Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[N:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1cncc(Nc2ccc3[nH]ccc3c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1cc(-c2cncc(Nc3ccc4[nH]ccc4c3)n2)ccn1
Yield: 31.1 %

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-1H-indol-5-amine (0.030 g, 0.123 mmol), pyridine-4-boronic acid (0.018 g, 0.147 mmol), sodium carbonate (0.067 g, 0.615 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-5-amine (0.011 g, 31%) as a yellow solid. 1H NMR (CD3OD) δ 8.70-8.68 (d, J=6.17 Hz, 2H), 8.47 (s, 1H), 8.15 (s, 1H), 8.14 (d, J=1.50 Hz, 2H) 7.96 (d, J=1.70 Hz, 1H), 7.45-7.43 (d, J=8.64 Hz, 1H), 7.37-7.35 (dd, J=10.46, 1.83 Hz, 1H), 7.29-7.28 (d, J=3.06 Hz, 1H), 6.49-6.48 (d, J=3.02 Hz, 1H); MS (API-ES/Positive); m/z: 288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C@@H:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:6].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](/[CH:33]=[CH:34]/[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43](O)=[O:44])[CH2:38]2)=[O:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C@@H:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:6][C:43]([C@@H:39]1[CH2:40][CH2:41][CH2:42][N:37]([C:35](=[O:36])/[CH:34]=[CH:33]/[CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH2:28][CH2:29]2)[CH2:38]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: COC(=O)C[C@H](N)CCc1ccc(OC)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](CCc1ccc(OC)c(OC)c1)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a mixture of 3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester (0.87 g), (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (1.19 g) and 1-hydroxybenztriazole (0.44 g) in dimethylformamide (9 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.59 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: n-hexane=(5:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester as a colorless oil (1.83 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Mg].II.[CH2:15]=[C:16]([CH2:19]Cl)[CH2:17][Cl:18].Cl>C(OCC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:19][C:16](=[CH2:15])[CH2:17][Cl:18])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=C(CCl)Cc1ccc(C(C)(C)C)cc1
Yield: 44.9 %

Procedure:
A solution of p-bromo-(t-butyl)benzene (21.3 g., 0.10 mole) in dry diethyl ether (100 ml.) was added dropwise to a mixture of magnesium turnings (2.4 g.), a single iodine crystal and dry diethyl ether (50 ml.). The mixture was allowed to react at ambient temperature for two hours. The resultant Grignard solution was transferred to a dry dropping funnel and added dropwise to a solution of methallyl dichloride (13 8 g., 0.11 mole) in dry diethyl ether (50 ml.). After complete addition of the Grignard solution, the mixture was refluxed for three hours and thereafter cooled with an ice-water bath while 15% hydrochloric acid (150 ml.) was added thereto. The mixture was extracted with diethyl ether and the organic phase dried over sodium sulfate, filtered and evaporated to yield a liquid. The liquid was distilled to provide 10 grams of 2-[(p-t-butylphenyl)methyl]-2-propenyl chloride. This product was characterized by a boiling point of 105° C. to 111° C. at a pressure of 0.25 mm Hg.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[CH2:18](O)[CH3:19]>>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1ccc(O)cc1

Procedure:
Sulfuric acid (230 g) was dropped under stirring for 10 minutes to an ethanol solution (1500 mL) of 3-(4-hydroxyphenyl)propionic acid (1150 g), and refluxed successively for 5 hours. The reaction mixture was concentrated and the obtained concentrated solution was poured into water (1,000 mL) and stirred with addition of ethyl acetate. After separation of the solution, an ethyl acetate layer was neutralized with an aqueous solution of a saturated sodium carbonate, washed with a small amount of water and then dried over anhydrous magnesium sulfate. Ethyl acetate and unreactcd ingredients were distilled off from the ethyl acetate layer to obtain concentrates (1,400 g). The concentrates were purified by distillation under a reduced pressure to obtain ethyl 3-(4-hydroxyphenyl)propionate (1,144 g). The boiling point was 160° C./4.0 hPa.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[O:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[I:18]I>O1CCCC1.ClCCl>[I:18][C:5]1[S:1][C:2]([C:14]2([OH:17])[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[N:3][CH:4]=1
Reactant: c1cscn1
Reactant: II
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC1(c2ncc(I)s2)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of thiazole (2.0 mL, 28.2 mmol) in tetrahydrofuran (140 mL) was added n-butyllithium (11.4 mL, 28.2 mmol, 2.48 M in hexane) dropwise. After 15 minutes, dihydro-2H-pyran-4(3H)-one (2.59 mL, 28.2 mmol) was added in a single portion. After 30 minutes, n-butyllithium (11.4 mL, 28.2 mmol, 2.48 M in hexane) was added dropwise. The reaction was allowed to stir for an additional 20 minutes, after which a solution of iodine (7.24 g, 28.2 mmol) in tetrahydrofuran (15 mL) was added dropwise. The reaction was then quenched by the addition of saturated aqueous Na2S2O3 and ethyl acetate (100 mL) and allowed to warm to ambient temperature. The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated to give a dark solid. Trituration of the residue with dichloromethane gave the title compound as a beije solid. MS (ESI) m/z 312 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].[C:20]([O:23][C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)(=[O:22])[CH3:21].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([N:3]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:23][C:20](=[O:22])[CH3:21])([CH3:31])[CH3:32])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CC(=O)OC(C)(C)CCCCCBr
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 11 h
Yield: 68.1 %

Procedure:
A stirred mixture of the product from Example 7, Step II (1.5 g, 0.00524 mol), the product from Step V above 1.45 g, 0.00576 mol), sodium bicarbonate (0.88 g, 0.0105 mol) and acetonitrile (45 ml) was warmed at 90°-95°, under nitrogen for 6 hours and kept at ambient temperature for 11 hours. It was then filtered. The filtrate was concentrated and the residue chromatographed on silica gel with 0.5% NH4OH-6% MeOH--CH2Cl2 to give 1.63 g of the titled compound which is a compound of Formula I'. The high resolution mass spectrum had m/z 456 (M+). Theory for C23H40N2O5S: 456.2658; measured: 456.2650.
Reaction SMILES: [N:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:10]([CH2:20][CH3:21])=[N:11][N:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][CH3:29])[CH3:25]>C(#N)C.CCOC(C)=O.[Cu]I>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]1[N:3]=[N:2][N:1]([C:4]2[CH:23]=[CH:22][C:7]([CH2:8][C:9]3[C:10]([CH2:20][CH3:21])=[N:11][N:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=34)=[CH:6][CH:5]=2)[CH:29]=1)[CH3:25]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(CC)OCC
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nn1

Procedure:
A solution of 3-(4-azido-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (20) (2 g, 6.53 mmol), propionaldehyde diethylacetal (1.294 g, 9.79 mmol) and copper(I) iodide (1.492 g, 7.83 mmol) in 33 ml of acetonitrile was stirred at r.t. for 24 h. The reaction was diluted in EtOAc and washed with sat aq Na2 CO3, water and brine. The organic layer was dried over anhydrous Na2 SO4, filtered and concentrated under HV. The crude product was purified by flash chromatography (silica gel, EtOAc/DCM 0% to 50%) to give a pale yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:23]=[C:22]([CH2:24]O)[CH:21]=[C:20]([CH2:26][CH2:27][CH3:28])[C:5]=1[O:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH3:3].P(Br)(Br)[Br:30].Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:23]=[C:22]([CH2:24][Br:30])[CH:21]=[C:20]([CH2:26][CH2:27][CH3:28])[C:5]=1[O:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OCC)c1cccc(C)c1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OCC)c1cccc(C)c1

Procedure:
To a solution of 2.03 g (5.29 mmol) of the product of Step B dissolved in 10 mL of carbon tetrachloride was added 0.50 mL (5.29 mmol) of phosphorous tribromide and the reaction mixture was magnetically stirred at room temperature for 1 hour as hydrogen bromide was evolved. The magnetic stir bar was removed, and the reaction mixture was concentrated in vacuo. The residue was redissolved and evaporated from methylene chloride three times to remove most of the hydrogen bromide. Finally, the residue was purified by rapid flash chromatography on a silica gel column eluted with 20% EtOAc-hexane. Combination and evaporation of the purified fractions in vacuo afforded 2.27 (96%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[NH:23][C:22]2=[O:37])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:42](=[O:46])[C:43]([O-:45])=[O:44])(C)(C)C.O>C1C=CC=CC=1>[OH:46][CH:42]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:22]1=[O:37])[C:43]([O:45][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:44]
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Reactant: O=C1NC(SCC#CCOC2CCCCO2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1

Procedure:
3-(Triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidin-2-one (934 mg) and t-butylglyoxylate (2.5 g) were refluxed in benzene (20 ml) with provision for the removal of water. After 1 hour the cooled solution was washed with water (6 × 5 ml), dried and evaporated. Chromatography on silica gave 1-(1-hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio)azetidine-2-one which still contained some t-butylglyoxylate. Re-chromatography on silica affored the pure material as an amorphous solid (519 mg) νmax (CHCl3) 3500, 3350, 1770, 1738 cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:20])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:12])([CH3:13])[CH3:14])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)[C@H]1[C@H](c2cnc(C(C)(C)C)nc2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)O)C2(C)C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution of ethyl trans-2,2-dimethyl-3-[2-(2-methyl-prop-2-yl)pyrimidin-5-yl]cyclopropane carboxylate (2.6 g) in ethanol (50 cm3) was mixed with a solution of sodium hydroxide (1.0 g) in water (50 cm3) and the mixture stirred at the ambient temperature for 5 hours. After removal of the bulk of the ethanol by evaporation under reduced pressure the pH of the residual mixture was adjusted to 3 with dilute hydrochloric acid. The mixture was extracted with diethyl ether (2×200 cm3), and the combined extracts washed with water and dried over anhydrous magnesium sulphate. Evaporation of the ether under reduced pressure yielded trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylic acid (2.1 g), melting point 168°-9° C.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[N:23]O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].O=P(Cl)(Cl)Cl.O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:19][CH2:18][C:17]([C:22]#[N:23])([CH2:20][CH2:21]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2nc(C34CCC(C=NO)(CC3)CC4)[nH]c2n(CCC)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2nc(C34CCC(C#N)(CC3)CC4)[nH]c2n(CCC)c1=O
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a stirred suspension of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde oxime (400 mg, 1.03 mmol) in CHCl3 (20 ml), cooled with the aid of an ice bath, was added POCl3 (neat, 1.5 eq, 237 mg) and the resulting mixture was allowed to reach ambient temperature overnight (17 h). The reaction mixture was poured into water, the phases were separated and the organic phase was washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to give a white, brittle foam (360 mg, 95%). MS: 370 (MH+).
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:20][CH2:19]1)[C:16]([OH:18])=[S:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:21]([N:23](CC)CC)C.CC(OC(=S)C1OC1)CCCCCCCCCCCC.[CH2:48]([NH+:50](CC)CC)[CH3:49].ClC(OCC)=O.C(N)C>O1CCCC1>[CH3:21][NH:23][C:16](=[O:18])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])[O:20][CH2:19]1.[CH2:48]([NH:50][C:16](=[S:17])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])[O:20][CH2:19]1)[CH3:49]
Reactant: CCCCCCCCCCCCC(C)C1(C(O)=S)CO1
Reactant: CCN(CC)CC
Reactant: CC[NH+](CC)CC
Agent: CCCCCCCCCCCCC(C)OC(=S)C1CO1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCC(C)C1(C(=O)NC)CO1
Product: CCCCCCCCCCCCC(C)C1(C(=S)NCC)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.3 g (0.001 mole) of 2-tetradecylthioglycidic acid in 10 ml of anhydrous tetrahydrofuran (THF) at 0° C. (ice water bath) is added 1.01 g (0.001 mole) of triethylamine in a small amount of THF. The mixture is stirred at 0° C. for about 30 minutes. To the thus-formed triethylammonium 2-tetradecylthioglycidate is added 0.108 g (0.001 mole) of ethyl chloroformate in a small amount of THF and the mixture is stirred at about 0° C. (ice water bath) for about 3 hours to prepare the corresponding mixed anhydride (a ppt. of Et3NHCl is observed). A stoichiometric excess of ethylamine in THF is then added and the mixture stirred at room temperature for 16 hours. The THF solvent is concentrated to approximately 1/4 volume, water is added and the mixture extracted with ether. After drying the ether extract (Na2SO4), the solvent is removed in vacuo giving the desired product, N-ethyl-2-tetradecylthioglycidamide, in good yield.
Reaction SMILES: [C:1]([CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13].O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1([Cl:13])[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)#[N:2]
Reactant: N#CC1CC2C3CC4C2C4C13
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CC1(Cl)CC2C3CC4C2C4C31
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 8-cyanotetracyclo[4,3,0,02,4,03,7 ]nonane (87 g.) in carbon tetrachloride (600 ml.) was added phosphorus pentachloride (168 g.). The mixture was heated under reflux for 60 hours, cooled and poured into a mixture of crushed ice and water (1 l.). The mixture was stirred for 30 minutes and the organic layer separated. This was washed with a 10% w/v aqueous solution of sodium carbonate (200 ml.), saturated brine (100 ml.) and then dried over anhydrous potassium carbonate. The filtrate was then evaporated in vacuo to remove solvent and then distilled in vacuo to give 8-cyano-8-chlorotetracyclo[4,3,0,02,4,03,7 ]nonane, b.p. 136°-140° C./20 mm., in 83% yield.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1)C.[CH2:10]([Li])[CH2:11]CC.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]=[O:26])=[N:21][NH:22]2)=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]([OH:26])[CH2:9][C:5]3[CH:4]=[CH:3][C:8]([CH2:10][CH3:11])=[CH:7][N:6]=3)=[N:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: CCc1ccnc(C)c1
Reactant: O=Cc1n[nH]c2cc(Cl)ccc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(CC(O)c2n[nH]c3cc(Cl)ccc23)nc1
Reaction time: 0.17 h
Yield: 24.9 %

Procedure:
To a stirred solution of 4-ethyl-2-methylpyridine (0.458 9, 3.79 mmol) in THF (4mL) at −50 degrees Celsius, add butyl lithium (1.5 mL, 2.5 M, 3.79 mmol) slowly and stir for 10 minutes. To the reaction, slowly add a solution of 6-Chloro-1H-indazole-3-carbaldehyde (0.5 g, 1.89 mmol) in THF (4 mL). After stirring for 10 minutes, the reaction was quenched with 1 N citric acid (10 mL). The mixture was diluted with EtOAc (50 mL), water (20 mL), and saturated NaCl (10 mL). The layers were separated, and the aqueous was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl (20 mL). After drying the organic layer over Na2SO4, the solids were removed by filtration and the liquid was concentrated to an oil by rotary evaporation. Chromatography (40 g silica gel, 60–100% EtOAc/hex) yields the desired product (142 mg, 32%) and recovered 6-Chloro-1H-indazole-3-carbaldehyde (348 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].S(Cl)([Cl:23])(=O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([Cl:23])[C:6](=[O:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CCCOCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)CCCOCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of 13.9 g of crude 6-Benzyloxy-3-oxo-hexanoic acid ethyl ester in 50 ml dichloromethane were added dropwise 4.3 ml sulfuryl chloride. The reaction mixture was stirred at 0° C. and then at room temperature for thirty minutes. The reaction mixture was poured on ice and extracted three times with portions of 150 ml dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and then the solvent was evaporated in vacuo to obtain 14.9 g of crude 6-Benzyloxy-2-chloro-3-oxo-hexanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]12[S:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][CH:11]([C:17]#N)[CH2:10]2.C1C[O:22]CC1>>[C:1]1([C:17]([CH:11]2[CH2:12][CH:13]3[S:16][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1CC2CCC(C1)S2
Reactant: C1CCOC1
Reactant: Br[Mg]c1ccccc1
Product: O=C(c1ccccc1)C1CC2CCC(C1)S2
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A 3M etheral solution of phenyl magnesium bromide (6.72 ml, 20.16 mmol) was added at 0° C. to a solution of the above nitrile (1.03 g, 6.72 mmol) in dry THF (10 ml). After 30 minutes, the ice bath was removed and the reaction continued at room temperature for 16 hours. The reaction was carefully quenched by addition of a saturated aqueous NH4Cl solution. After addition of ether, organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residual oil was chromatographied on silica gel (hexane/AcOEt 94/6) to give the phenyl(8-thiabicyclo[3.2.1]oct-3-yl)methanone 22 as a colorless oil (586 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2(C(=O)O)CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(O)C1(c2ccc(CBr)cc2)CCCC1
Yield: 133.4 %

Procedure:
To a solution of 1-(4-methylphenyl)cyclopentane carboxylic acid tbutyl ester (2.00 g, 7.68 mmol) in CCL4 (80 mL) was added N-bromosuccinimide (1.37 g, 7.68 mmol) and benzoyl peroxide (0.050 g). This mixture was brought to reflux by heating, and maintained at reflux for 2 hours using a sun lamp (250 W). Additional N-bromosuccinimide (0.34 g, 1.9 mmol) was added, and after 20 minutes the solution was concentrated to 40 mL. The white precipitate was removed by filtration. The filtrate was concentrated to give 1-(4-bromomethylphenyl)cyclopentane carboxylic acid tbutyl ester (2.9 g, 100%) as a yellow oil which was used without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15][S:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=3)(=[O:27])=[O:26])[CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1cccc(COCc2ccc(Cl)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(Cl)cc2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.092g) as a light yellow gum (0.039 g). MS (ESI−): 472.8 ([M−H]−).