Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13]C(=O)C)[CH:10]=[CH:9]1.O.[OH-].[Li+].COC(C)(C)C.O>C1COCC1.CO.O.C(Cl)(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1
Reactant: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
Dissolve (-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (106 mg, 0.47 mmol, prepared in example 11) in THF/methanol/water (1.5/0.5/0.5 mL). Add lithium hydroxide monohydrate (0.57 mmol) with stirring. After stirring for about 3 hours at room temperature, dilute the reaction with tert-butyl methyl ether (10 mL) and water (10 mL). Extract with tert-butyl methyl ether (2×10 mL). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, 2.5 g, 1.7×2.5 cm column, 50% ethyl acetate/hexane, 150 mL) to provide the title compound (80 mg, 93% yield), [α]20D =+9.9°, (c=0.98, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][NH2:12].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][NH:12][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NNc1cc([N+](=O)[O-])ccc1Cl
Yield: 77.5 %

Procedure:
To a solution of 2-chloro-5-nitrophenylhydrazine (37.60 g) in dichloromethane (200 ml), triethylamine (22.27 g) and pivaloyl chloride (26.59 g) were added, and the resultant mixture was stirred at room temperature for 12 hours. The reaction mixture was combined with water. The dichloromethane layer was washed with water, dried and concentrated under reduced pressure to give 1-(2-chloro-5-nitrophenyl)-2-(2,2-dimethylpropionyl)hydrazine (42.23 g). m.p., 153.3° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[ClH:10].[N:11]([O-])=O.[Na+]>O>[ClH:10].[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][NH2:11])=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: CSc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CSc1ccc(NN)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(methylthio)aniline (6.3 g) and conc.HCl (45 ml) was added dropwise NaNO2 (3.6 g) in water (18 ml) under ice-cooling. After stirring for 30 min., SnC1H2O (28.6 g) in conc.HCl (24 ml) was added under ice cooling over 1 hour. After stirring for 1 hour, filtrate, washed with conc.HCl and water, and dried to give 14.1 g of [4-(methylthio)phenyl]hydrazine hydrochloride as a solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].C(O)(=O)C.C(N(CC)CC)C.O1[CH:20]2[CH:16]1[C:17](=[O:48])[CH:18]([CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:19]2[CH:21]=[CH:22][CH:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CO.O>[CH3:1][S:2][C:16]1[C:17](=[O:48])[CH:18]([CH:37]([OH:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:19]([CH:21]=[CH:22][CH:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:20]=1
Reactant: CCCCCC(C=CC1C2OC2C(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Reactant: C[S-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCC(C=CC1C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 100.4 %

Procedure:
A solution of sodium thiomethoxide (2.30 g) in methanol (100 ml) was cooled to 0° C., acetic acid (2.82 ml) was added, the mixture was stirred for 5 minutes, Triethylamine (915 ml) was added, and a solution of 2,3-epoxy-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)cyclopentanone (3.26 g) in methanol (40 ml) was added. After stirring at room temperature for 12 hours, water was added to the mixture, and the mixture extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 3.47 g (yield 96%) of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (260 mg, 0.54 mmol) in DMF (1 mL) at rt, was added 1-cyanocyclopropanecarboxylic acid (66 mg, 0.6 mmol), BOP (287 mg, 0.65 mmol) and DIPEA (0.3 mL, 1.7 mmol). The mixture was stirred for 2 h. The reaction was added water, stirred at rt for 2 h, filtered and rinsed with water to give 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (192 mg, 80% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (d, J=6.6 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.11 (d, J=17.8 Hz, 1H), 5.09-4.92 (m, 2H), 4.55 (br. s., 2H), 4.46-3.93 (m, 3H), 3.88-3.59 (m, 2H), 3.50 (d, J=14.1 Hz, 3H), 1.75-1.46 (m, 4H); MS (ES+) m/z: 446.1, 447.2 (M+H); LC retention time: 3.49 min (analytical HPLC Method B).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][NH2:9].C[O-].[Na+].C(O[C:16](=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH3:17])C>C(O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[N:8]1[C:21]([NH2:22])=[C:18]([C:19]#[N:20])[C:16]([CH3:17])=[N:9]1
Reactant: CC1CCCC1NN
Reactant: CCOC(C)=C(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C2CCCC2C)c(N)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
To a solution of 2-methylcyclopentylhydrazine hydrochloride (7.4 g, 48.8 mmol) in ethanol (100 ml) was added sodium methoxide (2.6 g, 48.8 mmol). The resulting white suspension was stirred for 10 minutes at room temperature and then (1-ethoxyethylidene)malononitrile (6.7 g, 48.8 mmol) was added. The reaction mixture was heated to reflux and was stirred for 5 hours. The solvent was removed in vacuo and the residue was partitioned between chloroform and water. The organic layer was separated and the aqueous layer was extracted with chloroform three times. The combined organic layers were washed with brine, then dried over anhydrous MgSO4. The solution was passed through a plug of silica gel and the solvent was removed in vacuo. The residue was washed with ether to afford 5.6 g (56%) of 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as a white powder, m.p. 158°-159° C.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.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>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cc(-c3ccc(Cl)cc3Cl)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
To a solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]pyridin-2-yl}acetamide (750 mg, 1.60 mmol) and tetrakis(triphenylphosphine)palladium (92.0 mg, 0.08 mmol) in DCM (12.0 mL) was added acetic acid (3.95 mL, 69.5 mmol) and phenylsilane (1.00 mL, 8.15 mmol) and the mixture was stirred for 24 hrs at 40° C. The reaction mixture was evaporated to remove volatiles and DCM added. To this solution was added saturated NaHCO3 and the resulting mixture was stirred for 30 min. The mixture was extracted with DCM (3×100 mL) and the combined DCM layers were washed with brine. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (SiO2, elution with 3-6% MeOH in DCM) to give crude product which was further purified by column chromatography (SiO2, elution with 100% EtOAc) to provide 589 mg of the product (84%). LC/MS (FA) ES+ 431. 1H NMR (400 MHz, d6 DMSO) δ: 11.8-11.9 (br s, 1H), 10.6 (s, 1H), 8.39 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.69 (s, 1H), 7.45-7.49 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 6.90-7.15 (br s, 2H), 2.12 (s, 3H).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:13]([NH2:18])[CH:14]=[N:15]2)=[CH:10][CH:9]=1>N1C=CC=CC=1.[Au]>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:1]([CH2:2][CH2:3][CH3:4])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Reactant: CCCC(=O)Cl
Agent: [Au]
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Temperature: 25 °C

Procedure:
Butyryl chloride (1.1 equivalent) was slowly added to a stirred solution of 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine (52.9 g, 0.18 mol.) in pyridine (700 mL) at room temperature. A pale yellow precipitate formed and then went into solution. The reaction mixture was heated at reflux for eight hours, and then allowed to slowly cool to room temperature over the weekend. The dark gold, turbid reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1 N hydrochloric acid and then adjusted to pH 14 with the addition of 10% aqueous sodium hydroxide. A precipitate formed, was isolated by filtration, washed with water (3×100 mL), and dried overnight on the filter funnel to provide 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as an off-white solid.
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)[CH:6]=CC=C[CH:2]=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH:40]1([CH:17]([CH:16]2[CH2:46][CH2:6][CH2:1][CH2:2][CH2:15]2)[C:18]([NH:20][C@@H:21]2[C@H:28]3[C@H:24]([CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=4)[CH2:27]3)[CH2:23][CH2:22]2)=[O:19])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting 2,2-dicyclohexylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.73 (s, 1H), 7.65 (d, J=7.6, 1H), 7.57-7.44 (m, 3H), 4.46 (dt, J=6.4, 12.6, 1H), 3.55 (d, J=12.9, 1H), 3.47 (d, J=12.8, 1H), 2.75 (d, J=8.1, 2H), 2.53-2.39 (m, 2H), 2.32 (t, J=8.2, 1H), 2.21 (t, J=8.3, 1H), 1.97-1.53 (m, 15H), 1.50-1.04 (m, 11H), 0.98 (dd, J=11.3, 23.1, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][F:14])[C:10](O)=[O:11])=O)(C)(C)C.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:16].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(O)(C(F)(F)F)=O>CN(C=O)C.C(OCC)(=O)C.ClCCl>[CH2:15]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:13][F:14])[CH2:24][CH2:25]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CF)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg (R)-tert-butoxycarbonylamino-3-fluoropropionic acid in 2 ml DMF were added 115 mg 1-ethoxycarbonylpiperazine, 0.18 ml N-ethylmorpholine and 238 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3, 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was deprotected by using 10 equivalents TFA in dichloromethane. After stirring for 12 h it was concentrated and codistilled twice with toluene. Yield: 216 mg colorless oil.
Reaction SMILES: C([O-])(=O)C.C([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]([OH:34])[C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])(=O)C>>[OH:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]([OH:34])[C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:30])([CH3:31])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12]
Reactant: CC(=O)Oc1cc(OCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)ccc1CO
Agent: CC(=O)[O-]
Product: CC1(C)CCC(C)(C)c2cc(C(O)COc3ccc(CO)c(O)c3)ccc21

Procedure:
acetate of 2-acetoxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzylalcohol;
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[CH2:11]([OH:13])[CH3:12]>C(OC(=O)C)(=O)C.[OH-].[Na+]>[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: CCO
Reactant: c1ccc2c(c1)NCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoxaline obtained in Reference Example 26 (360 mg) in ethanol (10 ml), acetic anhydride (254 μl) was added dropwise under ice cooling and stirred at room temperature for 10 minutes. The reaction mixture was diluted with 1M aqueous sodium hydroxide (10 ml) and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to give the titled compound, i.e., 1-acetyl-1,2,3,4-tetrahydroquinoxaline (494 mg) as a brown oil.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.[I-].[Zn+2].[I-].O>[NH2:6][CH2:5][C:15]1([OH:19])[C:16]2[C:11](=[CH:10][C:9]([O:8][CH3:7])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCCC2(O)CN
Temperature: 60 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
TMS-cyanide (8.52 mL, 68.1 mmol) was added to a solution of 6-methoxy-1-tetralone (6.0 g, 34 mmol) in toluene (50 mL). A trace amount (−20 mg) of zinc iodide was added, and the reaction was stirred at 60° C. for 16 hours. The solution was cooled to rt and diluted with THF (30 mL). This was added to a mixture of lithium aluminum hydride (2.58 g) in THF (50 mL), and the reaction mixture was heated at 42° C. for 2 h. The reaction was cooled to rt. EtOAc (10 mL) was slowly added, and the reaction stirred 30 min. Water (2 mL) and then 5N NaOH (1 mL) were slowly added, and the reaction stirred 1 h. The reaction mixture was diluted with EtOAc (100 mL), dried (MgSO4), and filtered through Celite. Purification by silica gel chromatography (10-20% MeOH/DCM) gave 4.82 g of 1-(aminomethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol as a clear oil.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.CCCCCC>CN(C=O)C.[Cl-].[Na+].O>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(CCS)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
1.8 g (16.0 mmol) potassium tert-butylate were added to a solution of 3.0 g (14.8 mmol) 2-(phenylsulfonyl)ethanethiol in DMF (35 ml) and the mixture was stirred for 30 min at room temperature. Then 2.5 g (15.8 mmol) 2-chloro-3-nitropyridine were added and the mixture was stirred for a further 1 h at RT. Then it was diluted with a brine/EE mixture (1:1 vv) and stirred for a further 30 min at RT. Then the organic phase was separated off, washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:1) of the residue yielded 2.2 g (6.8 mmol, 46%) 2-[2-(benzenesulfonyl)-ethylsulfanyl]-3-nitropyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([NH:26]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH2:13]2)=[CH:8][CH:7]=1>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3](=[O:34])[CH:4]([NH2:26])[CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:16](=[O:25])[C:17]3[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:23])[CH2:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc2c(c1)CN(C(=O)c1c(Cl)cccc1Cl)CC2)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)Cc1ccc2c(c1)CN(C(=O)c1c(Cl)cccc1Cl)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.5 %

Procedure:
A solution of 2-tert-butyloxycarbonylamino-3-[2-(2,6-dichloro-benzoyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl]-propionic acid methyl ester {1.7 g, Reference Example 9(b)} in a mixture of trifluoroacetic acid (10 mL) and dichloromethane (30 mL), under nitrogen, was stirred at room temperature for 1.5 hours then evaporated. The residue was dissolved in dichloromethane and this solution was washed with aqueous sodium bicarbonate solution, then with water, then dried over magnesium sulfate and then evaporated to give the title compound (1.18 g) which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15]O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18].O.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][Br:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCCN(Cc2ccccc2)C1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC1CCCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
8.3 g (0.038 mol) of 1-benzyl-3-hydroxymethyl-hexahydroazepine are dissolved in 200 ml of carbon tetrachloride and 16 ml of phosphorus tribromide are added. The mixture is stirred for 6 hours at ambient temperature, water is then added whilst the mixture is cooled with ice and it is made slightly alkaline with 2-molar sodium hydroxide solution. The aqueous solution is separated off and extracted twice with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 8.9 g (82% of theory).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 11.5 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 1,106 g of L-arginine were added 6,919 g of isopropyl alcohol and 2,964 g of water. Thereto were concurrently added dropwise 1,522 g of lauroyl chloride (manufactured by Nippon Oil and Fats Co., Ltd.) and 27 wt % NaOH aqueous solution over a period of 2 hours with the pH being maintained at 10.5 to 11.5 and the reaction temperature being maintained at 10 to 13° C. After 1 hour of aging, the reaction mixture was warmed to 50° C. and adjusted to pH 3.8 by adding concentrated hydrochloric acid to dissolve the reaction product completely. Thereafter, the pH was adjusted to 6.0 by adding 27 wt % NaOH aqueous solution to precipitate crystals and the resulting slurry was gradually cooled to 10° C. with stirring. When the slurry was cooled to 10° C., the crystals were collected by filtration and washed with 10 kg of water and 4.4 kg of isopropyl alcohol, successively. The resulting washed crystals were dried under reduced pressure to obtain 2,081 g of mono-Nα-lauroyl-L-arginine as flake-shaped crystals (yield 92.3%).
Reaction SMILES: [Se](O)(O)=[O:2].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]1[C:11]([Cl:21])=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2)[CH3:6]>O1CCOCC1.O>[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]1[C:11]([Cl:21])=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH:20]=[O:2])[CH:16]=[CH:15]2)[CH3:6]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C)nc12
Reactant: O=[Se](O)O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)nc12
Temperature: 100 °C
Yield: 77 %

Procedure:
Selenious acid (193 mg, 1.50 mmol, 1.1 equiv) was added to a solution of (7-chloro-2-methyl-quinolin-8-yl)-acetic acid ethyl ester in dioxane (12 ml). The reaction mixture was heated to 100° C. After 20 and 40 minutes, additional portions of selenious acid (88 mg each) were added, and heating was continued for a total of 90 minutes. After cooling, the reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 80:20) to afford the title compound (292 mg, 77%). 1H NMR (400 MHz, CDCl3): δ=10.18 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 4.61 (s, 2H), 4.22 (q, J=7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H). MS (ES+): 278.2 (M+H)+.