)c1C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Anhydrous stannous bromide (5g) was stirred to solution in 20 ml of hydrogen bromide in acetic acid (30-32 %). 2,4-Dimethyl-3-acetyl-pyrrole (548 mg) was added and the mixture was warmed to dissolve this, then cooled to 30° C. Acetone(0.6 ml) was added and the solution was stirred at 35° C. for 21/2 hrs then poured into water at 10° C. The product was separated and washed with dilute hydrochloric acid then with water. It formed colourless micro-prisms (549 mg. 77%), m.p. 166°-167° C. or 173-174.5° C. after changing to cubes at about 136° C. For analysis it was recrystallized from aqueous ethanol as prismatic rods, m.p. 172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=1)[CH:6]=[CH:5]2.[CH3:19][CH:20]([CH3:47])[CH:21]([C:23]1[N:24]=[CH:25][N:26](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)[OH:22]>>[CH3:17][C:15]1([CH3:18])[CH2:14][O:13][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:21]([C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)([OH:22])[CH:20]([CH3:47])[CH3:19])[CH:11]=[CH:10]3)=[N:16]1
Reactant: CC(C)C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC1(C)COC(c2ccc3cc(Br)ccc3c2)=N1
Product: CC(C)C(O)(c1ccc2cc(C3=NC(C)(C)CO3)ccc2c1)c1c[nH]cn1
Yield: 157.5 %

Procedure:
2-(6-Bromo-2-naphthyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (1.0 g) and 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (835 mg) were used as the starting materials. By the same procedure described in Reference example 1, the titled compound (1.25 g) was obtained as a colorless amorphous powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:9]([N+:21]([O-])=O)[CH:8]=1.[Cl-].[NH4+]>O1CCCC1.O.C(O)C.[Fe]>[NH2:21][C:9]1[CH:8]=[C:7]([CH2:6][O:5][C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=2)[CH:12]=[CH:11][C:10]=1[S:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cc(COc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(COc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 4-[4-(3-Bromo-phenoxymethyl)-2-nitro-phenylsulfanyl]-phenol (325 mg, 0.752 mmol), iron dust (210 mg, 3.76 mmol) and ammonium chloride (60 mg, 1.13 mmol) in tetrahydrofuran (5 mL), water (1.5 mL) and ethanol (5 mL) was heated at reflux for 2.5 hours. After cooling to room temperature, the solution was filtered through a pad of celite, which was washed with methanol. The filtrate was then concentrated under vacuum, then dissolved in water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic extracts were dried and concentrated under vacuum to provide the title compound as a light yellow solid (240 mg, 79%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>CCCCCC.CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 60% dispersion of NaH in mineral oil (1.07 g, 26.9 mmol) was washed with hexane, and the resulting powder was suspended in 40 mL of DMF. After cooling the stirred mixture to 0° C., ethyl 5-chloro-1H-indole-2-carboxylate (5.00 g, 22.4 mmol) was added in portions. The solution was warmed to room temperature, during which gas was released. After 15 minutes, the mixture was cooled again to 0° C., and benzenesulfonyl chloride was added dropwise (3.14 mL, 24.6 mmol). After warming to room temperature, the reaction was stirred for 1.5 hours, then poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting solid was stirred in 50 mL of a 10% EtOAc/hexane solution for 30 minutes, then filtered to provide the titled product as a white powder. Proton NMR for the product was consistent with the titled compound. ESI+MS: 364.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[OH-:19].[Na+].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29](Cl)(=[O:31])=[O:30]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([O:18][S:29]([C:23]2[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])(=[O:31])=[O:30])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29]([OH:31])(=[O:30])=[O:19]
Reactant: [OH-]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)c[nH]c12
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)c2c(F)cccc2F)cc2c(C3CCN(C)CC3)c[nH]c12
Product: O=S(=O)(O)c1c(F)cccc1F

Procedure:
By a method similar to Example 31, using 7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole-5-ol (3.1 mmol, 0.756 g), tetrahydrofuran (10 mL),0.2N sodium hydroxide (3.1 mmol, 15.5 mL) and 2,6-difluorobenzenesulfonyl chloride (3.7 mmol,0.7895 g) in tetrahydrofuran (10 mL) afforded the title compound as a fractional salt of 2,6-difluorobenzene sulfonic acid. The material was dissolved in methanol and 5N sodium hydroxide (1 eq) was added. The mixture was then applied to a Mega Bond Elute SCX column. The column was treated with one column volume of the following: methylene chloride, methanol, 3:1 methylene chloride:methanol. The product was eluted with 3:1 methylene chloride: 2M ammonium in methanol. Fractions containing the title compound were concentrated in vacuo to an oil. The oil was dissolved in diethyl ether, then placed in freezer (approximately −4° C.). The resulting crystals were collected by filtration to afford 0.296 g of the title compound. The filtrate was concentrated in vacuo and resubjected to SCX chromatography as described above. An additional 0.313 g of material was collected. A total of 0.609 g (47%) of the title compound was isolated: MS (ion spray): m/z=421(M+1); 1H NMR (DMSOd6): 11.04 (s, 1H), 7.90 (m, 1H), 7.40 (m, 2H), 7.16 (1H), 6.88 (1H), 6.69 (1H), 2.78 (m, 2H), 2.54 (m, 1H), 2.39 (s, 3H), 2.19 (s, 3H), 1.94 (m, 2H), 1.65 (m, 2H), 1.51 (m, 2H); Calculated for C21H22F2N2O3S: C, 59.99; H, 5.27; N, 6.66. Found: C, 59.96; H, 5.21; N, 6.65.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:10][CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:38]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[CH:10]([OH:38])[CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)=CC1CCNC(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: B
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(O)C1CCNC(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A solution containing 7 (440 mg, 0.92 mmol) in anhydrous THF (15 mL) was cooled to −30° C. Borane (1M/THF, 3.68 mL) was added dropwise. After 10 min, the reaction mixture was allowed to slowly warm to 0° C. at which point TLC analysis revealed complete consumption of 7. The reaction mixture was recooled to −10° C. and 1M NaOH (2.6 mL) was added followed by the addition of 35% hydrogen peroxide (0.73 mL). The reaction mixture was then warmed to 0° C. After 1 h, the reaction mixture was quenched by the addition of saturated aqueous Na2S2O3 and the product was extracted with EtOAc. The combined organic extracts were washed successively with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 250 mg (55%) of 8. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.25 (m, 5H), 6.07 (m, 0.6H), 5.93 (m, 0.2H), 5.67 (m, 0.2H), 5.00 (m, 2H), 4.03 (m, 1.5H), 3.84 (m, 0.75H), 3.75-3.63 (m, 1.5H), 3.54 (m, 1.25H), 3.37 (m, 0.6H), 3.26 (m, 0.4H), 3.13 (m, 1.5H), 2.95 (m, 0.75H), 1.90 (m, 1H), 1.67 (m, 1H), 1.36 (s, 9H), 0.80 (s, 9H), 0.00 (s, 6H) ppm. Mass spectrum, m/z [495.2] (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:35][CH2:36][CH3:37])[C:33]=1[F:34])[CH:29]=O)[CH3:24].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:29][C:28]3[CH:31]=[C:32]([O:35][CH2:36][CH3:37])[C:33]([F:34])=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=3)[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)([CH3:5])[CH3:21]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCNCC2)cc1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C(=O)OC)cc3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[4-(piperidin-4-ylcarbamoyl)-phenyl]-propionic acid methyl ester (example 60e) was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 501.2 (MH+).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@@H:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl.O>[C:2]([O:6][C:7](=[O:17])[C@@H:8]([NH:16][C:27](=[O:28])[CH2:26][Cl:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a mixture of 3.0 g (11.6 mmol) (S)-2-amino-3-phenyl-propionic acid tert-butyl ester hydrochloride (Aldrich) and 3.32 mL (23.9 mmol) triethylamine (Aldrich) in dichloromethane (30 mL), 0.97 mL (12.2 mmol) chloroacetyl chloride (Aldrich) is added dropwise and the resulting mixture is stirred at room temperature for 4 h. The reaction mixture is diluted with water (25 mL), the organic layer is separated, washed with 10% NaHCO3 solution (25 mL), dried (MgSO4) and finally evaporated under reduced pressure to yield the title compound (3.4 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@@H:7]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH3:4])([CH3:3])[CH3:2].[C-:37]#[N:38].[K+].C1OCCOCCOCCOCCOCCOC1>>[C:1]([O:5][C:6](=[O:36])[C@@H:7]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:13][C@@H:14]([OH:17])[CH2:15][C:37]#[N:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CCl)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CC#N)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 51.1 %

Procedure:
According to the method described for the preparation of 14a, 13b (3.23 g, 6.10 mmol) was reacted with KCN (3.96 g, 60.82 mmol) and 18-crown-6 (242 mg, 0.92 mmol) to obtain 14b (1.62 g, 51%) as a colorless oil: 1H NMR δ 1.20-1.84 (m, 6H), 1.44 (s, 9H), 1.45 (s, 9H), 2.55 (m, 2H), 3.20-3.50 (m, 4H), 3.92 (dd, 1H, J=8.2, 5.1), 4.07 (m, 1H), 5.13 (s, 2H), 7.26-7.41 (m, 5H); 13C NMR δ 24.1, 24.2, 28.3, 28.8, 32.4, 55.7, 67.1, 68.4, 80.4, 82.5, 118.9, 129.0, 129.2, 129.6, 138.0, 158.1, 173.7; HRMS m/z calcd for C27H42N3O7 520.3023, found 520.3048. Anal. calcd. for C27H41N3O7: C 62.41, H 7.95, N 8.09. Found: C 62.14, H 7.95, N 7.97. [α]22D−5.3 (c 1.15, CH3OH).