Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Na+].[CH3:18][C:19]([C:21](Cl)=[O:22])=[CH2:20].Cl>O.C(OCC)(=O)C>[C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:22])[C:19]([CH3:20])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In 9 l of water at 30° C. were dissolved 218 g of 12-aminododecanoic acid and 100 g of sodium hydroxide (purity: 93%), and 102 ml of methacryl chloride was added thereto over 1 hour while stirring. The reaction mixture was stirred for 2 hours and then heated to 60° C., at which 3 l of ethyl acetate and 300 ml of concentrated hydrochloric acid were added thereto successively. The mixture was filtered while hot (60° C.) to remove any insoluble matter, followed by liquid-liquid separation. The organic layer was dried over 30 g of magnesium sulfate and, after removal of the magnesium sulfate, cooled to 10° C., at which 6 l of n-hexane was added, whereupon a precipitate was formed. The precipitate was collected by filtration and thoroughly washed with 1 l of n-hexane. Recrystallization of the precipitate from 500 ml of ethyl acetate yielded 128 g of 12-methacryloylaminododecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:38][CH:37]=3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 1.5 g, 6.23 mmol) was dissolved in DMF (25 mL) to give an orange solution. The mixture was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.04 g, 6.23 mmol), followed by 4-methylsulfonylbenzyl bromide (1.71 g, 6.86 mmol), were added. The reaction mixture was stirred at 0° C. for 1 hour and was subsequently diluted with ethyl acetate and washed with brine (100 mL) to give a suspension. An orange precipitate was collected on a fitted glass funnel and was washed with water (3×20 mL) and dried over night in a stream of nitrogen. The crude solid was triturated with hot ethyl acetate (2×) to give the title compound which was used without further purification (1.78 g, 69.8%). ESI-MS m/z [M+H]+ calc'd for C17H17ClN4O4S, 409.07. found 409.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a mixture of 4-benzyloxy-phenyl-acetohydroximoyl chloride (140 mg, 0.51 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (10 mL) were added 3-ethynyl-pyridin-2,6-diamine (102 mg, 0.76 mmol) described in Manufacturing Example 13-1-3 and triethylamine (0.71 mL, 5.1 mmol), which was stirred overnight at room temperature. The reaction mixture was then stirred for further 1.5 hours at 55° C. The reaction solution was cooled to room temperature and concentrated under a reduced pressure. The residue was filtered by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. The crude product was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid). The solvent was evaporated under a reduced pressure, and the residue was filtered with NH silica gel to obtain the title compound (51 mg, 27%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[NH2:1][C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[F:47][C:46]([C:44]([OH:50])=[O:45])([F:49])[F:48]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)[C@H](N)Cc1ccc(OC)cc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Boc-D-Tyr(Me)-L-Ile-D-Pro-OBzl (1.19 g, 2.0 mmol) was dissolved in TFA (5 ml) and left with standing on ice for 30 minutes. On completion of the reaction, TFA was removed by evaporation, and the residue was vacuum-dried to obtain H-D-Tyr(Me)-L-Ile-D-Pro-OBzl-TFA. The compound was dissolved in DMF (4.0 ml), and Boc-L-Ab7-OH (652 mg, 2.0 mmol) was then added. HBTU (1.14 g, 3.0 mmol), HOBt.H2O (306 mg, 2.0 mmol), and triethylamine (1.4 ml, 10 mmol) were further added and stirred for 3 hours under ice-cooling. The reaction solution was concentrated, dissolved in ethyl acetate, and successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. The product was dried over MgSO4 and concentrated, and the resulting foam substance was purified by flash silica gel chromatography (4×30 cm, 2% methanol/chloroform) to obtain the foam title compound (1.51 g, 1.89 mmol, 94% yield). HPLC retention time: 9.15 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([O:13]C)=[C:8]([CH:11]=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([OH:13])=[C:8]([CH:11]=[O:12])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: COc1cc2c(cc1C=O)C(C)(C)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CCc2cc(O)c(C=O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 4.25 g (20.8 mmol) of 1,1-dimethyl-5-methoxyindan-6-carboxaldehyde in 25 ml of methylene chloride and cooled in an ice water bath was added 22 ml (22.0 mmol, 1M in methylene chloride) of boron tribromide. After stirring for 1 h, the reaction mixture was poured into 100 ml of ice water The organic phase was dried and evaporated. The residue was chromatographed on silica gel (50 g) using hexane as eluent There was obtained 3.37 g (17.7 mmol, 85%) of 1,1-dimethyl-5-hydroxyindan-6-carboxaldehyde as a white solid; mp 40°-40.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Br:30])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Br

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-bromophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 587.8.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:36]1[CH2:41][CH2:40][N:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:45]3[CH2:46][CH2:47][CH:42]([N:39]4[CH2:40][CH2:41][O:36][CH2:37][CH2:38]4)[CH2:43][CH2:44]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CC(N2CCOCC2)CCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCOCC2)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 4-morpholinopiperidine (Aldrich) in an analogous manner as described in example 25. HR-MS (ES, m/z): observed 663.2859, calculated for C37H45Cl2N4O3 [(M+H)+] 663.2863.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])(O)=[O:2].[OH-].[Na+]>O>[O:2]=[C:1]1[NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][S:5][CH2:4]1
Reactant: N[C@@H](CSCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CSCC(C(=O)O)N1
Reaction time: 48 h

Procedure:
In 40 ml. of water is suspended 3.6 g (0.02 M) of S-carboxymethyl-L-cysteine, followed by addition of 20 ml. of 1N-NaOH. The reaction is conducted in a sealed tubular reactor at 110° C for 48 hours. The reaction mixture is passed through a column (4.5 × 12.0 cm) of Amberlite IR-120 B (H+ -form), whereby it is desalted. The effluent is concentrated to dryness and the residue is dissolved in glacial acetic acid. Following addition of ether, the resultant crystals are recovered by filtration. Yield 1.55 g. (48.1%); melting point: 152.0°-153.0° C; optical rotation [α]D25 + 1.1° (c=0.64, in water).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH2:18])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N+:20]([C:23]1[C:24]([CH:34]=O)=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:27]=1)([O-:22])=[O:21]>CO>[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]2[NH:18][C:34]([C:24]3[C:23]([N+:20]([O-:22])=[O:21])=[CH:27][N:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=3)=[N:19][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(OCCCN2CCCCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1

Procedure:
A solution of 200 mg of 4-fluoro-5-(3-piperidin-1-ylpropoxy)benzene-1,2-diamine and 181 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde in 15 mL of methanol is stirred at ambient temperature over night. The reaction medium is concentrated to dryness under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on a 20 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. 280 mg of 5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazoleare isolated in the form of a red lake. Analytical LC/MS: Tr=2.51 min, [M+H]+=472.97 DAD=36%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:54])[CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH3:40])[CH:38]=2)[C:33]([Sn](CCCC)(CCCC)CCCC)=[N:32]1>CN(C=O)C.O.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.[Cu](I)I>[Si:17]([O:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[C:34]4[C:39](=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:31]([CH2:30][CH2:29][CH2:28][N:27]([CH3:54])[CH3:26])[N:32]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:12])([CH3:25])[CH3:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2cc(C)ccc12
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)nn(CCCN(C)C)c2c1
Temperature: 85 °C
Yield: 253.4 %

Procedure:
A mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (300 mg, 0.7 mmol) and N,N-dimethyl-3-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)propan-1-amine (1.4 g, 2.76 mmol) with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.087 mmol), copper iodide (10 mg, 0.52 mmol) in 15 mL of dry DMF was heated to 85° C. overnight under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water and the formed solid was separated by filtration. The solid was washed with 2-methoxy-2-methylpropane (5 mL) to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(1-(3-(dimethylamino)propyl)-6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1 g, crude) which was used in the next step directly without further purification. LCMS: (M+H)+=564.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].C(O)C.[F:11][C:12]([F:16])([F:15])[S:13]Cl>ClCCl>[F:11][C:12]([F:16])([F:15])[S:13][CH2:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)(C)C
Reactant: FC(F)(F)SCl
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)CSC(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 3,3-dimethyl-2-butanone (1.13 mole), ethanol (1.5 g.) and dichloromethane (300 ml) was introduced into a sealed and pressure tested 2-liter vessel under reduced pressure. Trifluoromethanesulfenyl chloride (1.05 mole) was then added to the cooled, evacuated vessel. (Caution: It should be noted that trifluoromethanesulfenyl chloride is a highly hazardous material which must be handled with care to avoid inhalation and contact with the skin.) The vessel was warmed to about 25°C. and then rocked for 21/2 to 3 days. The vessel was vented through a cold gas trap (-78°C.) to trap any unreacted trifluoromethane sulfenyl chloride, and then through a scrubbing system to remove the vented hydrogen chloride gas. Residual liquid was transferred to a flask and distilled to give 1-trifluoromethylthio-3,3-dimethyl-2-butanone, b.p. 65°C./10mmHg.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:10][CH2:11][CH2:12][N:13]([CH3:55])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][S:24]([N:27]2[CH2:32][CH2:31][C:30]([NH:36][C:37](=O)[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([O:48][CH2:49][CH2:50][CH:51]=[CH2:52])[CH:39]=3)([C:33]([NH2:35])=[O:34])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[C:18]([CH3:54])[CH:17]=1)=[O:15])[CH:8]=[CH2:9].[Cl-].[NH4+].O>C(O)C.[Cl-].[Na+].O>[CH2:7]([O:10][CH2:11][CH2:12][N:13]([CH3:55])[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][S:24]([N:27]2[CH2:28][CH2:29][C:30]3([N:36]=[C:37]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:47])[F:46])=[C:40]([O:48][CH2:49][CH2:50][CH:51]=[CH2:52])[CH:39]=4)[NH:35][C:33]3=[O:34])[CH2:31][CH2:32]2)(=[O:26])=[O:25])=[C:18]([CH3:54])[CH:17]=1)[CH:8]=[CH2:9]
Reactant: C=CCCOc1cc(C(=O)NC2(C(N)=O)CCN(S(=O)(=O)CCc3ccc(C(=O)N(C)CCOCC=C)cc3C)CC2)ccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C=CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)N(C)CCOCC=C)cc4C)CC3)C(=O)N2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (302 mg, 2.69 mmol) was added to a solution of the resulting 1-(2-{4-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-methyl-phenyl}-ethanesulfonyl)-4-(3-but-3-enyloxy-4-trifluoromethyl-benzoylamino)-piperidine-4-carboxylic amide in ethanol (6 ml), and the mixture was stirred at 80° C. for 30 minutes. A saturated aqueous ammonium chloride solution, water and saturated brine were sequentially added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give N-(2-allyloxy-ethyl)-4-{2-[2-(3-but-3-enyloxy-4-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3,N-dimethyl-benzamide (176 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])O)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:31])CC>>[CH2:1]([O:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])[F:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(OC)C(O)c1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CCN(CC)S(F)(F)F
Product: COP(=O)(OC)C(F)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
4-[(Dimethoxy-phosphoryl)-hydroxy-methyl]-benzoic acid benzyl ester (0.20 g, 0.22 mmol) was added over 30 mins to a stirring solution of DAST (1M in CH2Cl2) cooled to −78° C. under a dry nitrogen environment. The mixture was warmed to RT and stirred for 18 hours. The reaction mixture was then quenched with ethanol containing pyridine (pyr: twice volume of DAST). After another 30 mins the mixture was poured into ice cold water and extracted into DCM (3×). The combined organic extracts were washed with dilute aq HCl, water, brine, dried (MgSO4) then concentrated in vacuo. The residue was purified by HPLC (20-85% MeCN in Water w/0.025% TFA) to afford the title compound: MS: cal'd 353 (MH+), exp 353 (MH+)
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][C:9]2[CH:10]=[C:11]([C:21]3[N:22](C(OC(C)(C)C)=O)[C:23]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:24][CH:25]=3)[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][CH2:17][C@H:16]([CH3:20])[O:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([C:21]2[NH:22][C:23]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[CH:24][CH:25]=2)[CH:12]=1)[O:8][C:7]1[CH:38]=[CH:39][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 2.5 h
Yield: 93.9 %

Procedure:
t-Butyl 2-{3-(4-acetylphenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (73 mg, 0.133 mmol) synthesized in Example (39a) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (2.0 mL) was added dropwise with stirring under nitrogen atmosphere, and stirring was carried out at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-40%) to afford the desired compound (56 mg, yield 94%) as a pale yellow liquid.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[NH:41]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@@H:42]([C:51](O)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:19]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:31][CH2:30][N:29]([C:51](=[O:52])[C@H:42]([NH:41][C:54]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:55])[CH2:43][C:44]2[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=2)[CH2:28][CH2:27]1
Reactant: CS(=O)(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN2C(=O)c3ccccc3C2=O)S(C)(=O)=O)CC1
Yield: 92.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, (Step f) from 2-(2-[(methylsulfonyl)(2-(4-piperidyl)phenyl)amino]ethyl) isoindoline-1,3-dione hydrochloride (Step b) (1.28 g, 2.8 mmol), DIEA (0.54 mL, 3.0 mmol), Boc-p-Cl-D-PheOH (PepTech Corporation) (1.36 g, 4.5 mmol), HOAT (Aldrich) (0.615 g, 4.5 mmol) and EDC (Aldrich) (0.864 g, 4.5 mmol) in DMF (15 mL). Purification by silica gel chromatography (1:1 hexane:EtOAc) provided the title compound as a white foam (1.83 g %). MS (ESI, pos. ion) m/z: 709 (M+1); MS (ESI, neg. ion) m/z: 707 (M−1). Calc'd for C36H41ClN4O7S: 708.24.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=4)=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=4)=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-{[3-(4-fluorophenyl)-1H-indazol-5-yl]carbonylamino}benzoate (112 mg, 0.29 mmol) in methanol (20 mL) and water (20 mL) was added sodium hydroxide (25 mg, 0.64 mmol). The solution was stirred at room temperature for 2 hours when it was acidified and the methanol removed under vacuo. The resulting solid was filtered and dried to recover the product (55 mg, 51%). 1H NMR (DMSO-d6) δ 13.6 (s, 1H), 12.8 (br s, 1H), 10.6 (s, 1H), 8.69 (s, 1H), 8.12 (dd, 2H), 8.0 (d, 1H), 7.94 (s, 4H), 7.70 (d, 1H), 7.41 (t, 2H); ES-MS (m/z) 376 [M+1]+.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([O:10][CH:11]2[O:16][CH:15]([CH2:17][OH:18])[CH:14]([OH:19])[CH:13]([OH:20])[CH:12]2[OH:21])[CH:2]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C@@H:11]1([O:10][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]1[OH:21]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 80 %

Procedure:
p-nitrophenyl-β-D-glucopyranoside (Tokyo Chemical Industries) (250 mg) was dissolved in a methanol/tetrahydrofuran mixed solvent (20 ml/5 ml), and 10% palladium carbon (250 mg) was added to this solution. Hydrogen gas was introduced under a nitrogen gas atmosphere into the reaction solution at room temperature for 3 hours. The reaction mixture was filtered to remove palladium carbon, the filtrate was evaporated under vacuum, and solidified. This residue was purified by silica gel chromatography using a tetrahydrofuran/chloroform mixed solvent (1/1, volume ratio) as an eluant, and p-aminophenol-β-D-glucopyranoside was obtained.