Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:9]([C:11]([CH2:16][CH3:17])([CH2:14]O)[CH2:12][OH:13])[CH3:10].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([C:11]1([CH2:16][CH3:17])[CH2:12][O:13][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:14]1)[CH3:10]
Reactant: CCC(CC)(CO)CO
Reactant: O=C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(CC)COC2(CCC(=O)CC2)OC1
Temperature: 25 °C
Yield: 16365.5 %

Procedure:
30 g (0.27 mmol) of cyclohexane-1,4-dione, 35.4 g (0.27 mol) of 2,2-diethylpropane-1,3-diol and 360 mg of para-toluenesulfonic acid were heated in 200 ml of toluene on a water separator. After the mixture had been cooled to room temperature and the water of reaction separated off, the organic phase was washed with a semisaturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After the solvent had been evaporated, 65 g of crude product were obtained which was purified by flash chromatography (ethyl acetate/petroleum ether=1:4). The first fraction contained the 1,4-diketal which was formed as secondary product (10 g). The main fraction contained 28.5 g (47%) of a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[CH2:15]([O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][C:20]=1[CH:32]=O)[CH3:16]>ClCCl.C(N(CC)CC)C>[CH2:15]([O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][C:20]=1[CH:32]=[N:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[CH3:16]
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)cc1C=O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN=Cc1cc(Oc2ccccc2)ccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.4 %

Procedure:
To a dried flask with glycine ethyl ester hydrochloride salt (62 mg) was added anhydrous dichloromethane (2 mL), followed by triethylamine (124 μL). Then magnesium sulfate (pre-dried on high vacuum by heat gun, 100 mg) was added, followed by addition of a dichloromethane (1 mL) solution of 2-formyl-4-phenoxy-benzoic acid ethyl ester (120 mg). The flask of 2-formyl-4-phenoxy-benzoic acid ethyl ester was further rinsed with 0.5 mL of dichloromethane. The resulting mixture was stirred at room temperature under nitrogen for 15 h. The mixture was filtered and rinsed with dichloromethane. After removal of solvent, the reaction was diluted with ether (15 mL) and washed with brine twice and dried. Filtration and removal of solvent gave the title compound 160 mg as an oil with good purity. 1H NMR (200 MHz, CDCl3) δ 9.02 (d, J=1.2, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.63 (d, J=2.4, 1H), 7.40-7.32 (m, 2H), 7.20-7.11 (m, 1H), 7.06-6.97 (m, 3H), 4.41 (s, 2H), 4.35 (q, J=7.0 Hz, 2H), 4.21 (q, J=7.4 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15]C(OC(C)(C)C)=O)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 93.3 %

Procedure:
To a solution of 2-(3-tert-Butoxycarbonylamino-phenoxy)-2-methyl-propionic acid ethyl ester (0.8 g, 2.4 mmol) in DCM (10 ml) at 0° C. was added TFA (10 ml) and stirred at 0° C. for 100 min. The solvent was removed under reduced pressure; residue was dissolved in DCM and treated with 2.5M solution of NaOH. The organic layer was separated and dried over Na2SO4, concentrated to yield 2-(3-amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.5 g, mmol, 98%). 1H NMR (400 MHz, CDCl3): 1.25 (t, J=7.2 Hz, 3H), 1.56 (s, 6H), 3.62 (brs, 2H), 4.23 (q, J=7.2 Hz, 2H), 6.21-6.22 (m, 2H), 6.32 (d, J=7.2 Hz, 1H), 6.99 (t, J=8.4 Hz, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([C:14]2[Se:15][C:16]([Br:19])=[CH:17][CH:18]=2)[N:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:9]=1)=[O:7])C.O.Cl>CO>[Br:19][C:16]1[Se:15][C:14]([C:11]2[N:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:9]=[C:8]([C:6]([OH:7])=[O:5])[C:12]=2[CH3:13])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)[se]2)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)[se]1
Yield: 95.4 %

Procedure:
A solution of potassium hydroxide (442 mg, 7.88 mmol) in methanol (7 mL) was added to a magnetically stirred solution of 5-(5-Bromo-selenophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, 3.94 mmol) in methanol (15 mL). The mixture was heated under reflux for 3 h. The reaction mixture was cooled, poured into water, and acidified with 10% hydrochloric acid. The precipitate was filtered out, washed with water, and dried under vacuum to yield the corresponding acid (1.8 g, 95%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[NH2:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:9][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:5][C:6]([CH3:8])=[CH2:7])[CH2:3][CH2:2][NH:16][C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)CC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Yield: 94.1 %

Procedure:
A mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (5.16g, 23mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (6.9 g, 1.5 equiv), KI (4.0 g, 1.05 equiv), K2CO3 (4.77 g, 1.5 equiv) were mixed with acetonitrile (100 mL) and heated to reflux for 20 h. The mixture was filtered through a pad of Celite, concentrated and purified by chromatography on a 120 g silica gel column, eluted with a 0-10% methanol in CH2Cl2 gradient, to afford (3S)-tert-butyl 3-(3-hydroxy-5-methyl-3-phenylhex-5-enylamino)piperidine-1-carboxylate (8.41 g, 94% yield). LC-MS Method 1 tR=1.56 min., m/z 389 (M+1).
Reaction SMILES: O=S1[O:6][CH:5]([C@@H:7]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]O1.[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][NH:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][N:34]1[CH2:4][C@@H:5]([OH:6])[C@@H:7]([N:15]1[C:16](=[O:25])[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:23]1=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)C1COS(=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Yield: 65 %

Procedure:
A suspension of 0.35 g of the above 83:17 mixture of the two 1:1 mixtures of the (2R,4S) and (2S,4S) and respectively (2R,4R) and (2S,4R) isomers of 2-[(S)-1-[2-oxo-1,3,2-dioxathiolan-4-yl]-2-phenylethyl]-2,3-dihydro-1H-isoindol-1,3-dione, 0.24 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 0.21 g of sodium carbonate in 3.5 ml of isobutyl methyl ketone is heated to reflux for 24 hours, thereafter cooled and filtered. The filtrate is purified on silica gel with hexane/ethyl acetate (4:1). After evaporation and drying there is obtained 0.34 g (65%) of pure N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, IR (KBr): 3388 m (OH), 1771 m and 1708 s (C=O of imide).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C1(C)C=CC=CC=1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:12][CH2:11][CH2:10][O:5]1
Reactant: OCCO
Reactant: O=Cc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccccc1C1OCCO1

Procedure:
A 12 L 3-necked flask fitted with an overhead stirrer was charged with 2-bromobenzaldehyde (800 g, 4.324 moles), ethylene glycol (402.6 g, 6.485 moles), p-toluenesulfonic acid. H2O (3.95 g, 0.021 moles) and toluene (3.785 kg, 41.074 moles).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Br:16][C:17]1[C:18](=O)[NH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(=O)(O)[O-].[Na+]>O>[Br:16][C:17]1[C:18]([Cl:3])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: FC(F)(F)c1cnc(Cl)c(Br)c1
Temperature: 120 °C
Yield: 77.2 %

Procedure:
To phosphorous oxychloride (2.02 mL, 21.6 mmol) was added quinoline (1.34 mL, 11.2 mmol) followed by 3-bromo-5-trifluoromethyl-2(1H)-pyridone (5.0 g, 20.07 mmol). The mixture was heated at 120° C. for 3 hrs, then cooled to 100° C., whn water (10 mL) was carefully added. After cooling to room temperature, saturated sodium bicarbonate was added (100 mL) and the mixture extracted with ethyl acetate (2×100 mL). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as a liquid (4.05 g, 15.5 mmol, 75% yield).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>C(O)C>[CH2:25]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 70 %

Procedure:
4.17 g of sodium hydroxide was dissolved in 100 ml of ethyl alcohol. Then, 5.03 g of para-hydroxy benzoic acid and 12.2 ml of 1-bromododecane were added to the solution and refluxed for 15 hours. 50 ml of 10% aqueous sodium hydroxide solution was added and refluxed for another 2 hours. After cooling, concentrated HCl was dropped into the solution until it was acidic. Filtration and recrystallization from ethyl alcohol gave 7.66 g of pure product (yield 70%).
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1.[C:13](#[N:16])[CH:14]=[CH2:15].C(NCC)C.[OH-].[Na+]>>[F:2][C:3]([F:11])([F:12])[C:4]1[CH:5]=[C:6]([NH:10][CH:14]([CH3:15])[C:13]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C=CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Product: CC(C#N)Nc1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 2.5 h

Procedure:
A mixture of 70 parts of 3-(trifluoromethyl)benzeneamine hydrochloride, 26.5 parts of 2-propenenitrile and 36.5 parts of N-ethylethanamine was stirred for 2.5 hours at 180° C. After cooling to 0° C., the whole was treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 34.5 parts (45%) of 3-[[(3-(trifluoromethyl)phenyl]amino]propanenitrile as a residue (int. 105).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[CH3:21][Si:22]([C:25]#[C:26][Sn](CCCC)(CCCC)CCCC)([CH3:24])[CH3:23]>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Product: C[Si](C)(C)C#Cc1cc(-c2ccc(O)c(F)c2)nc2ccc(O)cc12
Yield: 94 %

Procedure:
This compound was prepared from 6b and (trimethylsilylethynyl)tributyltin according to method J. Red powder; Yield: 94%; 1H-NMR (300 MHz, acetone-d6) δ 0.43 (s, 9H), 7.21 (dd, J=8.8, 8.8 Hz, 1H), 7.51 (dd, J=9.1, 2.7 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H), 8.05 (m, 1H), 8.07 (d, J=9.0 Hz, 1H), 8.13 (s, 1H), 8.18 (dd, J=12.8, 2.1 Hz, 1H), 9.05 (s, 1H), 9.26 (s, 1H); MS (ESI) m/z 350 ([M−H]−), 352 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1.[CH:19]([Si:22](OS(C(F)(F)F)(=O)=O)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20].CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1N1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Dissolve 1-(2-methoxy-4-nitro-phenyl)-piperidin-4-ol (1.19 g, 4.72 mmol) in DMF (25 mL), followed by addition of triisopropylsilyl-trifluoromethanesulfonate (1.50 mL, 5.56 mmol) and Et3N (0.80 mL, 5.87 mmol). Stir the solution at room temperature for 2 h, then add water (50 mL) and extract with EtOAc (2×50 mL). Combine the organic solutions and wash with water (2×30 mL) and brine (30 mL), then dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 20% EtOAc/hexanes, to give the title compound as a yellow solid (1.55 g, 80%). MS (ES+) 409.3 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.84 (dd, 1H, J=8.8, 2.6 Hz), 7.68 (d, 1H, J=2.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 4.07-4.01 (m, 1H), 3.93 (s, 3H), 3.45-3.38 (m, 2H), 3.13-3.06 (m, 2H), 1.99-1.91 (m, 2H), 1.81-1.73 (m, 2H), 1.07-1.06 (m, 21H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[ClH:32].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[C:40][CH2:41][Cl:42])[CH:34]=1.[I-].[K+].O>CN(C)C=O>[ClH:42].[ClH:32].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:41][C:40]#[C:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: ClCC#Cc1cccnc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(CC#Cc3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.38 g) potassium carbonate (0.42 g), 3-(3-pyridyl)-2-propynyl chloride hydrochloride (1.9 ml) and small amount of potassium iodide in N,N-dimethylformamide (10 ml) was stirred for 2 hours at 40° C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3-pyridyl)-2-propynyl]piperazine dihydrochloride (0.26 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 35 °C
Yield: 58.7 %

Procedure:
To a mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (300 mg, 0.88 mmol) and 4 A MS (300 mg) in dry DMF (10 mL) were added 4-chlorophenylboronic acid (413 mg, 2.64 mmol), Cu(OAc)2 (160 mg, 0.88 mmol) and pyridine (1 mL). The reaction mixture was heated to 35° C. overnight under an O2 atmosphere, and filtered through a Celite pad. The filtrate was diluted with water (50 mL), extracted with EtOAc (30 mL×3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride) to give tert-butyl 3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (12) (234 mg, 59.1%). LC-MS (ESI): m/z (M/M+2) 453/455.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[OH:12][C:13]1([CH3:20])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CCO>[CH3:20][C:13]1([OH:12])[CH2:19][CH2:18][CH2:17][N:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14]1
Reactant: CC1(O)CCCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(O)CC1
Temperature: 130 °C
Yield: 67.2 %

Procedure:
To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (390 mg, 2.4 mmol) and 4-hydroxy-4-methylazepane hydrochloride (0.48 g, 2.9 mmol) in EtOH (9.5 mL) was added DIPEA (1.9 ml, 10.9 mmol). The reaction mixture was heated at 130° C. in a microwave for 1 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (0-5% MeOH/DCM) to give 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a colorless oil (410 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.77 (s, 3H), 3.56-3.47 (m, 1H), 3.28-3.20 (m, 2H), 3.08-3.04 (m, 1H), 2.17-2.03 (m, 1H), 1.95-1.81 (m, 4H), 1.78-1.67 (m, 1H), 1.56 (br s, 1H), 1.25 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.[OH:23][C:24]1[CH:25]=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: CCOC(=O)c1cc(O)ccc1-c1ccccc1
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)OCC)c1
Yield: 85.9 %

Procedure:
The above-prepared 6.20 g (19.1 mM) of 10-undecenyl p-toluenesulfonate, 4.62 g (19.1 mM) of ethyl p-hydroxybiphenylcarboxylate and 6 ml of dimethylformamide (DMF) were mixed and sufficiently stirred. To the mixture, 0.77 g (19.3 mM) of 60% -sodium hydride was added, followed by heat-refluxing for 7 hours. After the reaction, the reaction mixture was subjected to distilling-off of DMF and addition of water, followed by extraction with ether to obtain an extract. The extract was dried with anhydrous sodium sulfate, followed by distilling-off of ether and purification by column chromatography (eluent: methylene chloride) to obtain 6.46 g (16.4 mM) of ethyl p-(10-undecenyl)oxybiphenylcarboxylate (Yield: 86%).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O-:16])=[O:15])(OC(C)(C)C)=O.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([O:16][CH2:17][CH3:19])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCC[C@H]1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-2-(Boc-amino)cyclopentanecarboxylate (CAS: 1140972-29-7, TCI) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred at rt for 1 hour and then the solvent was removed under vacuum to give the crude product 50-B, which was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:42])([F:41])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:17][CH2:18][CH2:19][N:20]([CH2:27][C:28](O)=[O:29])[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[O:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:70][CH2:71][CH:72]1[CH2:76][O:75][CH:74]([O:77][CH2:78][CH2:79][CH2:80][C:81]([N:83]([CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][CH3:111])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])=[O:82])[O:73]1>ClCCl>[F:8][C:9]([F:41])([F:42])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])[CH2:17][CH2:18][CH2:19][N:20]([C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH2:27][C:28]([NH:70][CH2:71][CH:72]1[CH2:76][O:75][CH:74]([O:77][CH2:78][CH2:79][CH2:80][C:81]([N:83]([CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][CH3:111])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH3:97])=[O:82])[O:73]1)=[O:29])=[O:11]
Reactant: O=C(O)CN(CCCN(CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F)C(=O)C(F)(F)F
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CN)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CNC(=O)CN(CCCN(CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.9 ml of triethylamine (13.8 mmol), 2 g of [(3-{bis[3-(2,2,2-trifluoroacetylamino)propyl]amino}-propyl)trifluoroacetylamino]acetic acid (trifluoroacetate salt, 3.04 mmol) and 1.8 g of BOP (4.14 mmol) were successively added to 1.65 g of 4-(4-aminomethyl-[1,3]dioxolan-2-yloxy)-N,N-ditetradecylbutyramide (2.76 mmol) dissolved in 30 ml of dichloromethane. The solution was stirred for 1 hour at room temperature.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.Br[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1>[Cl-].[Zn+2].[Cl-]>[C:1]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)#[C:2][CH2:3][CH2:4][CH3:5]
Reactant: C#CCCC
Reactant: Brc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: CCCC#Cc1cccs1

Procedure:
Quantities: pent-1-yne (6.80 g, 0.10 mol), n-butyllithium (10.0 ml, 10.0M in hexane, 0.044 mol), zinc chloride (13.60 g, 0.10 mol), 2-bromothiophene (16.00 g, 0.098 mol), tetrakis (triphenylphosphine)palladium(O) (3.40 g 2.94 mol).