Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[N:3]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CCO>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=4)[N:3]=3)[CH2:26][CH2:27]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Clc1nc(-c2ccncc2)ns1
Reactant: COc1cccc(CCN2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cccc(CCN2CCN(c3nc(-c4ccncc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 15.5 %

Procedure:
A mixture of 5-chloro-3-(pyridin-4-yl)-1,2,4-thiadiazole (42 mg, 213 μmol), 1-(3-methoxyphenethyl)piperazine dihydrochloride (62.3 mg, 213 μmol) and DIPEA (137 mg, 186 μl, 1.06 mmol) in 10 mL EtOH was stirred for 2.5 h at RT the mixture was filtered, washed with EtOH and dried in vacuo at 50° C. for 2 hours to yield 12.6 mg (15%) of the title compounds as orange solid. MS (m/e): 382.2 (MH+).
Reaction SMILES: CO[C:3]1[CH:12]=CC=C2[C:4]=1CC(NCCCCN1C(=O)C3(CCCCC3)CC1=O)CO2.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[CH3:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH2:40][CH:41]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]1[C:57]3([CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)[C:56](=[O:63])[NH:55][C:54]1=[O:64])[CH2:42][O:43]2.C(O)(=O)C(O)=O>>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[CH2:4]([N:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]1[C:57]2([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]2)[C:56](=[O:63])[NH:55][C:54]1=[O:64])[CH:41]1[CH2:40][C:39]2[C:44](=[CH:45][CH:46]=[CH:47][C:38]=2[O:37][CH3:36])[O:43][CH2:42]1)[CH2:3][CH3:12]
Reactant: COc1cccc2c1CC(NCCCCC1C(=O)NC(=O)C13CCCCC3)CO2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Agent: O=C(O)C(=O)O
Product: CCCN(CCCCC1C(=O)NC(=O)C12CCCCC2)C1COc2cccc(OC)c2C1

Procedure:
Using the procedure described in Example 10, but replacing the compound of Example 9 by the compound of Example 28, the product of the title is obtained. It is salified with oxalic acid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][C:11]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C1COCC1.OS([O-])(=O)=O.[K+]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:34](=[O:36])[CH3:35])[CH2:16]3)=[N:12][C:11]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(-c2[nH]c(C3CCCNC3)nc2-c2ccncc2)cc1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)C1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a stirring solution of 3-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine dihydrochloride (0.76 mmol, 0.3 g) in THF (5.0 mL) was added triethylamine (3.3 mmol, 0.33 g) and acetyl chloride (2.3 mmol, 0.18 g). The reaction was stirred at room temperature for 1H, diluted with 10% KHSO4 (50 mL) and extracted with ethyl acetate (2×50 mL). The organics were combined, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica, eluting with 3% MeOH:CH2Cl2. The pure fractions were collected and evaporated under reduced pressure. The resulting film was evaporated from CH2Cl2 :hexanes to give 0.2 g of the title compound as a white foam.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1>CN(C)C=O>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:3])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Temperature: 0 °C
Yield: 92.3 %

Procedure:
Phosphorous oxychloride (16.76 g, 10.19 mL, 109.3 mmol) was added slowly dropwise to a suspension of 7-bromo-3-nitro[1,5]naphthyridin-4-ol (21.09 g, 78.1 mmol) in N,N-dimethylformamide (250 mL)(DMF) at ambient temperature and maintained overnight. The reaction mixture was then added to ice water (400 mL) with stirring. A solid precipitate formed, which was isolated by vacuum filtration and washed with water. The material was dried under high vacuum at ambient temperature overnight to yield 20.79 g of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine as a tan solid.
Reaction SMILES: [N:1]1([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([C:16]=2[CH:17]=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:29]1[CH2:28][CH:27]1[CH2:25][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([C:16]=2[CH:17]=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:2][CH2:3]1
Reactant: O=Cc1c(N2CCCNCC2)n(-c2ccccc2)c2ccccc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1c(N2CCCN(CC3CO3)CC2)n(-c2ccccc2)c2ccccc12
Yield: 41 %

Procedure:
A solution of 2-[1,4]diazepan-1-yl-1-phenyl-1H-indole-3-carboxaldehyde (438 mg, 1.37 mmol), epibromohydrin (188 mg, 1.37 mmol) and potassium carbonate (758 mg, 5.49 mmol) in acetonitrile (20 mL) is refluxed for 2.5 hr. The reaction mixture is cooled, the solvent is removed and the residue is purified by chromatography eluting with dichloromethane-1 to 5% methanol. Fractions containing product are combined and concentrated to afford 2-(4-oxiranylmethyl-[1,4]diazepan-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (41% yield) as a yellow solid. LC/MS: 376 (M+H), RT 2.65 min; NMR (CDCl3): 10.28 (1H, s), 8.26 (1H, d), 7.43-7.65 (3H, m), 7.17-7.42 (3H, m), 7.13(1H, t), 6.96 (1H, d), 3.49 (4H, m), 3.03 (1H, m), 2.56-2.86 (4H, m), 2.30-2.50 (2H, m), 1.74(2H, m), 1.56 (2H, s).
Reaction SMILES: C([O:5][C:6]([C@@H:8]([NH:10][C:11]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1)=[O:14])[CH3:9])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C@@H:8]([NH:10][C:11]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1)=[O:14])[CH3:9])([OH:7])=[O:5]
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of (S)-2-[1-(tert-butoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (104 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.6 mL), and the mixture was stirred for 2 hour at ambient temperature. The resulting mixture was evaporated in vacuo and the residue was triturated with diethyl ether to give (S)-2-(1-carboxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (76 mg) as a solid substance.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.[I-].[Na+]>>[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH:4]([CH2:3][CH3:2])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: O=C(CCCCl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Product: CCC(C(=O)c1ccccc1)N1[C@H](C)CCC[C@@H]1C
Temperature: 25 °C

Procedure:
A mixture of 619 g. of γ-chlorobutyrophenone, ethylene ketal, 700 g. of cis-2,6-dimethylpiperidine and 16 g. of sodium iodide is stirred and heated at reflux for 48 hours. The mixture is cooled, diluted with 1 l. of anhydrous ether and filtered to remove cis-2,6-dimethylpiperidine hydrochloride. The filter cake is washed with 1 l. of ether and the filtrate and washings combined. The resulting ether solution is washed five times with 500 ml. portions of water, then extracted with a solution of 300 ml. of concentrated hydrochloric acid in 3 l. of water. The acid extract is washed with 500 ml. of ether, then heated to 70°-80° and allowed to cool to room temperature over a period of 16 hours. The resulting solution is basified with 50% aqueous sodium hydroxide and the organic layer is separated. The aqueous layer is extracted with 500 ml. of ether and the extract is combined with the organic layer. The combined extract is washed several times with water, dried and evaporated. The oily residue is distilled at reduced pressure to give cis-α-(2,6-dimethylpiperidino)butyrophenone; b.p. 138°-141° C./0.1 mm.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][C@@H:3]([CH3:6])[CH2:4][O:5][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C[C@@H](CO)CBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](CBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-3-bromo-2-methylpropan-1-ol (7.30 g, 5 mL, 47.7 mmol) in anhydrous dichloromethane (100 mL) was mixed with 3,4-dihydro-2H-pyrane (4.63 g, 5.02 mL, 55 mmol) and pyridinium tosylate (50 mg) with ice cooling and then stirred for 1 h at room temperature. The reaction mixture was then washed with 5% sodium hydrogencarbonate solution and water (3×30 mL each). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19].[O-]CC.[Na+]>C1COCC1.ClCCl>[O:23]=[C:17]([CH2:2][C:1](=[O:3])[C:4]1[S:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C#Cc2ccccc2)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)C(=O)CC(=O)c1ccc(CCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-acetyl-5-(phenylethynyl)thiophene (1.81 g, 8.02 mmol), diethyl oxalate (2.17 mL, 16 mmol), and sodium ethoxide (1.09 g, 16 mmol) in anhydrous THF (25 mL) was stirred at rt under an atmosphere of argon for 5 hr. The resultant mixture was diluted with dichloromethane, and washed successively with dilute HCl, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide yellow solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5]O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>CCOCC>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][Cl:22]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Br)c(OC)c(CO)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cc(Br)c(OC)c(CCl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
To a solution of 8.18 gm (33.11 mmol) of 3-bromo-2,5-dimethoxybenzyl alcohol and 0.8 ml pyridine in 100 ml ether was added dropwise a solution of 8.5 ml (116 mmol) thionyl chloride in 20 ml ether. After stirring at ambient temperature for 20 hours, the reaction mixture was poured onto ice. The ether extract was washed with brine, dried (NaSO4), filtered and concentrated in vacuo to give 7.59 gm of a colorless oil. A portion, 3.9 gm, was purified by silica gel chromatography using 3:7 CH2 Cl2 :hexane to yield 3.62 gm of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[N:3]=1.C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH:10][C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: COc1ccc(N)nc1Br
Reactant: CC(=O)OC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)C(F)(F)F)nc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
2-Bromo-3-methoxy-6-aminopyridine (Desc. 6; 1.0 g, 4.9 mmol) in dichloromethane (25 ml) was treated with N,N-diisopropylethylamine (2.2 ml, 12.3 mmol) and the solution cooled to 0° C. Trifluoroacetic acetic anhydride (770 μl, 5.4 mmol) was then added dropwise and the solution stirred to 22° C. over 2 hours. The mixture was then poured into saturated sodium bicarbonate solution (25 ml) and extracted with dichloromethane (25 ml). The extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash silica chromatography to give the product as a white solid (890 mg, 3.0 mmol, 61% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:14][C:15]3[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:14][C:15]3[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:6]2
Reactant: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)[nH]c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1c(-c2ccc3cc(O)ccc3c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of 2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole (0.915 g, 2.66 mmol) in CH2Cl2 (30 mL) cooled to −78° C. was added BBr3 (9.86 mL, 1.0 M in CH2Cl2, 9.86 mmol) dropwise. The reaction was stirred at this temperature for 0.5 h and then warmed to rt for 2 h. The reaction mixture was quenched with MeOH (−5 mL) followed by dilution with H2O (20 mL) and EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc:petroleum ether gradient) to afford the product (0.677 g, 77%) as a foamy solid; 1H NMR (DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.23-1.42 (m, 4H), 1.58-1.76 (m, 2H), 2.89 (t, J=8.2 Hz, 2H), 7.00 (t, J=8.2 Hz, 1H), 7.06-7.19 (m, 3H), 7.35 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.2, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.74-7.88 (m, 2H), 7.98 (s, 1H), 9.83 (s, 1H), 11.14 (s, 1H); mass spectrum [(+) ESI], m/z 330 (M+H)+ and [(−) ESI], m/z 328 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:24]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:13]([N+:14]([O-])=O)=[CH:12][N:11]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[C:24]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][N:11]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4N)nc3cc2F)CC1
Yield: 98.2 %

Procedure:
A suspension of 11.9 g of 5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole in 260 mL of methanol and 1.2 g of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 18 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 10.9 g of 3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are obtained in the form of a brown powder. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.43 to 2.17 (m, 8H); 2.33 (s, 3H); 2.64 (m, 2H); 2.73 (m, 2H); from 3.20 to 3.40 (m masked, 4H); 3.62 (m, 1H); 3.95 (m, 1H); 4.92 (broad s, 2H); 5.31 (dd, J=2.5 and 10.0 Hz, 1H); from 6.91 to 7.36 (m, 2H); 7.31 (s, 1H); 12.4 (broad m, 1H). ES mass spectrum: m/z=414: MH+ (base peak)—m/z=330: (MH−C5H8O)+
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[S:11]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=O)(=[O:14])(=[O:13])[NH2:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:18]([C:17]3[CH:16]=[C:15]([S:11]([NH2:12])(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: N
Product: NS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-sulfamoylbenzoic acid (Oakwood). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.83 (t, J=7.9 Hz, 1 H), 8.21 (ddd, J=7.9, 1.8, 1.0 Hz, 1 H), 8.45 (dt, J=7.9, 1.4 Hz, 1 H), 8.58 (dt, J=8.0, 1.9 Hz, 1 H), 8.73-8.77 (m, 2 H), 9.31 (dd, J=2.2, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][OH:15])[CH2:9][C:10]([CH3:12])=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][O:15][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[CH2:9][C:10]([CH3:12])=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)CN(CCO)C(=O)OC(C)(C)C
Product: C=C(C)CN(CCOS(=O)(=O)c1ccc(C)cc1)C(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)glycine tert-butyl ester was reacted with 3-bromo-2-methylpropene according to Method B8b, Step 1 to give N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester. The ester was reduced according to Method B8b, Step 2 to give N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylprop-2-ene. The alcohol was treated with p-toluenesulfonyl chloride according to Method B8b, Step 3 to give N-(tert-butoxycarbonyl)-N-(2-tosyloxyethyl)-1-amino-2-methylprop-2-ene. The carbamate was deprotected according to Method B8b, Step 4 to give N-(2-tosyloxyethyl)-2-methylprop-2-en-1-ammonium trifluoroacetate. The tosylate was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C5a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2methylprop-2-enyl)-1,3-oxazolidine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([Cl:16])=[C:10]([CH3:15])[C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:6].[H-].[Na+]>CN(C)C=O>[Cl:16][C:9]1[C:10]([CH3:15])=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[N:7]1[CH2:2][CH2:3][CH2:4][C:5]1=[O:6]
Reactant: Cc1c(Cl)ccc(NC(=O)CCCCl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)ccc(N2CCCC2=O)c1Cl
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of 3-(4-chlorobutyryl)amino-2,6-dichlorotoluene (2.80 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% oil dispersion, 440 mg) in one portion at 5° C. The mixture was stirred for 10 minutes at 5° C. and then for 2 hours at 60° C. The cooled mixture was poured into ice water. The separated oil was extracted with dichloromethane. The organic layer was washed with water three times, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 1-(2,4-dichloro-3-methylphenyl)-2-pyrrolidinone (1.95 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40]C)=[O:38])=[CH:35][CH:34]=1.[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]O)=[CH:50][CH:49]=1)[CH2:45][CH2:46][CH3:47]>C1COCC1>[CH2:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][O:32][C:33]2[CH:43]=[CH:42][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:54][CH:55]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(COc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (656 mg, 2.50 mmol) in THF (12 mL) at 0° C. was treated with diethyl azodicarboxylate (442 mg, 2.54 mmol), stirred for 20 minutes, treated with ethyl 4-hydroxybenzoate (350 mg, 2-30 mmol) and 4-butylbenzyl alcohol (414 mg, 2.52 mmol), warmed to room temperature, stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:39]=[C:33]7[CH2:34][N:35]([CH3:38])[CH2:36][CH2:37][N:32]7[N:31]=6)[C:26](=[O:40])[N:25]([CH3:41])[CH:24]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][N:5]3[C:4]4[CH2:3][C:2]([CH3:1])([CH3:42])[CH2:13][C:12]=4[CH:11]=[C:10]3[C:9]2=[O:14])=[N:16][CH:17]=[CH:18][C:19]=1[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:39]=[C:33]3[CH2:34][N:35]([CH3:38])[CH2:36][CH2:37][N:32]3[N:31]=2)[C:26](=[O:40])[N:25]([CH3:41])[CH:24]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)cc2C1
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a solution of 141b (150 mg, 0.26 mmol) at room temperature in methanol (10 mL) was added sodium borohydride (29 mg, 0.78 mmol) and the resulting mixture was stirred for 30 minutes. It was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 141 (35 mg, 23.2%). LCMS: [M+H]+ 569.3. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J=5.0, 1H), 7.94 (d, J=2.5, 1H), 7.72 (d, J=2.0, 1H), 7.41 (s, 1H), 7.33 (d, J=5.5, 1H), 6.83 (s, 1H), 5.68 (s, 1H), 5.03-5.00 (m, 1H), 4.64-4.61 (m, 1H), 4.51-4.48 (m, 1H), 4.32-4.27 (m, 1H), 4.21-4.09 (m, 4H), 3.91-3.82 (m, 1H), 3.69 (s, 3H), 3.62-3.58 (m, 2H), 2.87 (t, J=2.5, 2H), 2.57 (d, J=4.0, 2H), 2.54 (s, 2H), 2.51 (s, 3H), 1.27 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]=O)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15]([NH:18][CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[CH3:16].C[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[CH2:23]([O:22][C:20]([C:19]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:12]([O-:14])=[O:13])=[CH:11][N:18]1[C:15](=[O:17])[CH3:16])=[O:21])[CH3:24]
Reactant: C=C(C=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2[N+](=O)[O-])=CN1C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 143.0 g (0.676 mol) of 2-(4-chloro-2-nitrophenyl) acrolein in 600 ml. of benzene was added over 1.5 hour to a stirred suspension of 148.5 g (0.684 mol) of diethyl acetamidomalonate and 0.80 g of sodium methoxide in 600 ml. of benzene. The Michael addition was complete after 30 minutes. 3.8 g of p-toluenesulfonic acid monohydrate was added and the mixture was heated at reflux for 40 minutes with constant removal of the water formed. The reaction mixture was washed with saturated sodium bicarbonate and brine. After drying with anhydrous NaSO4, the orange solution was concentrated to yield 278.5 g, m.p. 90-95°. Crystallization from ethanol (500 ml) gave 264.6 g (95%) of deep yellow crystals, m.p. 96-98°. A sample was recrystallized again from ethanol: m.p. 96.5-98°.