Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(COCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 0.76 g, 19 mmol) in anhydrous tetrahydrofuran (38 mL) was stirred at room temperature under a nitrogen atmosphere. A solution of 1-benzyl-4-hydroxymethyl piperidine (3.82 g, 18.6 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred for 2 h. 4-Fluorobenzyl bromide (2.4 mL, 19 mmol) was added dropwise, then the reaction mixture was stirred for 72 h. Water (50 mL) was added and the resulting mixture was extracted three times with ethyl acetate. Drying over magnesium sulfate, filtration and concentration in vacuo gave an oil. Vacuum distillation (170° C. (Kugelrohr oven), 1.0 Torr) gave a colorless oil (3.45 g, 59% yield): 'H-NMR: 7.34-6.98 (m, 9H), 4.46 (s, 2H), 3.50 (s, 2H), 2.93-2.87 (m, 2H), 2.02-1.59 (m, 5H), 1.39-125 HR-MS Calcd.: 313.1478; Found: 313.1479; (m, 2H); Anal. Calcd.: for C20H24FNO: C,76.65, H,7.72, N,4.47; Found: C,77.27, H,7.69, N,4.45.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[O:37][C:38]4[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)=[CH:31][CH:30]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]3)[N:3]=[C:2]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]4[O:37][C:38]5[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:39]=5[N:40]=4)=[CH:31][CH:30]=3)[C:10]=12
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: CC(C)c1cccc2nc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc12
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cccc(C(C)C)c5o4)cc3)c3c(N)ncnc32)C1

Procedure:
rac-N2-(4-{4-Amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-isopropyl-1,3-benzoxazol-2-amine was prepared from rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.515 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-7-isopropyl-1,3-benzoxazol-2-amine (0.244 g, 0.644 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.067 g, 25%). 1H NMR (DMSO-d6, 400 MHz) 1.361 (d, 6H), 2.30 (m, 2H), 2.66 (m, 2H), 2.76-2.83 (m, 3H), 3.17 (t, 1H), 3.24 (s, 3H), 3.38 (m, 1H), 3.45 (t, 2H), 5.37 (m, 1H), 7.04 (d, 1H), 7.18 (t, 1H), 7.32 (d, 2H), 7.67 (d, 2H), 7.95 (d, 2H), 8.24 (s, 1H), 10.88 (s, 1H); RP-HPLC Rt 12.337 min, 94% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 513 (MH+).
Reaction SMILES: C(O)C.F[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[N:6]=1.C(=O)(O)[O-].[Na+].[CH2:20]1[O:29][C:28]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=2[O:21]1>O>[F:14][C:7]1[N:6]=[C:5]([NH:25][C:24]2[CH:26]=[CH:27][C:28]3[O:29][CH2:20][O:21][C:22]=3[CH:23]=2)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)nc1Nc1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
In 75 ml. of ethanol was dissolved 3.2 g. (0.002 mole) of 2,6-difluoro-3-nitropyridine followed by 1.68 g. (0.02 mole) of sodium bicarbonate. To this stirred mixture, was added a solution of 2.74 g. (0.02 mole) of 3,4-(methylenedioxy) aniline in 50 ml. of ethanol dropwise over 45 minutes at room temperature. After one hour, 100 ml. of water was added and the deep-red crystalline solid product was collected. A small amount was crystallized from ethanol and melted at 161°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH:28]=[O:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.[OH-:37].[Na+].Cl>CC#N.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([C:28]([OH:37])=[O:29])=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: O=C(O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirring solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinaldehyde (150 mg, 0.294 mmol) in CH3CN (10 mL) was added silver nitrate (235 mg, 1.38 mmol), followed by 1.0 M aqueous NaOH solution (2.2 mL, 2.2 mmol). The resulting black mixture was stirred at room temperature for 1 h, then the reaction mixture was adjusted to pH 5 by dropwise addition of 1 N aqueous HCl solution. The resulting mixture was extracted with EtOAc (30 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure to obtain 150 mg of the title compound as a brownish solid. A portion (10 mg) of the product was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was partitioned between EtOAc and water, then adjusted to pH 6-7 with saturated aqueous NaHCO3 The EtOAc layer was washed with water, then saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 8.5 mg of the title compound as a yellow powder. HPLC/MS: retention time=2.58 min, [M+H]+=526.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([OH:29])=O)[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([NH:31][CH3:30])=[O:29])[CH:3]=1
Reactant: Cc1nc(N)cc(OCC(=O)O)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Reactant: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)COc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-(6-amino-3-((1-benzyl-1H-pyrazole-4-carboxamido)methyl)-2-methylpyridin-4-yloxy)acetic acid (35 mg, 0.051 mmol) was dissolved in DMF (1 ml), CDl (16.65 mg, 0.103 mmol) was added. After stirring for 15 min at rt Methylamin 2M in THF (0.257 ml, 0.513 mmol) was added and the reaction mixture was stirred 6 h at rt. Purification by prep HPLC (Nucleosil C18, 250×40 mm 5 to 100% ACN and 0.1% TFA, flow 40 mml/min.) offered the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.71 (d, 3H), 4.37 (d, 2H), 4.67 (s, 2H), 5.34 (s, 2H), 6.20 (s, 1H), 7.24 (m, 5H), 7.79 (s, 2H), 7.89 (s, 1H), 8.25 (d, 2H), 8.28 (s, 1H), 8.35 (t, 1H). HPLC/MS (Method B) Rtb=0.46 min, MS [M+H]+=409.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CON(C)[C:23](=[O:25])[CH3:24]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:23](=[O:25])[CH3:24])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Reactant: CON(C)C(C)=O
Product: CC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CC2(C)C

Procedure:
Prepared from 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester and N-methoxy-N-methyl-acetamide using a procedure analogous to that of Preparation 263. MS: [M+H]+=291.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=C/C(OC(C)(C)C)=O)=[C:11]([O:24][CH3:25])[CH:10]=1)#[N:8].[OH2:26]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C1COCC1.[Os](=O)(=O)(=O)=O>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][C:11]=1[O:24][CH3:25])=[O:26]
Reactant: COc1cc(C#N)ccc1/C=C/C(=O)OC(C)(C)C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
79 g (370 mmol) of sodium metaperiodate are added in portions to a vigorously stirred solution of 48 g (185 mmol) of tert-butyl (2E)-3-(4-cyano-2-methoxyphenyl)acrylate, 207 mg (0.81 mmol) of osmium tetroxide and 1.4 g (6.14 mmol) of benzyltriethylammonium chloride in 750 ml of water/THF (2:1), keeping the reaction temperature below 30° C. The solution is stirred further at RT for 1 h. Water (2000 ml) is added, and the mixture is then filtered. The remaining solid is dissolved in ethyl acetate, and the solution is washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is stirred with petroleum ether. 21.18 g (71% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(CCCC)(=O)=O)[N:15]=1)(=[O:4])=[O:3].Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:31][CH2:30]1.C(N(C(C)C)C(C)C)C>CCO>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:28][CH:29]2[CH2:30][CH2:31][CH:32]([C:35]([N:37]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:36])[CH2:33][CH2:34]2)[N:15]=1)(=[O:3])=[O:4]
Reactant: NC1CCC(C(=O)N2CCCC2)CC1
Reactant: CCCCS(=O)(=O)c1nccc(-n2ccc3c(S(C)(=O)=O)cccc32)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CS(=O)(=O)c1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)N3CCCC3)CC2)n1
Temperature: 170 °C
Yield: 29.9 %

Procedure:
4-Methylsulfonyl-1-(2-butylsulfonyl-pyrimidin-4-yl)-1H-indole (250 mg, 0.636 mmol), (4-amino-cyclohexyl)-pyrrolidin-1-yl-methanone hydrochloride (444 mg, 1.91 mmol), ethyl-diisopropylamine (333 μL, 1.91 mmol), and dry EtOH (5 mL) were placed in a vial, sealed, and heated in a microwave reactor at 170° C. for 1 h. The product was concentrated to dryness and purified by column chromatography (5% MeOH in DCM), clear fractions collected and evaporated to dryness, and dried overnight under vacuum. The product was recrystallized from CH3CN and dried under vacuum to provide {4-[4-(4-methanesulfonyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-pyrrolidin-1-yl-methanone (Compound 200, 89 mg).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 86.9 %

Procedure:
To a solution of 10.38 gm 185 mMol) potassium hydroxide in 200 mL methanol were added 10.0 gm (61.7 mMol) 5-nitro-1H-indole followed by 13.96 gm (123 mMol) 1-methyl-4-piperidone. The mixture was heated to reflux for 4 days under a nitrogen atmosphere. The reaction mixture was then allowed to cool to ambient and the solid which formed filtered and washed with methanol. This solid was dried under vacuum at 50° C. The combined filtrates were then concentrated under reduced pressure and the residue subjected to flash chromatography, eluting with 92.5:7.5 dichloromethane:methanol. Fractions shown to contain product were combined and concentrated under reduced pressure. This solid was combined with that isolated directly from the reaction mixture to give 13.79 gm (87%) 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[O:9][CH2:8][CH2:7][O:6]1.[O:18]=[C:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:18]=[C:19]1[C:23]2([CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][C:5]3([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])[O:9][CH2:8][CH2:7][O:6]3)[CH2:27][CH2:28]2)[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][NH:20]1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)c(F)c1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCC1(c3ccc(F)cc3F)OCCO1)CC2

Procedure:
A mixture of 4-chloro-1-(2,4-difluorophenyl)-1,1-ethylenedioxybutane (5.3 g), 4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane (4.6 g), anhydrous potassium carbonate (0.1 g) and dimethylformamide (58 ml) was heated under refluxing for 2.5 hours. After cooling, the reaction mixture was poured into cold water (400 ml) with vigorous stirring, and the precipitate was collected and washed with water to yield 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decan-8-yl)-1-(2,4-difluorophenyl)-1,1-ethylenedioxybutane. M.P. 58° - 62°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=1.N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1ccn(CCCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCO)n2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 114, 65 mg, 0.20 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 110 μL, 0.22 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 29 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol, diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (60 mg, 68%) as a white foam: [α]25589=−6.2° (c=0.21, methanol); ES-HRMS m/e calcd for C22H28N4O4S (M+H)+ 445.1904, observed 445.1903; 1H NMR (300 MHz, DMSO-d6) δ 1.11 (m, 2H, CH2), 1.38-1.90 (m, 10H, 5×CH2), 2.12 (m, 1H, CH), 3.33 (brm, 2H, OCH2), 3.36 (s, 3H, SO2CH3), 3.98 (m, 1H, ArCHCO), 4.02 (t, J=7.1 Hz, 2H, NCH2), 4.56 (t, J=5.0 Hz, 1H, OH), 6.40 (d, J=2.2 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.94 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.10 (d, Jm=1.6 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([O:12]C(C)(C)C)=[O:11])[N:7]([C:17](=[O:30])[C@H:18]([CH3:29])[CH2:19][S:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]1=[O:31])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([N:5]1[CH2:9][C@@H:8]([C:10]([OH:12])=[O:11])[N:7]([C:17](=[O:30])[C@H:18]([CH3:29])[CH2:19][S:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:6]1=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCN1C[C@@H](C(=O)O)N(C(=O)[C@H](C)CSC(=O)c2ccccc2)C1=O
Yield: 91.4 %

Procedure:
3.5 g of tert.-butyl (4S)-1-n-butyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate and 15 ml of trifluoroacetic acid are treated in the same manner as described in Example 2-(3). 2.8 g of (4S)-1-n-butyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 91.4% The physicochemical properties of this product are identical with those of the sample obtained in Example 6-(4).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH3:35][S:32]([C:29]1[CH:28]=[CH:27][C:26](/[C:19](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20]/[CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)=[CH:31][CH:30]=1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCO2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C/C2CCCO2)c2cc3cccnc3[nH]2)cc1
Yield: 75.1 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.24 g, 0.47 mmol) in ethanol (2 mL), tetrahydrofuran (2 mL) and an aqueous sodium hydroxide solution (10%, 1 mL) was heated at 50° C. for 2 h. The mixture diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (Z)-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 75%): LC/MS m/e calcd for C20H20N2O3S [M+H]+ 369.46, observed 369.3; and (E)-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (5 mg, 2%): LC/MS m/e calcd for C20H20N2O3S [M+H]+ 369.46, observed 369.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.28 (d, J=5.1 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.07-8.11 (m, J=8.3 Hz, 2H), 7.61-7.66 (m, J=8.1 Hz, 2H), 7.29-7.34 (m, 1H), 6.59 (d, J=9.1 Hz, 1H), 6.15 (s, 1H), 4.24 (q, J=7.4 Hz, 1H), 3.98 (q, J=7.0 Hz, 1H), 3.75-3.81 (m, 1H), 3.23 (s, 3H), 2.05-2.15 (m, 2H), 1.80-1.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:13])[CH:3]=1.CC1CCCN(C)C1(C)C.[Li].CN([CH:28]=[O:29])C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:28]=[O:29])=[C:4]([F:13])[C:5]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Reactant: CN(C)C=O
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of 1-chloro-3,5-difluoro-4-trimethylsilylbenzene (1.5 g, 6.8 mmol) in THF (10 mL) was added to a solution of lithium tetramethylpiperidine (14 mmol) in THF (15 mL) at −75° C. The solution was stirred for 2 hours then DMF (1.5 g, 20 mmol) was added and the solution allowed to warm to ambient temperature. The reaction was quenched with a saturated solution of ammonium chloride (25 mL) and extracted with ethyl ether (2×25 mL) and the combined extracts dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde (1.4 g, 5.6 mmol): LC/MS (m/z=248).
Reaction SMILES: [CH:1]1([S:4]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C(O)=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1C(=O)N([I:24])C(=O)C1>>[CH:1]1([S:4]([CH:7]([I:24])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccccc1)S(=O)(=O)C1CC1
Reactant: O=C1CCC(=O)N1I
Product: O=S(=O)(C1CC1)C(I)c1ccccc1
Yield: 32 %

Procedure:
However, the use of these reagents as source of iodine for reactions of iodo-de-carboxylation are limited. Reaction of N-halosuccinimides with aryl acrylic and aryl propiolic acids gives 1-halo-2-aryl-1-alkenes and 1-halo-2-aryl-1-alkynes (J. Org. Chem. 2002, v. 67, 7861; J. Org. Chem. 1999, v. 64, 6896; J. Org. Chem. 1997, v. 62, 199; Tetrahedron 2000, v. 56, 1369). All the reactions occur in the presence of catalyst. Reaction of α-(cyclopropylsulfonyl)phenylacetic acid with NIS gives α-iodobenzyl cyclopropyl sulfone only with 32% yield (J. Org. Chem. 1974, v. 39, 2516).
Reaction SMILES: O[C@H:2]([CH3:19])[CH2:3][N:4]1[C:18]2[C:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[N:5]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>O1CCCC1>[N:36]([C@@H:2]([CH3:19])[CH2:3][N:4]1[C:18]2[C:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[N:5]1)=[N+:37]=[N-:38]
Reactant: C[C@@H](O)Cn1ncc2ccc3oc(C(N)=O)nc3c21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)nc3c21)N=[N+]=[N-]
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 18.3 %

Procedure:
To a suspension of the product from Step D (0.90 g, 3.45 mmol) in tetrahydrofuran (20 mL) was added triethylamine (1.93 mL, 13.9 mmol); this mixture was cooled (ice bath), methane sulfonic anhydride (1.20 g, 6.92 mmol) was added, and the mixture was stirred for 20 minutes. Sodium azide (2.25 g, 34.6 mmol) was added and the mixture was evaporated to a residue which dissolved in dimethyl sulfoxide (20 mL) and heated at 90° C. for 2.5 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with water (100 mL), dried (magnesium sulfate), filtered, and evaporated to solid (0.97 g). This residue was purified by chromatography (silica gel, ethyl acetate gradient) and recrystallized from methanol and ethyl acetate to give a colorless solid (0.18 g, 18%): mp 162–164° C.; LC/MS m/z 286.