Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N+:54]1([O-:61])[C:55]([NH2:60])=[CH:56][CH:57]=[CH:58][CH:59]=1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][N+:54]=3[O-:61])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Reactant: Nc1cccc[n+]1[O-]
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1cccc[n+]1[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (88 mg, 0.219 mmol) in acetonitrile (4 mL) at 0° C. was added 4-methylmorpholine (0.053 mL, 0.482 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (DMTMM) (86 mg, 0.263 mmol). The solution was stirred for 15 min, and then 2-pyridinamine 1-oxide (31.4 mg, 0.285 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated away, and residue was dissolved in DCM. The solution was washed with 5% aq. NaHSO4 followed by water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude oil, which was purified by RP-HPLC to provide (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-(1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide as a colorless gum (67 mg, 62%). LCMS: (M+H)+: 494.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[H][H].O>CO.[Pt]>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cccnc1-c1ccccc1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: O
Solvent: CO
Product: N[C@H]1CCCN[C@H]1c1ccccc1
Yield: 87.3 %

Procedure:
In a bottle were placed 2.65 g (15.6 mmol) of 3-amino-2-phenylpyridine, 10.6 g of 5% platinum/carbon and 106 mL of 1.5 M HCl in methanol. The mixture was shaken under an atmosphere (ca. 40 p.s.i.) of hydrogen for 2.5 hours. Water was added to the system, the mixture was filtered through a pad of diatomaceous earth and the pad was rinsed with ca. 700 mL of water. The filtrate was made basic with solid sodium hydroxide and extracted with two portions of dichloromethane. The combined organic fractions were washed with water, dried (sodium sulfate) and concentrated with a rotary evaporator to obtain 2.4 g of the title compound as a yellow oil.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH2:10]([O:17][CH2:18]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(C(C)=O)C(C)C.COCCOCCN(CCOCCOC)CCOCCOC>[CH2:10]([O:17][CH2:18][N:5]1[C:6](=[O:8])[CH2:7][NH:3][C:4]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CNC(=O)N1
Reactant: ClCOCc1ccccc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1CNC(=O)N1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
In 5 ml of methyl isobutyl ketone were suspended 216 mg (3.85 mmoles) of potassium hydroxide and 73 mg (0.226 mmoles) of tris[2-(2-methoxyethoxy)ethyl]-amine followed by addition of 900 mg (8.99 mmoles) of imidazolidine-2,4-dione, and the mixture was stirred at room temperature for 10 minutes. Then, 704 mg (4.50 mmoles) of benzyloxymethyl chloride was added dropwise at 0° C. and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added water and the organic layer was separated and washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel chromatography (eluent: hexane:ethyl acetate =1:1) to give 687 mg (3.12 mmoles) of 3-benzyloxymethylimidazolidine-2,4-dione. Yield 70% (based on benzyloxymethyl chloride) 1H-NMR, δ(CDCl3): 3.90 (2H, s), 4.60 (2H, s), 5.05 (2H, s), 6.00-6.20 (1H, brs, -NH), 7.20-7.45 (5H, m)
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1([Mg]Br)CCCC1.[Si:14]([O:21][CH2:22][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24]O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.CCOCC>[Si:14]([O:21][CH2:22][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CO[Si](C)(C)C(C)(C)C
Reactant: BrC1CCCC1
Agent: Br[Mg]C1CCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC1CCCC1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A 100 mL, three-neck round bottom flask was charged with Mg powder (720 mg, 30 mmol), then a solution of cyclopentylbromide (3.73 g, 25 mmol) in THF (25 mL) was added dropwise while a heat gun heated the flask. After stirring for 2 h, most of the Mg was consumed. The cyclopentylmagnesium bromide was added to a suspension of CuBr—SMe2 (307.5 mg, 1.5 mmol) in THF (80 mL) at −78° C., the cuprate was stirred for 30 min and a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-hydroxypropan-2-ylcarbamate (2.87 g, 10 mmol) in Et2O (30 mL) was added. After stirring for 2 h, the reaction mixture was washed with saturated NaHCO3 (2×20 mL) and brine (30 mL). The organic layer was dried with MgSO4, the solvent evaporated, and the residue purified by silica gel chromatography to obtain (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopentylpropan-2-ylcarbamate as an oil (2.9 g, yield 81%). 1H NMR (CDCl3, 400 MHz) δ 4.60 (brs, 1H), 3.58 (m, 3H), 1.81 (m, 3H), 1.60 (m, 3H), 1.50 (m, 3H), 1.44 (s, 9H), 1.10 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:21])=[CH:7][CH:6]=1)[CH3:3].[CH3:24][N:25]1[C:29]([CH:30]=O)=[N:28][CH:27]=[N:26]1.[CH3:32][CH2:33][O-:34].[Na+]>C(OCC)(=O)CC>[CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][C:8]([CH:9]2[CH:30]([C:29]3[N:25]([CH3:24])[N:26]=[CH:27][N:28]=3)[C:33](=[O:34])[C:32]3[C:16]([C:15]([O:14][CH2:13][CH3:12])=[O:21])=[CH:17][C:18]([F:20])=[CH:19][C:11]=3[NH:10]2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: Cn1ncnc1C=O
Reactant: CC[O-]
Reactant: CN(C)Cc1ccc(/C=N/c2cc(F)cc3c2COC3=O)cc1
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(CN(C)C)cc1)N2
Temperature: 48 °C
Reaction time: 3 h
Yield: 9.2 %

Procedure:
To a solution of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (4.2 g, 13.5 mmol) and compound 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (3.0 g, 27 mmol) in ethyl propionate (150 mL) was added rapidly NaOEt [sodium (870 mg, 37.8 mmol) in 70 mL ethanol] at 40° C., then the mixture was stirred at 48° C. for 3 hr. The resulting mixture was concentrated under reduced pressure and extracted with ethyl acetate (250 mL×3). The extract was evaporated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane:methanol=50:1 to 10:1) to obtain the title compound (560 mg, yield 9%) (a mixture of cis and trans isomers). LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]1([C@@H:20]([CH3:23])[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>O>[C:14]1([C@@H:20]([CH3:23])[CH2:21][NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](CN)c1ccccc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Product: C[C@@H](CNC(=O)c1cnc2ccccc2n1)c1ccccc1
Yield: 76.4 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (R)-2-phenyl-1-propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.49 g (76%) of (172):
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][F:6].[F:7][C:8]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C(O)C.[OH-].[K+]>O>[F:7][C:8]1[CH:16]=[C:15]([O:17][CH2:2][CH2:3][CH2:4][CH2:5][F:6])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: FCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCCF)cc1F
Temperature: 80 °C
Reaction time: 17 h
Yield: 39.1 %

Procedure:
1-Bromo-4-fluorobutane (3.57 g, 23.1 mmol) was added dropwise to a mixture of 2-fluoro-4-hydroxybenzoic acid (3.00 g, 19.2 mmol), ethanol (11.5 ml) and water (2.3 ml), potassium hydroxide (2.37 g, 42.3 mmol) at 80° C., and the mixture was stirred at 80° C. for 17 hrs. The solvent was evaporated under reduced pressure. The residue was dissolved in water and the solution was acidified by adding 1N hydrochloric acid. The insoluble materials were filtered off and dried to give the title compound (1.73 g) as a pale-brown powder.
Reaction SMILES: Cl[Sn]Cl.C1(S)C=CC=CC=1.C1(N(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:30]([C:33]1[C:34]2[CH2:35][CH2:36][N:37]([CH3:62])[C@@H:38]([C@@H:48]3[C:56]4[C:51](=[C:52]([O:59][CH3:60])[C:53]([O:57][CH3:58])=[CH:54][CH:55]=4)[C:50](=[O:61])[O:49]3)[C:39]=2[C:40]([O:46][CH3:47])=[C:41]2[O:45][CH2:44][O:43][C:42]=12)=[N+]=[N-]>C1COCC1>[CH3:62][N:37]1[C@@H:38]([C@H:48]2[O:49][C:50](=[O:61])[C:51]3[C:52]([O:59][CH3:60])=[C:53]([O:57][CH3:58])[CH:54]=[CH:55][C:56]2=3)[C:39]2[C:40]([O:46][CH3:47])=[C:41]3[O:45][CH2:44][O:43][C:42]3=[C:33]([NH2:30])[C:34]=2[CH2:35][CH2:36]1
Reactant: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(c(N=[N+]=[N-])c3c(c2OC)OCO3)CCN1C
Agent: Cl[Sn]Cl
Agent: Sc1ccccc1
Agent: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(c(N)c3c(c2OC)OCO3)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50-mL of round-bottomed flask containing a solution of SnCl2 in THF (10 mL) were added thiophenol and triphenylamine. The reaction mixture was added slowly to a solution of azido-noscapine (3, 0.2 g, 0.440 mmol) in THF (5 mL) and the reaction mixture stirred at room temperature. The reaction progress was monitored by thin-layer chromatography at 30 minutes intervals. The reaction was found to be completed after 2 h, the solvent was removed in vacuo. The residue was diluted with chloroform (20 ml) and was added sodium hydroxide solution (20 mL). the aqueous phase was separated and extracted with chloroform (2×20 mL). the combined organic phase was dried over sodium sulfate and concentrated to obtain amino-noscapine as colorless oil, which was then treated with ethereal HCl to obtain its salt as white crystals. Yield, 83%; mp (HCl. Salt) 112.2-112.6° C.; IR: 1725, 1362 cm−1; 1H NMR (CDCl3, 400 MHz): δ 7.12 (d, 1H, J=7.4.0 Hz), 7.02 (d, 1H, J=7.4 Hz), 6.02 (s, 2H), 5.92 (d, 1H, J=4.0 Hz), 4.42 (d, 1H, J=4.0 Hz), 4.20 (bs, 2H), 4.02 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 2.74-2.64 (m, 2H), 2.61-2.56 (m, 2H), 2.52 (s, 3H); 1H NMR (CDCl3+D2O, 400 MHz): δ 7.12 (d, 1H, J=7.4.0 Hz), 7.02 (d, 1H, J=7.4 Hz), 6.02 (s, 2H), 5.92 (d, 1H, J=4.0 Hz), 4.42 (d, 1H, J=4.0 Hz), 5.12 (bs, confirms NH2 group), 4.02 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 2.74-2.64 (m, 2H), 2.61-2.56 (m, 2H), 2.52 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 169.5, 156.8, 152.6, 147.8, 142.7, 141.8, 135.0, 134.2, 123.2, 120.8, 119.9, 119.4, 114.1, 100.8, 87.6, 63.7, 56.8, 56.4, 56.1, 51.4, 39.2, 27.5; HRMS (ESI): m/z Calcd. for C22H24N2O7 (M+1), 428.3481; Found, 428.1562 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].II.[C:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:21]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Yield: 42.6 %

Procedure:
Preparation according to Preparation 1. 1-Bromo-3,4-difluorobenzene (5 g, 25.9 mmol) in dry tetrahydrofuran (100 ml), magnesium turnings (0.62 g, 25.9 mmol) and one crystal of iodine. 1-N-boc-3-pyrrolidone (4.79 g, 25.9 mmol) in dry tetrahydrofuran (50 ml). The crude product was purified by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (3.3 g, 43%). MS m/z (rel. intensity, 70 eV) 243 (33), 198 (45), 141 (39), 127 (44), 57 (bp).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=1[CH:10]=O.Cl[CH2:18][C:19]([CH2:21]Cl)=[O:20]>CC(=O)CC>[Br:7][C:8]1[C:9]2[CH:10]=[C:18]([C:19]([C:21]3[O:4][C:1]4[CH:13]=[CH:12][CH:9]=[C:8]([Br:7])[C:15]=4[CH:14]=3)=[O:20])[O:16][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cccc1Br
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1cc2c(Br)cccc2o1)c1cc2c(Br)cccc2o1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
Dried K2CO3 (7g, 50.1 mmol) was added to a solution of 2-bromo-6-hydroxybenzaldehyde (80) (6.57 g, 32.3 mmol) in dry butanone (35 mL). The suspension was refluxed for 30 min and cooled to room temperature. A solution of 1,3-dichloroacetone (3 g, 24.23 mmol) in 5 mL of dry butanone was added. The reaction mixture was refluxed for 4 hours, cooled down, filtered through a pad of Celite (2 cm) and concentrated. A dark residue was recrystallized from CHCl3 to give 82 as brown solid (5.05 g, 76%): mp 223-225° C. 1H NMR (DMSO-d6) δ8.10 (s, 2H), 7.92 (d, J=8.2 Hz, 2H), 7.70 (d, J=7.7 Hz, 2H), 7.57 (dd, J=8.2, 7.7 Hz, 2H). HPLC (method B) tR 9.83 min (100.00 area %). Anal. (C17H8Br2O3) C, H, Br.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:1](=[NH:2])[NH:11][OH:12])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(Br)cc1
Reaction time: 7 h
Yield: 86.2 %

Procedure:
A mixture of 4-cyano-bromobenzene (0.5 g, 2.75 mmol), HCl×NH2OH (0.476 g, 6.9 mmol) and Na2CO3 (0.731 g, 6.9 mmol) in a mixture of EtOH and H2O (25 ml: 5 ml) was stirred for 7 h at reflux. The solvent was evaporated to dryness and the residue was taken in EtOAc (100 ml) and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the product as colourless solid (0.51 g, 87%). 1H-NMR (DMSO-d6) 5.81 (broad s, 2H); 7.53 (d, 2H, J=6.66 Hz); 7.58 (d, 2H, J=6.54 Hz); 9.69 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][CH:13]([NH:17][C:18]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:24])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCO)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Methanesulfonyl chloride (0.097 mL, 1.25 mmol) was added dropwise to tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 30) (0.326 g, 1.14 mmol) and triethylamine (0.191 mL, 1.37 mmol) in DCM (15 mL) at 22° C. The resulting solution was stirred at 22° C. for 2 hours. The mixture was concentrated and the residue was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (0.366 g, 88%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[S:17][C:18]([CH:21]=[CH:22][N+:23]([O-])=O)=[CH:19][CH:20]=1.[CH2:26](N)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:23]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:21]([C:18]2[S:17][C:16]([Cl:15])=[CH:20][CH:19]=2)=[CH:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)s1
Reactant: NCc1ccccc1
Product: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)s1

Procedure:
The title compound (82.3 mg) was prepared from 0.56 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL of benzylamine, and 0.53 g of 2-chloro-5-(2-nitro-vinyl)-thiophene. MS (ESI): exact mass calculated for C18H17ClN2S, 328.08; found, m/z 329.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.33 (m, 2H), 7.30-7.27 (m, 1H), 7.17-7.15 (m, 2H), 7.12 (s, 1H), 6.89 (d, J=3.8 Hz, 1H), 6.73 (d, J=3.8 Hz, 1H), 5.12 (s, 2H), 4.31 (s, 2H), 3.48 (t, J=6.3 Hz, 2H), 2.84 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14]CC)=O)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[OH-].[K+].[C:29]1(=[O:35])[O:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[OH:14][C:12]1[C:11]2[C:10](=[N:20][CH:19]=[CH:18][CH:17]=2)[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:33](=[O:34])[C:32]=1[CH2:31][CH2:30][CH2:29][OH:35]
Reactant: CCOC(=O)c1cccnc1Nc1ccc(OC)cc1
Reactant: O=C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(-n2c(=O)c(CCCO)c(O)c3cccnc32)cc1
Temperature: 100 °C

Procedure:
A mixture of delta-valerolactone (120 ml.), ethyl 2-(4-methoxyphenylamino)nicotinate (12 g.) and potassium t-butoxide (24 g.) was stirred and heated in an atmosphere of nitrogen to 100° C. for 2 hrs. After cooling, the mixture was poured into 1000 ml. of 5% KOH solution and stirred overnight. The aqueous solution was extracted with ether (2×250 ml.) which was discarded. The aqueous solution was then acidified to pH 4.5 with conc. HCl. The product was filtered off, washed with water, dried in air and recrystallized from CHCl3 /isopropanol to yield the desired product, m.p. 229°-231° C.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:10][C:9]2([CH3:30])[CH3:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:32]1[O:37][CH2:36][C:35]2([CH2:42][O:41][P:40](Cl)[O:39][CH2:38]2)[CH2:34][O:33]1>>[CH:1]1([O:7][N:8]2[C:9]([CH3:29])([CH3:30])[CH2:10][CH:11]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[P:32]3[O:37][CH2:36][C:35]4([CH2:42][O:41][P:40]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:11]5[CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]6)[C:9]([CH3:29])([CH3:30])[CH2:10]5)[O:39][CH2:38]4)[CH2:34][O:33]3)[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Reactant: CCCCCCCCCCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Product: CCCCCCCCCCCCN(C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1)P1OCC2(CO1)COP(N(CCCCCCCCCCCC)C1CC(C)(C)N(OC3CCCCC3)C(C)(C)C1)OC2

Procedure:
The title compound is prepared as a viscous oil from 1-cyclohexyloxy-4-dodecylamino-2,2,6,6-tetramethylpiperidine (made in Example 12A) and 3,9-dichloro-2,4,8,10-tetraoxa-3, 9-diphosphaspiro-[5.5]undecane according to the procedure of Example 14.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:36])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)N1CCOCC1
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCNC(=O)N1CCOCC1
Yield: 69.3 %

Procedure:
Using the general method of Example 150, 1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 5.32 mmol) was reacted with 4-morpholinecarbonyl chloride (880 mg, 5.86 mmol) to provide 1.8 g of N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a light yellow crystalline solid, m.p. 198.8-199.9° C. Analysis: Calculated for C27H32N6O3%C, 66.37; %H, 6.60; %N, 17.20; Found: %C, 66.31; %H, 6.70; %N, 17.40.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: CO
Product: COC(=O)[C@@H]1CC(O)CN1
Product: Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 33.0 g (0.25 mol) of 4-hydroxy-(L)-proline and 200 mL of MeOH was added 20 mL (0.27 mol) of thionyl chloride. The reaction was warmed to reflux for 16 h and then cooled to rt and concentrated in vacuo. Trituration with Et2O afforded 44 g (97%) of 4-hydroxy-(L)-proline, methyl ester hydrochloride as a white solid which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][N:49]1[CH:53]=[CH:52][N:51]=[C:50]1[C:54](O)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:50]2[N:49]([CH3:48])[CH:53]=[CH:52][N:51]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1ccnc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 1-methyl-1H-imidazole-2-carboxylic acid as starting materials in 70% yield. LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.