Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:35]([O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47]Br)=[CH:41][CH:40]=1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:24])[CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:41][CH:40]=1)[CH3:36]
Reactant: CCOC(=O)c1ccc(OCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Yield: 17.1 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (prepared in Example 1A, Step C) (250 mg, 0.719 mmol) was alkylated with NaHMDS (1M in THF, 0.86 mL, 0.86 mmol) and 4-(2-bromo-ethoxy)-benzoic acid ethyl ester (216 mg, 0.791 mmol). The reaction temperature was maintained at 50° C. over 24 h. Purification by radial chromatography (hexanes to 4:1 hexanes:EtOAc) provided 4-(2-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-ethoxy)-benzoic acid ethyl ester (66.4 mg). 1H NMR (CDCl3) (selected peaks) δ7.96 (m, 2H), 7.29-7.13 (m, 5H), 6.84 (m, 2H), 4.33 (q, 2H), 4.12 (m, 2H), 3.90 (m, 2H), 3.68 (m, 1H), 3.34 (m, 1H), 2.73 (m, 2H), 2.32 (m, 2H), 1.36 (t, 3H), 0.85 (s, 9H), −0.03 (s, 3H), −0.15 (d, 3H).
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][CH:21]([NH2:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34].C([O:43]C1C=CC=CC=1C(C=O)=O)C1C=CC=CC=1>CS(C)=O>[CH3:20][CH:21]([N:35]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:43])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34]
Reactant: COc1ccc(CC(C)N)c(OC)c1OC
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)c(OC)c1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
10.3 g of 2-benzyloxyphenylglyoxal hydrate are dissolved in 5 ml of dimethylsulfoxide. 7.6 g of α-methyl-2,3,4-trimethoxyphenethylamine are dissolved in 6 ml of dimethylsulfoxide, and the solution is added to the 2-benzyloxyphenylglyoxal solution under ice-cooling. The mixture is stirred at 20° C. for 2 hours, whereby a solution of α-(α-methyl-2,3,4-trimethoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: C(OC([N:8]([CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH:18]=[C:19]([C:20]([OH:22])=O)[C:13]=2[N:12]=1)[CH3:9])=O)(C)(C)C.[C:36](O)([C:38](F)(F)F)=O.[CH2:43]([Cl:45])Cl>>[Cl:45][C:43]1[C:36]([CH3:38])=[C:13]([NH:12][C:20]([C:19]2[C:13]3[N:12]=[C:11]([CH2:10][NH:8][CH3:9])[NH:15][C:14]=3[CH:16]=[C:17]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:34])([F:33])[F:35])=[O:25])[CH:18]=2)=[O:22])[CH:14]=[CH:16][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CN(Cc1nc2c(C(=O)O)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1)C(=O)OC(C)(C)C
Product: CNCc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Reaction time: 0.5 h

Procedure:
2-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbon yl}amino)-1H-benzimidazole-4-carboxamide (9 mg) was obtained according to the procedure as described in Step 7 of Example 11, using 2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid instead of 2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid. This was dissolved in methylene chloride (1 mL). To the residue was added TFA (0.5 mL) under ice-cooling, and it was stirred for 0.5 hour. To the reaction mixture were added ice and then saturated aqueous sodium bicarbonate, and it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-2-[(methylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (5 mg) as slightly yellow powder. This was dissolved in MeOH (0.5 mL), and treated with 1M hydrochloric acid (2 Eq), and concentrated to obtain the titled compound (5 mg) as slightly yellow powder.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:21]([C:20]4[CH:24]=[CH:25][C:17]([C:14](=[O:16])[CH3:15])=[CH:18][CH:19]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Reactant: CC(=O)c1ccc(C(=O)Cl)cc1
Product: CC(=O)c1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 4-acetylbenzoyl chloride. 1H NMR (400 MHz, CDCl3) δ 0.42-0.52 (m, 4H), 1.62-1.68 (m, 1H), 1.86-1.96 (m, 2H), 2.04-2.12 (m, 2H), 2.33-2.39 (m, 2H), 2.67 (s, 3H), 2.85-2.93 (m, 1H), 3.09-3.17 (m, 2H), 8.07 (d, 2H), 8.21 (d, 2H). HPLC: Rt=8.42 min.
Reaction SMILES: [S:1]1[C:5]([SH:6])=[N:4][N:3]=[C:2]1[SH:7].[H-].[Na+].I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl[C:17]1[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][N:22]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:11]([S:6][C:5]1[S:1][C:2]([S:7][C:17]2[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][N:22]=2)=[N:3][N:4]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1nccnc1Cl
Reactant: Sc1nnc(S)s1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to Example 4 by using 1,3,4-thiadiazole-2,5-dithiol (300 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), 1-iodopentane (0.30 ml, 2.30 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (8 ml, 1/1) by stirring at room temperature under nitrogen atmosphere overnight.
Reaction SMILES: I[C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25]S(C)(=O)=O)=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Cl.CN([CH:34]([SH:36])C)C.[OH-].[Na+].[CH3:39][N:40]([CH3:43])[CH:41]=O>>[CH3:39][N:40]([CH3:43])[CH2:41][CH2:34][S:36][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CN(C)C=O
Reactant: CC(S)N(C)C
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCSc1c2ccccc2c(-c2ccc(O)cc2)c2c1sc1ccccc12
Temperature: 155 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a suspension of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (1.00 g, 1.89 mmol), dimethylaminoethanethiol hydrochloride (0.614 g, 4.34 mmol, 2.3 eq) and copper I oxide (0.316 g, 8.69 mmol, 1.17 eq) in anhydrous N,N-dimethylformamide (24 mL) was added finely ground sodium hydroxide (0.348 g, 8.69 mmol, 4.6 eq) at room temperature in a pressure vessel. The vessel was flushed with argon, sealed and heated with stirring at 155° C. (oil bath) for 6 hours and at ambient temperature for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with ether. The solid which remained as a suspension in the aqueous phase was filtered. The filtrate was extracted once more with ether. The extracts were combined and silica gel was added. The solvents were removed and the adsorbate was flash chromatographed (gradient 94/6-95/5) methylene chloride:isopropanol to give the title compound as a solid (0.707 g, 87%): NMR (DMSO-d6); δ 9.83 (s, 1H, OH), 8.65 (d, J=8 Hz, 1H), 7.98 (d, J=8 Hz, 1H), 7.71 (ddd, J=8, 7, 1 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.43 (ddd, J=8, 7, 1 Hz, 1H), 7.21-7.05 (m, 3H), 7.08-7.04 (m, 2H), 6.73 (d, J=8 Hz, 1H), 3.35-3.27 (m,), 3.10 (t, J=6 Hz, 2H), 2.21-2.08 (broad singlet, 6H); MS(EI): [M+] 429.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35](Cl)(=[O:37])=[O:36])=[CH:30][CH:29]=1>>[CH3:25][C:22]1([CH3:26])[CH2:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[NH:1][S:35]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:33][CH:32]=4)(=[O:36])=[O:37])[N:9]=3)[C:24]=2[O:23]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: O=S(=O)(Cl)Nc1ccc(F)cc1
Product: CC1(C)Cc2cccc(Nc3ccc4c(NS(=O)(=O)Nc5ccc(F)cc5)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=479.0 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and 4-fluoro-phenylsulfamoyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]1([CH3:75])[CH:57]=[CH:56][C:55]([S:58]([O:61][CH2:62][CH2:63]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH:14]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]2)[CH2:24]1)=[O:22])[C:10]1[CH:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:63][CH2:62][O:61][S:58]([C:55]3[CH:56]=[CH:57][C:52]([CH3:75])=[CH:53][CH:54]=3)(=[O:60])=[O:59])=[CH:7][CH:6]=2)[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
82.0 mg (0.13 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 7a) were dissolved in 5.1 ml N,N-dimethylformamide. 129 mg (0.40 mmol) cesium carbonate and 73.2 mg (0.20 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 20 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 64 mg (59%) tert-butyl 4-{3-[(3R)-3-{[3-methoxy-1-{5-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:21])[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C1C=CC=CC=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:22]1([CH:10]2[CH:11]3[CH2:20][CH2:19][C:18](=[O:21])[C:13]4[C:12]3=[C:17]([CH:16]=[CH:15][CH:14]=4)[NH:9]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CCC2c3c1cccc3N(C(=O)c1ccccc1)C2c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCC2c3c(cccc31)NC2c1ccccc1
Yield: 111.1 %

Procedure:
A portion (4.25 g) of the compound obtained in Example 1 was dissolved in ethanol (40 ml). To the solution was added conc. hydrochloric acid (40 ml) and the resulting mixture was heated to reflux for 2 hours. After allowing to cool, the mixture was diluted with water, adjusted to pH 9 with potassium carbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent to yield 3.33 g (92%) of the titled compound as crystals.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18](Cl)=[CH:17][C:16]([CH:20]([CH3:22])[CH3:21])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:25]>CO>[C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18]([NH2:25])=[CH:17][C:16]([CH:20]([CH3:22])[CH3:21])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nn2c(Cl)cc(C(C)C)nc2c1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C(C)C)nc2c1S(=O)(=O)c1ccccc1

Procedure:
In an analogous manner to that described in Example 4, from 3-benzenesulphonyl-7-chloro-5-isopropyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-benzenesulphonyl-5-isopropyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 210-211°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12](Cl)(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC(C)=O.[NH3:23]>O>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([NH2:23])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(N)(=O)=O

Procedure:
4-Chloro-3,5-dinitro-o-toluenesulfonyl chloride (10 grams, 0.0318 mole) is dissolved in 150 ml. of acetone and chilled to -15° C. Ammonia (1.08 grams, 0.064 mole) is condensed and then vaporized into the acetone solution. When the addition is complete, the reaction mixture is poured into an equal volume of water and the precipitated solid collected. The crude yield of white solid is 6.8 grams with melting point 205° C. to 215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=2.[H+].[B-:18]([F:22])([F:21])([F:20])[F:19].[N:23]([O-])=O.[Na+]>O1CCCC1.O>[F:19][B-:18]([F:22])([F:21])[F:20].[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=[CH:3][C:2]=1[N+:1]#[N:23]
Reactant: COc1cc2ncc(N)c(Cl)c2cc1OC
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2ncc([N+]#N)c(Cl)c2cc1OC
Yield: 89 %

Procedure:
3-amino-4-chloro-6,7-dimethoxyquinoline (3.3 g) was dissolved in tetrahydrofuran (70 ml) with stirring and then cooled in an ice/water bath to below 10° C. 48% aqueous fluoboric acid (7.3 ml) was then added and the mixture stirred for 5 minutes. A solution of sodium nitrite (1.05 g) in water (2 ml) was added keeping the temperature below 10° C. The reaction mixture was then stirred for 30 minutes with cooling. The resulting yellow solid was filtered off, washed with fresh tetrahydrofuran. Carefully vac dried. To give 4-chloro-6,7-dimethoxyquinoline-3-diazonium tetrafluoroborate (4.15 g, 89%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)C.[CH:12]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[O:20][CH2:21][O:22][C:14]=2[CH:13]=1.O>O1CCCC1.CS(C)=O>[CH2:21]1[O:22][C:14]2[CH:13]=[CH:12][C:17]([CH:18]3[CH2:1][O:19]3)=[CH:16][C:15]=2[O:20]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: c1cc2c(cc1C1CO1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To an ice-cooled suspension of potassium tert-butoxide (0.82 g) in tetrahydrofuran (6.6 ml) was added trimethylsulfonium iodide (98% purity; 1.5 g) in dimethyl sulfoxide (6.6 ml). After the addition was complete, piperonal (1.0 g) in tetrahydrofuran (3.3 ml) was added dropwise to the mixture while the internal temperature was maintained below 5° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted once with ethyl acetate. The extract was washed twice with water and once with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 3,4-methylenedioxyphenyloxirane (1.0 g), which was used for next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[C:9]([O-:12])(O)=[O:10].[Na+].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C2C(=O)N(C([O-])=O)C=CC=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C1COCC1>[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:12][C:9]([NH:1][C@@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:10])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 85.3 %

Procedure:
To a stirred mixture of L-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine 1-carboxylate (0.538 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.33 g, 88%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 332 [M−Na]+, 327 [M−NH4]+; (ESI) m/z: 308 [M−H]−. 1H NMR (DMSO-d6) δ 1.08 (d, J=6.3 Hz, 3H), 1.29-1.39 (m, 2H), 1.53-1.63 (m, 4H), 2.57 (t, J=7.7 Hz, 2H), 3.89-3.99 (m, 3H), 4.01-4.11 (m, 1H), 6.67 (d, J=9.0 Hz, 1H), 7.13-7.30 (m, 5H), 12.33 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:19])(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[Br:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][CH2:9][CH:8]([NH2:7])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of compound 3i (2.2 g, 4.3 mmol) in DCM (20 mL) was added slowly TFA (2 mL) at 0° C. The mixture was stirred at 0° C. for 2 hr. LCMS analysis indicated the total consumption of compound 3i. The solvent was removed in vacuum to give 3k as a white solid (1.68 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]2[CH2:17][CH2:18][C:19](O)=[O:20].[C:22](OC(=O)C)(=[O:24])C.O>C(O)=O>[CH:22]([N:9]1[C:10]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]3[C:19](=[O:20])[CH2:18][CH2:17][CH:7]([C:6]=23)[CH:8]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2c1NC(c1ccccc1)C2CCC(=O)O
Solvent: O
Solvent: O=CO
Product: Cc1ccc2c3c1N(C=O)C(c1ccccc1)C3CCC2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
7-methyl-2-phenyl-2,3-dihydroindole-3-propionic acid (13.47 g) synthesized as in Example 1, steps 1 and 2 was dissolved in formic acid (50 ml) and to the solution was added acetic anhydride (4.53 ml) under cooling with ice. The mixture was stirred for 3 days at room temperature. After adding water, the reaction mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent to yield 13.07 g (97%) of the titled compound as pale brown crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]#[N:12].C1COCC1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCOC(C)=O>[CH3:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: Cc1c(C#N)ccc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C#N)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a stirred solution of 160 (8.3 g, 52.5 mmol) and THF (100 mL) at RT under nitrogen was added, 3,4-dihydro-2H-pyran (35 g, 420 mmol) and p-TsOH.H2O (0.9 g, 5.3 mmol) and the reaction mixture was heated at 75° C. for 4 h. The mixture was cooled to RT, diluted with EtOAc and sequentially washed with sat'd. aq. NaHCO3, and brine. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 5% MeOH) to afford 9.8 g (77%) of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (162) as a light yellow solid: MS (ESI) m/z=242 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=O)[O:5]CC)[CH3:2].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[CH2:9]([P:4]([Cl:23])(=[O:5])[O:3][CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCCCCCCCCCP(=O)(OCC)OCC
Solvent: ClCCl
Product: C=CCCCCCCCCCP(=O)(Cl)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-undecenylphosphonic acid diethyl ester (53.51 g, 180 mmol) in CH2Cl2 (350 mL) was cooled to about −8° C. Oxalyl chloride (32 mL, 370 mmol, 2 eq.) was added slowly to the mixture, the mixture was warmed to room temperature and stirred overnight. Solvent was removed to dryness and the excess oxalyl chloride was azeotropically removed with hexane three times (100 mL). The mixture was dried in a vacuum oven at 40° C. overnight and the product was used without further purification. 1H NMR (400 MHz CDCl3) δ=5.8 (m, 1H), 5.0 (m, 2H), 4.3 (m, 2H), 2.2–2.0 (m, 4H), 1.7 (m, 2H), 1.5–1.2 (M, 15H). 31P NMR (CDCl3) δ=46.2.