Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]([O:17][CH3:18])=[O:16])=[O:9])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]([O:17][CH3:18])=[O:16])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCCN1C(=O)c1ccc(N)cc1
Yield: 85.1 %

Procedure:
N-(4-nitrobenzoyl)-2-carbomethoxypyrrolidine (0.54 g, 1.94 mmol) in MeOH (50 mL) with 10% Pd-C (0.10 g) was shaken under an atmosphere of H2 gas (50 psi) for 4 h. The reaction was filtered through a plug of Celite® and evaporated to give 0.41 g of the aniline; LRMS (M+H)+ m/z=249.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[CH:12]=2)[NH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:16])=[O:17])[CH:12]=2)[NH:7][CH2:6]1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCN(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)Cc1ccc2c(c1)C(CCN(C)C)CN2
Reaction time: 0.08 h
Yield: 15.9 %

Procedure:
To a suspension of 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide (0.5 g) in trifluoroacetic acid (15 ml) at -10° was added borane-tetrahydrofuran complex (45 ml; 1M) keeping the temperature below +2°. The resulting suspension was stirred at 0° for 5 min, poured onto saturated potassium carbonate (50 ml) and extracted with ethanol (2×20 ml). The ethanolic extract was evaporated and the residue purified by column chromatography (A) to give the title compound as an oil (80 mg). T.l.c. (N), Rf 0.53 (IPA, CeIV).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH3:25]>CN(C)C=O>[CH2:23]([N:3]1[N:2]=[N:1][C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4]1)[CH2:24][CH3:25]
Reactant: CCCBr
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1nnc(-c2cnc3ccccn3c2=O)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A mixture of 0.4 g (0.00187 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 15 ml of dimethylformamide, 0.25 g (0.00187 moles) of anhydrous potassium carbonate and 0.34 ml (0.00374 moles) of propyl bromide was stirred at 90° C. for 1 hour. The hot dark brown solution was filtered, and the filtrate was evaporated. The dark brown oily residue, which is the mixture of the title compounds, started to crystallize. To the oily crystals 10 ml of ethanol were added, and the crystals were collected. 0.15 g (31.3%) of 3-(2-propyl-2H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2 -a]pyrimidine was obtained, in the form of pale-yellow crystals, m.p.: 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[NH:18][C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=S.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(#N)C>[CH3:17][C:4]1[CH:5]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[N:18]=[C:19]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1N=C=NC(C)(C)C

Procedure:
A reaction vessel is charged with 16.6 g of N-[2,6-dimethyl-4-(3,5-dichloro-2-pyridyloxy)phenyl]-N'-tert-butylthiourea and 12.8 g of 2-chloro-1-methylpyridinium iodide in 150 ml of acetonitrile. With stirring, a solution of 8.4 g of triethylamine in 80 ml of acetonitrile is added dropwise at room temperature. The reaction mixture is subsequently stirred for 2 hours at 80° C. and then concentrated by rotary evaporation at 50° C. 150 ml of hexane are added to the residue and the resultant solution is filtered. The hexane phase is washed with three 30 ml portions of cold water, dried over sodium sulfate and filtered. The filtrate is concentrated by evaporation, affording the title compound of the formula ##STR5## as a clear pale yellow oil which crystallises on standing and has a melting point of 69°-71° C. (compound 1).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=1.Cl>C1COCC1.O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.098 ml of 1 N lithium hydroxide solution was added to a solution of 0.051 g of ethyl 2′,4′-difluorobiphenyl-4-carboxylate in 1ml THF/water (1:1), and the mixture was stirred at room temperature overnight. 5% hydrochloric acid was used to neutralize the solution, which was concentrated in vacuo, and the residue was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([C:10]1[C:11](O)=[C:12]([C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21](CCCCCCCCC)[C:20]=2[OH:35])=[O:18])C=C(C)C=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCC.B.[Na].C(O)(=O)C>C(O)C.O.[OH-].[Na+]>[OH:18][CH:17]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[OH:35])[CH2:12][CH2:11][CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCc1cc(C)cc(C(=O)c2cc(C)cc(CCCCCCCCC)c2O)c1O
Agent: B
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCC(O)c1cc(C)ccc1O
Temperature: 40 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
52.5 g of n-nonyl-2-hydroxy-5-methylphenylketone were dissolved in 100 ml of ethanol. A solution of 9.1 g of sodium boron hydride dissolved in 50 ml of water containing 1.1 g of sodium hydroxide was added dropwise thereto. The mixture was stirred at 40° C. for 2 hours. 100 ml of water was added thereto. Further, 20 ml of acetic acid was slowly added dropwise thereto. After the addition, the reaction mixture was extracted with ethyl acetate, and the organic layer was concentrated. 200 ml of hexane was added thereto, and the precipitated crystals were recovered by filtration to obtain 7.1 g of 2-(1'-hydroxydecyl)-4-methylphenol.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]([OH:15])=[CH:5][CH:4]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C1C=CN=CC=1.O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:15][C:6]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CSc1ccc(O)c(-c2ccccn2)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COc1cc2nccc(Oc3ccc(SC)nc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
6-Methylsulfanyl-[2,2′]bipyridin-3-ol (6 mg), 4-chloro-6,7-dimethoxyquinoline (18 mg), 4-dimethylaminopyridine (10 mg), and cesium carbonate (27 mg) were suspended in N,N-dimethyl sulfoxide (1 ml), and the suspension was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (1 mg, yield 8%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH2:6]([O:5][CH2:4][CH2:3][CH2:2][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using benzyl 3-bromopropyl ether to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (94%): mp 37-38° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.33-7.23 (m, 6H), 7.14-7.12 (m, 1H), 7.02-6.94 (m, 2H), 6.47 (d, J=0.9 Hz, 1H), 6.18 (d, J=0.9 Hz, 1H), 4.70 (ABq, 2H), 4.47 (s, 1H), 4.18-4.08 (m, 4H), 3.96-3.78 (m, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.01 (d, J=6.6 Hz, 2H); MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+:10]>O>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:7])=[O:8].[Na+:10]
Reactant: O=C1CCCCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])CCCCCO
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 34.3 g of 6-hexanolactone, 20 g of water, and 48 g of a 25 wt % aqueous NaOH solution. The reaction mixture was stirred for 30 min while cooling down slowly. The sodium 6-hydroxyhexanoate solution formed was cooled to 4° C. and to this solution 130 mg of N-methylmorpholine was added. Then, 34 g of isopropyl chloroformate was added in 2 min. The reaction mixture was stirred for 90 min at 10° C. Chloroformate level in the organic layer was low and mixed anhydride was formed according to analysis by FT-IR. To this reaction mixture, 6.5 g of a 70 wt % aqueous H2O2 Solution was added with stirring and the temperature was kept at 10° C. for 120 min. The pH was kept at 6-7 by addition of 3 g of a 25 wt % aqueous NaOH solution. The white solid formed was filtered and washed with 300 g of cold water. Vacuum drying of the solid resulted in 29 g of di(6-hydroxyhexanoyl)peroxide with an active content of 86% in a yield of 68%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[CH2:34]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[CH:8]=2)=[O:14])[CH2:43][CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred mixture of 6-hydroxy-2-napthoic acid (100 mg, 0.531 mmol) in anhydrous dimethylormamide (5 mL) was added triethylamine (163 μl, 1.168 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg, 0.584 mmol), and 1-benzyl-piperidine-4-amine (100 μl, 0.531 mmol). The mixture was allowed to stir at room temperature overnight, then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield N-(1-benzylpiperidin-4-yl)-6-hydroxy-2-naphthamide as a light brown solid (0.191 g, 80%).
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][CH:12]=1)=[O:6].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O=P(Cl)(Cl)Cl.C(OCC)(=O)C>[C:19]1([C:2]2[O:6][C:5]([C:7]3[CH:8]=[N:9][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][CH:12]=3)=[N:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CNC(=O)c1cnc(-c2ccccc2)nc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: c1ccc(-c2ncc(-c3ncc(-c4ccccc4)o3)cn2)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
To a solution consisting of N-(2-oxo-2-phenylethyl)-2-phenylpyrimidine-5-carboxamide (Step A, 80 mg, 0.25 mmol) in POCl3 (1.0 mL) was added pyridine (2.0 mL). The solution was heated at 70° C. for six hours and was subsequently allowed to cool to room temperature. The solution was diluted with ethyl acetate (10 mL) and poured into a chilled saturated aqueous sodium bicarbonate solution (40 mL). After stirring for 15 minutes, the mixture was extracted with ethyl acetate (3×25 mL) and the combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography (0-5% methanol in dichloromethane gradient) through a 40-g Silicycle® flash silica cartridge to afford the title compound as an off-white solid (49 mg, 65% yield); Rf 0.80 with 2% methanol in dichloromethane; 1H-NMR (300 MHz; DMSO-d6) δ 9.52 (s, 2H), 8.48 (dd, 2H), 7.99 (s, 1H), 7.94 (dd, 2H), 7.43-7.60 (m, 6H); MS (ESI+) m/z 300 (M+1); H-PGDS FPBA IC50: >20 μM.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1
Reactant: OB(O)c1cccs1
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1Oc2ccc(-c3cccs3)cc2NC1=O
Temperature: 100 °C
Yield: 33 %

Procedure:
315 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is mixed in 4 ml of DME with 0.2 g of 2-thiopheneboronic acid and 150 mg of tetrakis-triphenylphosphine-palladium (O) and 340 mg of sodium bicarbonate (dissolved in 4 ml of water). It is stirred for some time at 100° C. The product is diluted with ethyl acetate, extracted 3 times with water, and dried with magnesium sulfate. It is concentrated by evaporation. The crude product is purified by column chromatography with a hexane/ethyl acetate mixture and yields pure 33% product.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][C:11]=1[CH3:19].C(N(CC)CC)C.Cl>O1CCCC1.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:12][C:11]=1[CH3:19]
Reactant: O=C(Cl)C1CCC1
Reactant: COc1ccc(CCN)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CCNC(=O)C2CCC2)cc1C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Cyclobutanecarbonyl chloride (7 g) was added dropwise to a solution of 2-(4-methoxy-3-methylphenyl)ethylamine (11.36 g) and triethylamine (13 ml) in tetrahydrofuran (150 ml) and the resulting suspension stirred for 16 hours. The mixture was poured into water (150 ml), acidified with dilute hydrochloric acid and extracted with ethyl acetate (4×50 ml). The combined organic extracts were washed with brine then dried over magnesium sulphate and the solvent removed in vacuo. The residue was washed with petroleum ether (bp 40°-60° C.) to give crude N-[2-(4-methoxy-3-methylphenyl)ethyl]cyclobutanecarboxamide (12 g). A sample recrystallised from acetonitrile had mp 103°-104° C.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC=C(OC)C=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:26][CH:25]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)c1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COc1cccc(I)c1
Product: COc1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 78 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(3-methoxyphenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (190 mg, 0.287 mmol) and 1-iodo-3-methoxybenzene following General Procedure A. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (107 mg, 78%): 1H NMR (CDCl3, 500 MHz) δ 8.40 (m, 1H), 8.07 (d, 1H, J=8.0 Hz), 7.90 (d, 1H, J=8.0 Hz), 7.58 (t, 1H, J=7.6 Hz), 7.44 (s, 1H), 7.35-7.32 (m, 2H), 7.25-7.23 (m, 3H), 4.93 (t, 1H, J=6.0 Hz), 4.03 (s, 3H), 2.67 (t, 2H, J=7.4 Hz), 2.04-1.99 (m, 2H), 1.75-1.68 (m, 2H), 1.45-1.37 (m, 6H), 1.00 (s, 9H), 0.20 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.9, 165.7, 150.6, 143.1, 131.4, 129.7, 129.5, 128.9, 128.8, 128.6, 128.6, 126.1, 125.8, 123.5, 69.1, 52.7, 36.8, 36.4, 31.8, 29.6, 29.6, 26.2, 25.6, 14.1, −4.5, −4.6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:14]([CH:38]=[O:39])[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][Mg+].[Br-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[C:14]([CH:38]([OH:39])[CH3:46])[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(C)(C)[Si](OCc1cc2cc(OCc3ccccc3)ccc2c(-c2ccccc2)c1C=O)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of aldehyde (1.1 g) from Step 3 in THF (15 mL) at -78° C., was added MeMgBr (1.4M PhMe-THF, 2.8 mL) dropwise. After 10 min, the bath was removed and the reaction mixture quenched with a saturated solution of NH4Cl. The reaction was diluted with Et2O, washed with saturated NH4Cl solution, H2O, brine, dried over MgSO4, and the solvent evaporated to afford the title product as a foam.
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)C>C(O)(C)C>[CH:24]1([CH2:23][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)N1CCC(c2cn(CC3CC3)c3ccccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc2c(c1)c(C1CCNCC1)cn2CC1CC1
Temperature: 97.5 °C

Procedure:
A solution of 4.95 g (75 mmol) of potassium hydroxide in 25 mL of iso-propanol was added to 4.7 g (15 mmol) of 4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and the mixture was heated at 95-100° C. for 16 hours. The solvent was removed under reduced pressure and the crude mixture was extracted between water and toluene. The organic layer was dried over sodium sulfate and after filtration the solvent was removed under reduced pressure affording 3.2 g (89% of yield) of the desired product.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([C:21](=[O:28])[NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:3]12.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([C:21]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:28])[N:3]2[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)Nc3nccs3)N2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)Nc3nccs3)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a round bottom flask was added tert-butyl (4S,7S,10aS)-5-oxo-7-(thiazol-2-ylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (35 mg, 0.082 mmol) and 4 M HCl in dioxane (1 mL). The mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give (4S,7S,10aS)-4-amino-5-oxo-N-(thiazol-2-yl)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxamide hydrochloride salt (30 mg, 0.082 mmol, 100% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:17][S:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>CCOC(C)=O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[C:21]([S:18]([NH2:17])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(S(N)(=O)=O)c3)nc12

Procedure:
3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzenesulfonamide was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and (3-aminosulfonylphenyl)Boronic Acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant provided 60 mg (37%) of a pale yellow solid. MP 275-277° C., M+H=359.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[O:8]=[C:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[S:22][C:21]([CH2:23][CH2:24][C@@H:25]([NH:37]C(=O)OC(C)(C)C)[CH2:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[N:20][N:19]=3)[CH:15]=2)[NH:10]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:37][C@@H:25]([CH2:26][C:27]1[CH:28]=[N:29][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:31][CH:32]=1)[CH2:24][CH2:23][C:21]1[S:22][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:8])[CH2:17]3)=[N:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CCc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl (R)-4-(5-(2-oxoindolin-5-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (185 mg, 347 μmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting yellow oil was purified by reversed phase HPLC (Shimadsu Valiant, Phenomenex Gemini C18 5 μm 100×30 mm, 10% to 70% H2O/MeCN, 0.1% TFA) to provide 5-(5-((R)-3-amino-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)indolin-2-one trifluoroacetate as a white solid (38 mg, 88%). LCMS (API-ES) m/z: 434.0 (M+H+); 1H NMR (300 MHz, CD3OD) δ ppm 2.24 (q, J=7.4 Hz, 2 H), 3.12 (dd, J=14.3, 7.4 Hz, 1 H), 3.24 (dd, J=14.3, 6.7 Hz, 1 H), 3.33-3.40 (m, 2 H), 3.61 (s, 2 H), 3.78 (quin, J=6.7 Hz, 1 H), 7.01 (d, J=8.0 Hz, 1 H), 7.76-7.83 (m, 2 H), 8.01 (dd, J=8.0, 1.1 Hz, 1 H), 8.68 (d, J=1.1 Hz, 1 H).