Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[NH3:17]>ClCCl.CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:17])=[O:6]
Reactant: N
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A suspension of 3-iodobenzoic acid (4.04 g, 16.2 mmol) in dichloromethane (30 mL) was treated with 2M oxalyl chloride (16 mL, 32 mmol, hexane) followed by two drops of N,N-dimethylformamide and stirred at ambient temperature for 2 hours. After this time the solvent was removed in vacuo and the residue dissolved in tetrahydrofuran (30 ml). The solution was cooled to 0° C. and treated with 2M ammonia (20 mL, 40 mmol, methanol) and the mixture stirred for 30 minutes. The mixture was then filtered and the solvent removed in vacuo. Recrystallization of the residue from methanol afforded 3.5 g (87%) of 3-iodobenzamide, as a white solid.
Reaction SMILES: N([O-])=O.[Na+].[CH:5]1[C:14]2[C:9](=[C:10](N)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1.[BrH:16].[NH4+]>O>[Br:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[CH:7][N:6]=[CH:5]2
Reactant: Nc1cccc2cnccc12
Reactant: Br
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Brc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A solution of sodium nitrite (2.15 g, 31.21 mmol) in water (2 mL) was added to a solution of isoquinolin-5-ylamine (3.0 g, 20.80 mmol) in aqueous 46% hydrogen bromide (9.98 g, 124.84 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min then a solution of cuprous bromide (3.58 g, 24.96 mmol) in aqueous 46% hydrogen bromide (9.98 g, 124.84 mmol) was added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The resulting mixture was basified with aqueous ammonium and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to afford the crude compound. Purification by column chromatography over silica gel (100-200 mesh) with 20% ethyl acetate in petroleum ether as eluent afforded 5-bromoisoquinoline (2.3 g, 53%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[O:14][CH2:13][CH2:12][N:11](S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Li+].[OH-].C(S)CC>C(#N)C.O.CCOC(C)=O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CCO2)c1
Agent: CCCS
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C2CNCCO2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 54 %

Procedure:
Dissolve 2-(3-methoxyphenyl)-4-(4-nitrophenyl)sulfonyl-morpholine (11.2 g, 29.6 mmol) in ACN (150 mL) and water (2.67 mL). Add LiOH (6.21 g, 147.99 mmol) while stirring the mixture and followed by 1-propanethiol (13.42 mL, 147.99 mmol). Stir the mixture for 25 h at ambient temperature. Dilute the mixture with EtOAc and add brine. Extract twice with EtOAc. Collect and concentrate the extracts to ˜200 mL under reduced pressure, then wash three times with 1N HCl. Combine the aqueous acid extracts and add Na2CO3 until the mixture is basic. Extract the basic solution three times with EtOAc; combine the extracts; wash the extracts with brine; and dry over Na2SO4. Filter; collect the filtrate; and remove the solvents under reduced pressure to provide a residue. Purify the residue via flash column chromatography eluting with EtOAc, followed by a 5-100% gradient of (10% 2M NH3 in MeOH)/DCM. Combine the product fractions, and remove the solvents under reduced pressure to provide the title compound as a yellow oil (3.09 g, 15.99 mmol). MS (m/z): 194 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12]([CH3:23])=[CH:13][CH:14]=[CH:15][C:16]([CH3:22])=[CH:17][CH2:18][O:19][CH:20]=[O:21].C[C:25]1[CH2:30][CH2:29][CH2:28][C:27](C)([CH3:31])[C:26]=1/[CH:33]=[CH:34]/[C:35](/C)=[CH:36]/[CH:37]=[CH:38]/[C:39](/C)=[CH:40]/CO.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C\C(\C)=C\CO.C(O)C(N)(CO)CO.SC[C@H]([C@@H](CS)O)O.CCCCCCCCCCCCCCCC(OC[C@@H](OC(CCCCCCCCCCCCCCC)=O)COP(OCC[N+](C)(C)C)([O-])=O)=O>>[CH3:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:26][CH2:25][CH2:30][CH2:29][CH2:28][CH2:27][CH2:31][C:20]([O:19][CH2:18]/[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])\[CH3:23])\[CH3:22])=[O:21]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CCOC=O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C\C(C)=C\CO)C(C)(C)CCC1
Agent: CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Agent: NC(CO)(CO)CO
Product: CCCCCCCCCCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Reaction time: 0.17 h

Procedure:
Isomeric preference of the mRPE65/tLRAT mediated esterification of retinols: The effect of mRPE65 on the processing of 11-cis-and all-trans-retinols was determined by monitoring the formation of tLRAT catalyzed retinyl esters from added all-trans-retinol [11,12-3H2], 11-cis-retinol [15-3H] and mRPE65. The reaction mixture (volume 0.1 mL) contains 100 mM Tris (pH 8.4), 5 μM of tLRAT 0.3% CHAPS, 1 mM dithiothreitol and 0.2 μm of all-trans-retinol [11,12-3H2] or 11-cis-retinol [15-3H] and mRPE65 (0.02 μM) or 200 μM/0.4% DPPC/BSA was incubated for 10 min at room temperature. After 10 min the reaction was quenched with 500 μL methanol, 100 μL of water and 500 μL of hexane. The amount of retinyl palmitate formed, as determined by normal phase-HPLC, was used as a measure of activity. Each experiment was done in triplicate, and the data points used are an average of these three points. The standard error was presented as error bars.
Reaction SMILES: [ClH:1].NC[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.C1(C(CC)C(OCC)=O)C=CC=CC=1>>[Cl:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(CC)c1ccc(CCN)cc1
Reactant: Cl
Agent: CCOC(=O)C(CC)c1ccccc1
Product: CCOC(=O)C(CC)c1ccc(CCl)cc1

Procedure:
For the preparation of ethyl 2-[4-(2-aminoethyl)-phenyl]-butyrate hydrochloride, ethyl 2-phenylbutyrate is chloromethylated and the ethyl 2-(p-chloromethylphenyl)-butyrate obtained (b.p. 117°-123° C./0.2 mm Hg) is reacted with potassium cyanide in acetone to give ethyl 2-(p-cyanomethylphenyl)-butyrate (b.p. 156°-160° C./0.3 mm Hg). By the catalytic hydrogenation of the nitrile group in the presence of a palladium/charcoal catalyst in alcoholic hydrochloric acid solution, there is obtained ethyl 2-[4-(2-aminoethyl)-phenyl]-butyrate hydrochloride, which does not crystallize.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:25][CH3:26])=[C:9]([CH:24]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:11])(=[O:3])N.C([OH:29])C.[OH-].[Na+].O>C(OCC)C>[CH3:26][O:25][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:1]([OH:29])=[O:3])=[CH:24][C:9]=1[C:10](=[O:11])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(CC(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(CC(=O)O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1

Procedure:
To 700 mg of 5-carbamoylmethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 21 ml of ethanol, 7 ml of 1 mol/l aqueous solution of sodium hydroxide, and the mixture was refluxed for 18 hours. The reaction mixture was poured into water, washed with ethyl acetate, and further the aqueous layer was adjusted to pH value of 1 to 2 with 2 mol/l hydrochloric acid, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence and dried again over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was suspended with diethyl ether to collect the crystals by filtration. The crystals obtained were recrystallized from methylene chloride to obtain 435 mg of aimed product as colorless crystals.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33][O:34][S:35]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=4)(=[O:37])=[O:36])[CH:29]=3)[NH:24][N:23]=2)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[CH2:1]([N:24]1[C:25]2[C:30](=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:27][CH:26]=2)[C:22]([S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:20])=[O:21])=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzyl bromide (0.46 mL, 3.9 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (1.85 g, 3.54 mmol) and cesium carbonate (1.28 g, 3.93 mmol) in acetone (60 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 1.5 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 40-50% ethyl acetate in hexane. Drying at 80° C. in vacuo for 30 minutes yielded toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester as a light buff foam (1.39 g, 64.1%); Mass Spectrum (+EI, [M+H]+) m/z 613. 1HNMR (500 MHz, DMSO-d6): δ8.74-8.77 (m, 1H), 8.55-8.57 (m, 1H), 8.25-8.27 (m, 1H), 8.01-8.05 (m, 1H), 7.64-7.76 (m, 4H), 7.58-7.64 (m, 2H), 7.25 (d, 2H, J=7.93 Hz), 7.10-7.19 (m, 5H), 7.07 (d, 1H, J=2.19 Hz), 6.94-6.97 (m, 1H), 5.69 (s, 2H), 4.30-4.32 (m, 2H), 4.14-4.16 (m, 2H), 2.18 ppm (s, 3H). Elemental Analysis for C33H28N2O6S2.0.60 mol H2O: Calcd: C, 63.57; H, 4.72; N, 4.49; Found: C, 63.17; H, 4.63; N, 4.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOCC>CO.O>[CH2:26]([O:16][C:15](=[O:17])[C@@H:12]([CH2:13][OH:14])[NH:11][C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)=[O:10])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(COC(=O)N[C@H](CO)C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(COC(=O)N[C@H](CO)C(=O)OCc2ccccc2)cc1
Yield: 82 %

Procedure:
N-p-Methoxybenzyloxycarbonyl-D-serine (5.39 mg, 2.00 sm:ol; prepared as a colourless solid of m.p. 96°-97° C. in 60% yield by the dissolved in methanol and treated with a solution of potassium carbonate (138 mg, 1.00 mmol) in water (2 ml). The mixture is evaporated by dryness, N,N-dimethyl-forimide (DMF) is added and re-evaporated (2×2 ml), and the solid residue is then dissolved in dry warm DMF, benzyl bromide (248 μl, 2.1 mmol) is added and the solution is warmed in a dry closed flask at 50° C. for 1 hour. The resulting mixture is portioned between ether (10 ml) and water (10 ml) and the aqueous layer is extracted with ether (2×10 ml). The combined ether extracts are washed with saturated sodium bicarbonate (5 ml) and saturated brine (5 ml), dried and evaporated to dryness. The residue is purified on a column of silica gel using 1:1 v/v ethyl acetate:petroleum ether as eluant to yield to title compound as a homogenous oil (590 mg, 82%) which crystallises on standing to give a colourless solid of m.p. 67°-68° C. (from diethyl ether); [α]D20 --6.3° (c 4.0, CHCl3).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].[OH-].[Na+]>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: NCCO
Reactant: COc1ccc(Nc2ccnc(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2ccnc(NCCO)c2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
36 mg of (2-fluoro-N-(4-methoxyphenyl)pyridin-4-amine were mixed with 80.6 mg of ethanolamine and the mixture obtained was heated in a screw cap vial under argon to 150° C. for 3 days. The mixture obtained was cooled to r.t. and 5 mL of 2N NaOH were added, the mixture obtained was extracted with EtOAc for three times and from the organic layer obtained solvent was evaporated off. 2-(4-(4-Methoxyphenylamino)pyridin-2-ylamino)ethan-1-ol was obtained in the form of a brown solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]([CH3:19])([CH3:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:20])[CH:15]=3)[C:10]2=[O:21])[CH:6]=[N:7][CH:8]=1.CCN(CC)CC.[CH3:29][C:30]1[C:31]([C:36](O)=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[Cl:20][C:14]1[CH:15]=[C:16]2[C:11]([C:10](=[O:21])[N:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:36]([C:31]4[C:30]([CH3:29])=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:37])[CH:8]=[N:7][CH:6]=3)[C:17]2([CH3:18])[CH3:19])=[CH:12][CH:13]=1
Reactant: Cc1cccnc1C(=O)O
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccnc1C(=O)NCc1cncc(N2C(=O)c3ccc(Cl)cc3C2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
To solution of 2-(5-aminomethyl-pyridin-3-yl)-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (30 mg, 0.1 mmol), Et3N (15.3 mg, 0.15 mmol) and 3-methyl-pyridine-2-carboxylic acid (13.7 mg, 0.1 mmol) in DMF (3 mL) was added HATU (57.0 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Both water and EtOAc were added and the organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a residue which was then purified by Prep HPLC to give the title compound (10 mg, 24%) as a solid. MS: 421.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:9]=[N+:10]=[N-:11].[Na+].CS(C)=O>>[CH:1]1([CH2:7][N:9]=[N+:10]=[N-:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCCCC1
Reaction time: 21 h

Procedure:
Cyclohexylmethyl bromide (200 mg, 1.13 mmol) was added to a stirred solution of 0.5 M sodium azide in DMSO (2.48 mL, 1.24 mmol) at room temperature, under an atmosphere of nitrogen. After 21 h, the reaction was quenched by the addition of water (5 mL) and extracted with diethyl ether (3×4 mL). The combined organic layers were washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude oil (136 mg) which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[CH3:21][C:22]1[C:26]([CH2:27][CH2:28][NH2:29])=[C:25]([CH3:30])[NH:24][N:23]=1>>[CH3:21][C:22]1[C:26]([CH2:27][CH2:28][NH:29][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:25]([CH3:30])[NH:24][N:23]=1
Reactant: Cc1n[nH]c(C)c1CCN
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Product: Cc1n[nH]c(C)c1CCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)C)C1=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]amine dihydrochloride in a similar manner as described for Example 24 with TEA as base. 1H NMR (500 MHz, CDCl3): δ 7.53-7.48 (m, 2H), 7.47-7.43 (m, 3H), 5.34 (t, 1H), 4.41 (sept, 1H), 3.01 (q, 2H), 2.41 (t, 2H), 2.05 (s, 6H), 1.58 (d, 6H); 13C NMR (125 MHz CDCl3): δ 158.8, 135.3, 131.5, 129.9, 129.0, 125.3, 111.2, 107.2, 47.8, 43.9, 23.7, 20.4, 10.9; Mass Spectrum: M+H+ 389
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][O:9][C:10]=1[C:11]([CH3:19])([CH3:18])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O)C.[BH4-].[Li+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[C:14]([SiH2:13][O:12][C:11]([CH3:19])([CH3:18])[C:10]1[O:9][N:8]=[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6]=1[CH2:4][OH:3])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1c(-c2ccccc2)noc1C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1onc(-c2ccccc2)c1CO
Reaction time: 1 h
Yield: 40.5 %

Procedure:
5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-phenyl-isoxazole-4-carboxylic acid ethyl ester (12.2 g, 34 mmol) was dissolved in THF (200 mL), lithium borohydride (1.47 g, 67 mmol) was added and the reaction mixture was heated under reflux overnight. After cooling to room temperature aqueous saturated Seignette salt solution was added and the mixture was stirred for 1 h. After extractive workup (ethyl acetate/diethylether) the organic phase was dried over sodium sulfate, filtered and concentrated. Chromatographic purification (silica, heptane:ethyl acetate=100:0 to 85:15) afforded the title compound as a light yellow oil (4.4 g, 41%). MS: m/e=320.4 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH:41]([NH:44]C(=O)OC(C)(C)C)[CH2:40][CH2:39]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.CC(C)([O-])C.[Na+]>COCCOC.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:44][CH:41]1[CH2:42][CH2:43][CH:38]([CH2:37][NH:36][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][N:9]=3)[N:7]=2)[CH2:39][CH2:40]1
Reactant: Brc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncccc23)n1
Reactant: CC(C)(C)OC(=O)NC1CCC(CN)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: NC1CCC(CNc2cccc(-c3n[nH]c4ncccc34)n2)CC1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a stirred solution of 3-(6-bromo-2-pyridyl)-1-trityl-pyrazolo[5,4-b]pyridine (100 mg, 0.1933 mmol) and tert-butyl N-[4-(aminomethyl)cyclohexyl]carbamate (52.97 mg, 0.232 mmol) in DME (1.5 mL) was added Palladium acetate (4.340 mg, 0.01933 mmol) followed by dicyclohexyl-[2-(o-tolyl)phenyl]phosphane (7.046 mg, 0.01933 mmol) and sodium t-butoxide (27.87 mg, 0.2900 mmol). The reaction mixture was allowed to stir at 120 degrees in the microwave for 2 hours at which time consumption of the SM was observed. The mixture was diluted with DCM and filtered through a 2.5 g celite cartridge, combined washings were evaporated down to a smaller volume (5 ml) and the resultant solution was cooled to 0 degrees (with the aid of an ice bath) and treated with triethylsilane (0.4 mL, excess) followed by TFA (0.8 mL, excess). The reaction was allowed to stir at 0 degrees for 3 hours at which time LCMS analysis showed presence of product. The mixture was evaporated to dryness, taken up in DMSO and purified by the Fractionlynx system. Relevant fractions were collated together and filtered through a NaHCO3 cartridge to give the free base. The washings were evaporated to dryness, taken up in a small amount of MeCN/water and freeze-dried to give the required product as a white solid (19.5 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[NH4+:21].[OH-]>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:21])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reaction time: 1 h
Yield: 92 %

Procedure:
The product from Example 168b (1.8 g, 6.13 mmol) was added to cold NH4OH (15 mL) and stirred for 1 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to gave the title compound (1.66 g, 92%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C.[C-:31]#[N:32].[Na+]>C(#N)C.CN(C)C=O.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][C:31]#[N:32])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (10 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilylchloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C., 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a-bromo-3-cyclopentyloxy-4-methoxyolunene in dimethylformamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 10% ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p. 32°-34° C.; an additional quantity (1.3 g) of slightly impure material also was isolated.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][CH3:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:15]O>C(O)(=O)C>[NH2:1][C:2]1[S:6][C:5]([S:7]([CH3:8])=[O:15])=[N:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OO
Reactant: CSc1nc(-c2ccccc2)c(N)s1
Solvent: CC(=O)O
Product: CS(=O)c1nc(-c2ccccc2)c(N)s1
Yield: 87 %

Procedure:
To 5-amino-2-(methylsulfanyl)-4-phenylthiazole (305 mg, 1.37 mmol) in acetic acid (3.0 ml) was added aqueous hydrogen peroxide (660 μl, 30% wt, 6.9 mmol) dropwise at ambient temperature. After 4 hr the mixture was partitioned between dichloromethane (60 ml) and water (60 ml). The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded pure 5-amino-2-(methylsulfinyl)-4-phenylthiazole (285 mg, 87%).