Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][NH2:65])[CH:59]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:65][CH2:64][C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 39.2 %

Procedure:
A solution of 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid (420 mg, 0.99 mmol, 1.00 equiv), EDCI (230 mg, 1.20 mmol, 1.22 equiv), HOBt (170 mg, 1.26 mmol, 1.27 equiv), triethylamine (300 mg, 2.97 mmol, 3.01 equiv) and pyridin-3-ylmethanamine (140 mg, 1.30 mmol, 1.31 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. The product was precipitated by the addition 60 mL of water/ice. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to give 0.20 g (39%) of 4-(5-methyl-4-((4-(trifluoromethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 557 [M+CH3CN+H]+, 516 [M+H]+, 102. 1HNMR (400 MHz, CDCl3, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.06-7.89 (m, 6H), 7.82 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.38-7.36 (m, 1H), 4.84 (s, 2H), 4.51 (d, J=5.2 Hz, 2H), 2.24 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])=[N:6][CH:7]=1.[CH2:20]([OH:24])[CH2:21][C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.[Pd].[Cu]I>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][CH3:17])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:6]=[CH:7][C:2]([C:23]#[C:22][CH2:21][CH2:20][OH:24])=[CH:3][CH:4]=1
Reactant: CCCc1ccc(Oc2ccc(Br)cn2)c(OC)c1
Reactant: C#CCCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCCc1ccc(Oc2ccc(C#CCCO)cn2)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine (0.19 mmol; 60 mg) under argon, in degased DME (1 mL) were added 3-butyn-1-ol (0.47 mmol; 33 mg), Pd/C (0.02 mmol; 42 mg), CuI (0.04 mmol; 7.6 mg), K2CO3 (0.47 mmol; 64 mg), and triphenylphosphine (0.08 mmol; 21 mg). The reaction mixture was stirred at 80° C. overnight, then filtered on celite, washed with ether (3 mL) then ethyl acetate (3 mL). Combined organic phases were washed with saturated NH4Cl (3 mL), dried over MgSO4, concentrated. The residue was purified by preparative TLC (dichloromethane/ethyl acetate) to yield the desired compound as a clear oil (25 mg; 0.08 mmol; 42%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1ccc([N+](=O)[O-])cc1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 450.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[N+]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:31])([O-])=O.O>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:22]2[CH:21]=[C:20]3[C:16](=[CH:15][CH:14]=2)[C:17](=[O:31])[N:18]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:19]3=[O:23])=[CH:6][CH:5]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1Cc1cccnc1
Reactant: Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Sc3ccc(Cl)cc3)cc2C(=O)N1Cc1cccnc1
Temperature: 120 °C
Yield: 50.9 %

Procedure:
To a suspension of 42 mg of sodium hydride (about 60%) in 10 ml of dimethylformamide was added 150 mg of 4-chlorothiophenol, and the resultant mixture was stirred at 60° C. for 30 minutes and mixed with 300 mg of 5-nitro-2-(3-pyridylmethyl)-1H-isoindole-1,3 (2H)-dione. The mixture was heated at 120° C. for 8 hours under stirring, mixed with water and shaken with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resultant, residue was chromatographed on a column of silica gel, eluting with chloroform to give 201 mg of the titled compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 138–140° C.; 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1 H), 6.89 (d, J=2.2 Hz, 1 H), 6.75 (d, J=2.5 Hz, 1 H), 4.34–4.24 (m, 2 H), 4.10–4.01 (m, 1 H), 3.76 (s, 3 H), 3.09 (t, J=7.9 Hz, 2 H), 1.91–1.74 (m, 2 H), 1.06–0.98 (m, 1 H), 0.95–0.86 (m, 3 H), 0.79–0.72 (m, 1 H), 0.53–0.44 (m, 2 H), 0.35–0.24 (m, 1 H); HRMS (CI) calcd for C19H22N3O2BrCl (M+H)+: 438.0584; found m/z 438.0570.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16](=[O:19])([O-])O.[Na+]>>[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:3]3[CH2:2][CH2:11][CH2:6][CH:16]([OH:19])[CH2:4]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Agent: [Na+]
Product: O=S(=O)(c1cccc2cnccc12)N1CCCC(O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 100 ml of ice water was dissolved 10.6 g of 5-isoquinolinesulfonyl chloride hydrochloride, and the pH of the solution was adjusted to 6 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with of 200 ml of dichloromethane. The dichloromethane layer was added dropwise to a 100 ml of dichloromethane solution containing 6.0 g of 3-hydroxypiperidine and 6.0 g of triethylamine over 30 minutes while cooling with ice. The mixture was stirred at a temperature of 15° C. to 20° C. for 3 hours, washed with water, and dried with anhydrous magnesium sulfate. Then, the dichloromethane was removed under reduced pressure to obtain 8.50 g of 1-(5-isoquinolinesulfonyl)-3-hydroxypiperidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)[CH:4]=1)#[N:2].[H][H].[ClH:32]>C(O)C.O1CCOCC1.[Pd]>[ClH:32].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g (7.5 mmol) of ethyl 3-[4-cyano-(2R)-2-(1-t-butoxycarbonylpyrrolidine-2-ylmethoxy)phenyl]acrylate was dissolved in 20 ml of ethanol. 600 mg of 10% palladium/carbon (50% aqueous) was added to the obtained solution, and they were stirred in the presence of hydrogen overnight. The reaction solution was filtered through Celite, and the solvent was evaporated. The obtained crude product was dissolved in 10 ml of 4 N solution of hydrogen chloride in dioxane, and the obtained solution was stirred at room temperature for 3 hours. The solvent was evaporated to obtain hydrochloride of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=1.Cl.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([NH:34][C:35]([CH:37]2[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]2)=[O:36])=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C1COCC1.CN(C=O)C>[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([N:39]2[CH2:40][CH2:41][CH2:42][CH:37]([C:35]([NH:34][C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[O:36])[CH2:38]2)=[O:15])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)C1CCCNC1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)C1CCCN(C(=O)c2cccc(-c3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.3 %

Procedure:
A catalytic amount of DMF and 114 mg (0.900 mmol) of oxalyl chloride were added at 0° C. to 2 mL of THF solution comprising 119 mg (0.600 mmol) of biphenyl-3-carboxylic acid, and the mixture was stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and then 2 mL of DMAc, 200 mg (0.600 mmol) of the methyl 5-chloro-2-[(piperidin-3-ylcarbonyl)amino]benzoate hydrochloride obtained in Example 11-(ii), and 0.092 mL (0.660 mmol) of triethylamine were added in this order to the residue at 0° C., and the mixture was stirred for 3 hours. After the completion of the reaction, saturated sodium bicarbonate water was added under ice-cooling, and the mixture was stirred. The resulting solids were collected by filtration, washed with water, and dried under reduced pressure at 50° C. for 3 hours, thereby giving 270 mg of methyl 2-({[1-(biphenyl-3-ylcarbonyl)piperidin-3-yl]carbonyl}amino)-5-chlorobenzoate (yield: 94%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)C.[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]OS(C)(=O)=O>>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:34][CH2:33][C:23]1[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=1[CH3:21])[C:11]([CH3:16])=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Product: CCOC(Cc1ccc2c(c1)cc(C)n2CCc1nc(-c2ccccc2)oc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester to give rac-2-ethoxy-3-{2-methyl-1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-5-yl}-propionic acid as light yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C@@H:12]([C:17]([OH:19])=[O:18])[C:13]([SH:16])([CH3:15])[CH3:14]>CO.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[NH:11][C@@H:12]([C:17]([OH:19])=[O:18])[C:13]([CH3:15])([CH3:14])[S:16]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O
Solvent: CO
Product: CC1(C)SC(c2ccc(Cl)cc2Cl)N[C@H]1C(=O)O

Procedure:
3.5 g (20 mmoles) of 2,4-dichlorobenzaldehyde dissolved in 17 ml of methanol are added to a solution containing 3.0 g (20 mmoles) of D-penicillamine in 65 ml of water while stirring. After stirring for 16 hours, the precipitate is filtered, washed with 50% methanol and dried to give the title acid in a yield of 5.82 g (95%), m.p.: 150°-151° C., [α]D20 =+353° (c=0.45, dimethylsulphoxide).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][CH2:37][C:38]#[N:39])[CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][CH2:37][C:38]#[N:39])[CH2:31]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: N#CCCC1CCCC(Nc2c(N)cnc3ccsc23)C1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCCC(CCC#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (194 mg, 2.18 mmol) and triethyloxonium tetrafluoroborate (0.41 g, 2.2 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of 3-{3-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}propanenitrile (131 mg, 0.436 mmol) and the above made reagent in ethanol (4.7 mL) was heated at reflux for 2 h. The mixture was filtered, diluted with MeOH and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (60 mg, 39%). LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.0.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[NH2:34][CH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Agent: Cl
Solvent: CO
Product: NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)n1)c1ccccc1

Procedure:
To a solution of (4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (30 mg, 0.045 mmol) in methanol (30 mL) was bubbled in HCl (gas) for 3 hours at room temperature. The mixture was then concentrated by evaporation to afford N-{3-[2-(3-amino-1-phenyl-propylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 17 mg, 65.8%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][C@@H:22]([CH3:24])[NH:21][CH2:20][C@@H:19]1[CH3:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>>[C:11]([O:15][C:16]([N:18]1[CH2:23][C@@H:22]([CH3:24])[N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][C@@H:19]1[CH3:25])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc([N+](=O)[O-])cn1
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 6.3 mmol), and potassium carbonate (1.7 g, 13 mmol) was stirred in DMSO (5.0 mL, 70 mmol) at 100° C. overnight. The reaction mixture was filtered thru a silica gel pad, which was washed with EtOAc (200 mL). The filtrate was washed with water (2×10 mL), concentrated, and purified by silica gel chromatography (eluted with ethyl acetate/hexane=0 to 80%) to give the title intermediate (1.724 g, 81% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O=C1CCC(=O)N1[O:32][C:33]([C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41](=[O:57])[CH2:42][CH2:43][CH:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[CH2:36]1)=O.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH2:18]([O:17][C:15]1[CH:16]=[C:11]([C@@H:2]([NH:1][C:33]([C@@H:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41](=[O:57])[CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:46][CH2:45]3)[CH2:36]2)=[O:32])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:12]=[N:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1cncc(OCc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccccc2)c1

Procedure:
To tert-butyl (3S)-3-amino-3-[5-(benzyloxy)pyridin-3-yl]propanoate (1.15 g, 3.5 mmol) in DMF (13.4 mL) was added tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate and triethylamine (1.46 mL, 10.5 mmol) in dichloromethane (13.5 mL) at 0° C. After 3 hours the mixture was quenched by addition of saturated aqueous ammonium chloride solution, phases were separated and the aqueous phase was extracted with diethyl ether. Combined organic extracts were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 20 to 100% followed by methanol in ethyl acetate 0 to 20%) to yield 1.76 g tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(benzyloxy)pyridin-3-yl]-3-tert-butoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C(OC(=O)[N:7]([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1)[CH2:8][CH2:9][NH:10][CH2:11][CH:12]([C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)[CH2:13][CH:14]=[CH2:15])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:29][C:27]1[CH:28]=[C:23]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]([I:22])=[CH:20][CH:21]=2)[CH2:13][CH:14]=[CH2:15])[CH:24]=[C:25]([Cl:30])[CH:26]=1
Reactant: C=CCC(CNCCN(C(=O)OC(C)(C)C)c1cc(Cl)cc(Cl)c1)c1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC(CNCCNc1cc(Cl)cc(Cl)c1)c1ccc(I)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a stirred solution of (3,5-dichloro-phenyl)-{2-[2-(4-iodophenyl)-pent-4-enylamino]-ethyl}-carbamic acid tert-butyl ester (0.493 g, 0.85 mmol) in CH2Cl2 (20 mL) at 0° C. was added TFA (5 mL). The mixture was stirred and warmed to room temperature for 4 h. The solvent was removed by rotary evaporation and the residue was dissolved in EtOAc and washed twice with NaHCO3 (10% in H2O). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give N-(3,5-dichloro-phenyl)-N′-[2-(4-iodo-phenyl)-pent-4-enyl]-ethane-1,2-diamine (0.386 g, 0.81 mmol, 95%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.73 (d, 2H), 7.03 (d, 2H), 6.56 (t, 1H), 6.50 (d, 2H), 5.75 (m, 1H), 5.08 (m, 2H), 4.42 (br s, NH), 3.15 (m, 2H), 3.40 (m, 5H), 2.44 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[K+].[CH3:6][S:7]([NH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([CH2:17][C:18]([O:20]CC)=[O:19])=O)=[CH:13][CH:12]=1)(=[O:9])=[O:8].Cl.[NH2:26]O.CO>O>[CH3:6][S:7]([NH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]2[CH2:17][C:18](=[O:19])[O:20][N:26]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C2=NOC(=O)C2)cc1
Yield: 55.1 %

Procedure:
Potassium acetate (8.2 g) was added to a mixture of ethyl 4-methanesulfonamidobenzoylacetate (23.0 g), hydroxylamine hydrochloride (5.8 g) and methanol (35 ml), and the mixture was heated for refluxing for 30 minutes. The reaction mixture was poured into water (210 ml) to filter off the deposited crystals and dry them, whereby 3-(4-methanesulfonamidophenyl)isoxazoline-5-one (11.3 g) was obtained.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[K+].[K+].[K+]>O>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reaction time: 0.03 h

Procedure:
Potassium citrate ##STR90## The resulting product is added to 16 ounces of boiling water and stirred for a period of 1.5 minutes. The resulting material is poured into a mold and is permitted to cool. The resulting jell has an excellent "true fruit" flavor with intense blueberry and blackcurrent nuances. Note: CARMEL KOSHER® vegetable jell is produced by Carmel Kosher Food Products, Inc. of Chicago, Ill. 60632.
Reaction SMILES: [F:1][C:2]([F:14])([S:11]([O-:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[Na+:15].[OH2:16]>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:14][C:2]([F:1])([S:11]([O-:16])(=[O:13])=[O:12])[CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:8])([CH3:9])[CH3:7].[Na+:15]
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)[O-]
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)[O-]
Reaction time: 1 h
Yield: 91 %

Procedure:
A glass flask equipped with a thermometer, a condenser and a dropping funnel was charged with 290 g (0.74 mole) of 65% purity sodium 1,1-difluoro-2-(pivaloyloxy)ethane-1-sulfinate, a catalytic amount of sodium tungstate (IV) dihydrate, 600 ml of water, followed by stirring. Then, 170 g (1.5 moles) of 30% oxygenate was added dropwise in an iced bath. After the termination of the dropping, stirring was conducted for 1 hour at room temperature. Then, the termination of the reaction was confirmed by 19F NMR. The reaction solution was concentrated and then rinsed with 500 ml of diisopropyl ether. Subsequently, filtration was conducted and a solid obtained therewith was dried, thereby obtaining 278 g of sodium 1,1-difluoro-2-(pivaloyloxy)ethanesulfonate in the form of a white solid (91% yield, 65% purity).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:29]3[CH2:30][CH2:31][N:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ccccc4)CC3)s2)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride (70 mg, 0.22 mmol) in methylene chloride (5 mL) is added 1-phenylpiperazine (30 mg, 0.22 mmol), piperidinomethyl polystyrene (75 mg, 0.262 mmol) and the mixture is stirred overnight at room temperature under a nitrogen atmosphere. After the reaction is completed (determined by TLC) it is filtered and the filtrate concentrated. The residue is purified by chromatography on a 5 g silica gel cartridge (eluting with ethyl acetate-50% heptane then 100% ethyl acetate) affording the corresponding sulfonamide as a solid (95% yield). LC/MS: RT 3.79 min; m/e 444 (M+H); 1H NMR (δ, ppm): 11.83 (1H, s), 7.65 (1H, d); 7.38 (1H, s); 7.28 (1H, d), 7.21 (2H, m), 6.94 (2H, d), 6.81 (1H, t), 3.26 (4H, br d), 3.12 (4H, br d), 2.38 (2H, q), 2.32 (3H, s), 1.09 (3H, t).