Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:17])[C:10]([C:14]([OH:16])=[O:15])=CNC=2)=[CH:4][CH:3]=1.F[C:19]1C=CC(CC(Cl)=O)=C[CH:20]=1.CC1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:17])[CH2:10][C:14]([O:16][CH2:19][CH3:20])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(=O)Cc1ccc(F)cc1

Procedure:
The intermediate, 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (8) can be obtained using the chemistry described in Scheme 2. Thus, 2-(4-fluorophenyl)acetyl chloride (10) can be treated with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) in the presence of pyridine and the resulting adduct can be refluxed in ethanol to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (12). Treatment of intermediate 12 with triazine and sodium ethoxide in ethanol can furnish the requisite ester intermediate, which can be readily hydrolyzed in the presence of sodium hydroxide at elevated temperature to furnish intermediate 8.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:47])=[CH:43][C:44]=2[F:46])[N:39]=[C:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[C:37]=1[CH3:54].[NH2:55][C:56]1[CH:57]=[C:58]([NH:68][C:69](=[O:71])[CH3:70])[CH:59]=[C:60]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[CH:61]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:46][C:44]1[CH:43]=[C:42]([F:47])[CH:41]=[C:40]2[C:45]=1[C:36]([NH:55][C:56]1[CH:57]=[C:58]([NH:68][C:69](=[O:71])[CH3:70])[CH:59]=[C:60]([N:62]3[CH2:67][CH2:66][O:65][CH2:64][CH2:63]3)[CH:61]=1)=[C:37]([CH3:54])[C:38]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)=[N:39]2
Reactant: CC(=O)Nc1cc(N)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X by stirring palladium (II) acetate (1.5 mg, 6.88 μmol), XPhos (9.9 mg, 0.021 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.040 g, 0.138 mmol), N-(3-amino-5-morpholinophenyl)acetamide (0.034 g, 0.144 mmol), potassium carbonate (0.048 g, 0.344 mmol), and tert-butanol at 110° C. for 2 h. Purification by reverse-phase HPLC (0-70% acetonitrile in water) afforded N-(3-((5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)phenyl)acetamide as a yellow amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.69 (1H, dq, J=4.8, 1.0 Hz), 7.80-7.95 (3H, m), 7.59 (1H, ddt, J=9.6, 2.2, 1.0, 1.0 Hz), 7.37-7.44 (1H, m), 7.12-7.22 (2H, m), 7.01 (1H, ddd, J=13.8, 8.5, 2.5 Hz), 6.31-6.36 (1H, m), 6.23 (1H, t, J=2.2 Hz), 3.81-3.87 (4H, m), 3.15-3.22 (4H, m), 2.12 (3H, s), 2.10 (3H, s). Mass Spectrum (ESI) m/e=490.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]=3[C:3]=1[CH2:17][C:18]([OH:20])=[O:19].S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[CH3:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]=3[C:3]=1[CH2:17][C:18]([O:20][CH2:26][CH3:27])=[O:19]
Reactant: Cc1c(CC(=O)O)c2cc([N+](=O)[O-])cc3c2n1CCC3
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(C)n2c3c(cc([N+](=O)[O-])cc13)CCC2

Procedure:
44.5 g of 5,6-dihydro-2-methyl-8-nitro-4H-pyrrolo[3,2,1-ij]quinoline-1-acetic acid (preparation see Example 20 A) were heated under reflux for 1 hour in 450 ml of ethanol after addition of 8.63 ml of sulfuric acid. To work up the reaction mixture the ethanol was removed by evaporation, the residue was taken up in a mixture of water and dichloromethane, and the organic phase was separated, washed with water until neutral, dried and evaporated. Some diethyl ether was added to the oily crude product which remained as a residue, and the resulting precipitate was filtered out. 32.4 g of ethyl 5,6-dihydro-2-methyl-8-nitro-4H-pyrrolo[3,2,1-ij]quinoline-1-acetate were obtained as a greenish-ochre-colored powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH:7]([C:9]#[N:10])[C:6]=2[CH:11]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.COC(C)(C)C.C(O)(=O)C>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH:7]([C:9]#[N:10])[C:6]=2[CH:11]=1
Reactant: COC(C=O)OC
Reactant: N#CC1Cc2ccc(N)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(CNc1ccc2c(c1)C(C#N)C2)OC
Temperature: 29 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 13.5 g of 5-aminobenzocyclobutane-1-carbonitrile in 400 ml of 1,2-dichloroethane there are added rapidly dropwise 26.5 ml of a 45% solution of 2,2-dimethoxyacetaldehyde in tert-butyl methyl ether, followed by 16 ml of acetic acid and then, in portions, 39.7 g of sodium triacetoxyborohydride. After increasing the temperature to 29° C., the reaction mixture is brought to ambient temperature, stirred for 1 hour 15 minutes and then hydrolysed by pouring the mixture into 500 ml of a saturated aqueous solution of NaHCO3. The organic phase is removed, washed with water, and concentrated under reduced pressure to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=1)=[O:4].[CH2:18]([NH2:21])[C:19]#[CH:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[F:16][C:2]([F:1])([F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](=[O:15])[NH:21][CH2:18][C:19]#[CH:20])[CH:7]=1)=[O:4]
Reactant: C#CCN
Reactant: O=C(O)Cc1cccc(NC(=O)C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C#CCNC(=O)Cc1cccc(NC(=O)C(F)(F)F)c1
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To the mixture of 2-(3-(2,2,2-trifluoroacetamido)phenyl)acetic acid (2.96 g, 12 mmol), propargylamine (0.97 ml, 15 mmol), HATU (4.5 g, 12 mmol) in acetonitrile (50 ml), added DIPEA (5.2 ml, 30 mmol) slowly. Stirring was kept 2 hours at room temperature. Removed solvent, extracted with EtOAc, washed with 1N HCl, water and brine, dried over sodium sulfate. Concentrated to get 1.42 g 2,2,2-trifluoro-N-(3-(2-oxo-2-(prop-2-ynylamino)ethyl)phenyl)acetamide as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:31]1[C:40]2[CH2:39][CH2:38][N:37]=[CH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:37]5[CH2:38][CH2:39][C:40]6[N:31]=[CH:32][CH:33]=[CH:34][C:35]=6[CH2:36]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Reactant: C1=NCCc2ncccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4ncccc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 7,8-dihydro-[1,6]naphthyridine following a procedure analogous to that described for Intermediate 42. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:10]=2[C:11]([O:13]CC2C=CC(C(F)(F)F)=CC=2)=[O:12])=[CH:5][CH:4]=1.C(OC1C=CC(C=O)=CC=1C(O)=O)C1C=CC=CC=1>>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:10]=2[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)c(C(=O)OCc2ccc(C(F)(F)F)cc2)c1
Agent: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Product: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)c(C(=O)O)c1

Procedure:
2-(4-Trifluoromethylbenzyloxy)-5-formylbenzoic acid was prepared from 4-trifluoromethylbenzyl 2-(4-trifluoromethylbenzyloxy)-5-formylbenzoate (1.41 g, 1 eq) using the same procedure as for 2-benzyloxy-5-formylbenzoic acid. The product was obtained as a white powder (764 mg, 67%). 1H NMR (CDCl3) δ9.97 (s, 1H, O═C—H), 5.41 (s, 2H, CH2Ar).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:53])[C@@H:14]([NH:39][S:40]([C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH2:15][NH:16][C:17]1[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1)(C)(C)C>C(Cl)Cl>[CH3:23][C:21]1[N:22]=[C:17]([NH:16][CH2:15][C@H:14]([NH:39][S:40]([C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:42])[C:13]([OH:53])=[O:12])[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=1
Reactant: Cc1nc(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 ml of TFA were added to a solution of 75 mg of (2S)-3-(2-methyl-7-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(naphthalene-1-sulfonylamino)-propionic acid tert-butyl ester (example 3c) in 5 ml of DCM and stirred for 2 h at room temperature. Solvent and TFA were removed in vacuo, the residue was lyophilized from AcOH/H2O (1:1). Yield: 84 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][C:48]([N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)=[CH:49][N:50]=2)[N:45]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:14])([CH3:13])[C:10]([N:57]1[CH2:58][CH2:59][N:54]([C:48]2[CH:49]=[N:50][C:51]3[C:46]([CH:47]=2)=[N:45][C:44]([Cl:43])=[CH:53][CH:52]=3)[CH2:55][CH2:56]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Clc1ccc2ncc(N3CCNCC3)cc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a stirred mixture of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (180 mg, 0.89 mmol, 1.5 eq), triethylamine (209 mg, 2.07 mmol, 3.5 eq) and HOBt (120 mg, 0.89 mmol, 1.5 eq) in anhydrous CH2Cl2 (10 mL), EDCI (170 mg, 0.89 mmol, 1.5 eq) was added. The resulting mixture was stirred at RT for 30 min, and then 2-chloro-7-(piperazin-1-yl)-1,5-naphthyridine (D-19) (0.59 mmol, 1.0 eq) was added. The reaction mixture was stirred at RT for 20 h, and then quenched with water (30 mL) and CH2Cl2 (15 mL), and the organic layer was separated. The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (2% MeOH—CH2Cl2) to afford the desired product, tert-butyl(1-(4-(6-chloro-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (D-20) (193 mg, 75.4% yield, 2 steps). ESI-MS m/z: 434.18[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13]C)=[O:12])[CH2:8][CH2:7][N:6]1[C:15]([O:17][CH3:18])=[O:16].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)ccc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cc(F)ccc1F
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of dimethyl 2-(2,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.08 g, 24.69 mmol) in acetonitrile (85 mL) and water (1.7 mL) was added lithium bromide (4.95 mL, 197.48 mmol) and triethylamine (13.69 mL, 98.74 mmol). The reaction mixture was heated to reflux for 2.5 h, then allowed to cool to room temperature. Water (150 mL) and MTBE (300 mL) was added. The aqueous phase was separated and the organic phase was extracted twice with water. The water phases were combined and 4.0 M HCl was added until a pH of 1 was obtained. The aqueous was extracted with MTBE (300 mL×2). The organic phases were combined, washed with brine, dried with Na2SO4 and evaporated under reduced pressure to give 2-(2,5-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.4 g, 96%). MS m/z 314 (M+H)+
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([OH:15])[C:13]#[CH:14].CCOC(C)=O>CN(C=O)C.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.[Cu]I>[OH:15][CH2:12][C:13]#[C:14][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1I
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C#CCO
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Methyl 2-iodobenzoate (25 g, 95 mmol), prop-2-yn-1-ol (8.02 g, 143 mmol) and TEA (26.6 ml, 191 mmol) were added to a deareated mixture of Pd(PPh3)4 (0.220 g, 0.191 mmol), copper(I) iodide (0.073 g, 0.382 mmol) in DMF (60 ml). The resulting mixture was stirred at 90° C. for 5 hrs and then at 40° C. overnight. The reaction mixture was poured into EtOAc (600 ml) and washed with brine (600 ml). Organic phase was then concentrated and the dark oil was rinsed with Et2O (600 ml). The mixture was filtered, and then concentrated to give the title compound as deeply brown oil (13.0 g). This compound was used in the next step without any further purification and characterization.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[NH2:28][OH:29]>CO>[CH3:21][C:17]1([CH3:22])[C:18]2[C:13](=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][C:4]([C:3]([NH:28][OH:29])=[O:2])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:14]([CH3:24])([CH3:23])[CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: NO
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccc(C(=O)NO)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-terephthalamic acid methyl ester 7 (0.20 g, 0.55 mmol) in MeOH (2 mL) was added an hydroxylamine solution (1.76 M, 2 mL) in MeOH and the reaction mixture was stirred 1 h at room temperature under magnetic stirring. The reaction mixture was adjusted to pH=5, concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was dried with Na2SO4 and the product was crystallized by dissolving the mixture at 80° C. in CH3CN to give N-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)-N′-hydroxyterephthalamide EHT 7706 (0.05 g, 25% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:18])[N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:19](Br)[C:20]#[CH:21]>>[CH3:18][C:13]1[N:14]([CH2:15][CH2:16][O:17][CH2:21][C:20]#[CH:19])[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1
Reactant: C#CCBr
Reactant: Cc1nc2c(N)nc3c(c2n1CCO)CCCC3
Product: C#CCOCCn1c(C)nc2c(N)nc3c(c21)CCCC3
Yield: 47.7 %

Procedure:
Using the general method of Example 1 Part A, 2-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.763 g, 3.098 mmol) was reacted with propargyl bromide (80% in toluene, 1.1 mL, 9.29 mmol) to provide 0.42 g of 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@@H:10]2[CH2:15][O:14][C:12](=[O:13])[CH2:11]2)[CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.[H-].[Na+].CO.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@@H:10]2[CH2:15][O:14][C:12](=[O:13])/[C:11]/2=[CH:24]/[C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:8]=1
Reactant: COc1cc(C[C@@H]2COC(=O)C2)cc2c1OCO2
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(/C=C2/C(=O)OC[C@H]2Cc2cc(OC)c3c(c2)OCO3)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 48 h
Yield: 47.6 %

Procedure:
A solution of (S)-3-[1-(5-methoxy-3,4-methylenedioxyphenyl)methyl]butanolide (25.0 g, 0.1 mol) and 3,4,5-trimethoxybenzaldehyde (31.0 g, 0.16 mol) in 400 ml of toluene was cooled to 0° C. under an argon stream, followed by the addition of 10.8 g of sodium hydride (60%, 0.27 mol) and 0.4 ml (0.01 mol) of methanol. After stirred at 0° C. for 15 minutes and further at room temperature for 48 hours, the reaction mixture was ice-cooled and added with 100 ml of 6N-HCl. After the removal of the water layer, the organic layer was washed successively with water, saturated NaHCO3 and saturated NaCl, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography (silica gel: "MERCK #9385", 500 g, eluent: 1:2 mixed solvent of ethyl acetate and hexane), whereby 20.38 g of the title compound were obtained as colorless oil (yield: 48%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])C)C=[CH:6][CH:7]=1.NC1C=C(C([O:31]C)=S)SC=1C.C(OC1C=C(C=CC=1)C=O)(=O)C>>[OH:31][C:3]1[CH:4]=[C:8]([CH2:9][NH:11][C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])[CH:6]=[CH:7][CH:2]=1
Reactant: COC(=S)c1cc(NC(C)Cc2cccc(O)c2)c(C)s1
Reactant: COC(=S)c1cc(N)c(C)s1
Agent: CC(=O)Oc1cccc(C=O)c1
Product: COC(=S)c1cc(NCc2cccc(O)c2)c(C)s1

Procedure:
Methyl 4-{[(3-hydroxyphenyl)methylethyl]amino}-5-methylthiothiophene-2-carboxylate: Using the procedure described in Example 220, step (a), 61.6 mg (0.30 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.5 mg (0.30 mmol) of 3-acetoxybenzaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAc)3 were allowed to react to give methyl 4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C14H16NO3S2, 352.07 (M+H), found, 350.2 (imine), 352.1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:5]C1CCCCO1)[CH3:4].[H-].[Na+].CN(C)C=O.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:1][CH2:2][C@@H:3]([OH:5])[CH3:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](CO)OC1CCCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@H](O)COCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
(S)-1-hydroxy-2-tetrahydropyranyloxypropane (120 g, 0.75 mol) prepared according to the method of C. Malanga et al, Synthetic Communications, 12,(1), 67-70 (1982)) was dropwise added to sodium hydride (44.8 g, 1.87 mol) in tetrahydrofuran (400 ml) (hereinafter abbreviated to THF), followed by adding dimethylformamide (hereinafter abbreviated to DMF) (200 ml), agitating the mixture for 2 hours, dropwise adding benzyl bromide (140.8 g, 0.82 mol) at 30° C. or lower, agitating the mixture at room temperature for 6 hours, adding toluene, sufficiently agitating the mixture, washing the resulting organic layer with 2N-NaOH aqueous solution and then with water, drying it over anhydrous magnesium sulfate, distilling off toluene, adding to the resulting oily residue, (S)-1-benzyloxy-2-tetrahydropyranyloxypropane, pyridium p-toluenesulfonate (18 g) and ethanol (500 ml), heating the mixture to 70° C. for one hour, distilling off ethanol, adding toluene to the residue, sufficiently washing it with water, distilling off toluene, and distilling the residue to obtain (S)-1-benzyloxy-2-hydroxypropane (98 g)(b.p. 94.0° C./2.5 mmHg). A mixture of this (S)-1-benzyloxy-2-hydroxypropane (60 g, 0.36 mol) with anhydrous pyridine (300 g) was cooled with ice, followed by dropwise adding a solution of p-toluenesulfonyl chloride (75.8 g, 0.20 mol) in pyridine (70 ml) at 0° C., agitating the mixture at room temperature for 3 hours, adding toluene (800 ml), agitating the mixture, several times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate and distilling off toluene to obtain (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (115.2 g). On the other hand, a solution of 4-hydroxy-4'-octyloxybiphenyl (50 g, 0.17 mol) in THF (200 ml) was dropwise added to a mixture of sodium hydride (8.5 g, 0.35 mol) with THF (100 ml), followed by dropwise adding a solution of the above (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (64.5 g)(0.20 mol) in DMF (100 ml), agitating the mixture at 60° C. for 4 hours, allowing the mixture to cool down, adding toluene, agitating the mixture, washing with 6N-HCl, then with 2N-NaOH and further with water, drying over anhydrous magnesium sulfate, distilling off toluene, dissolving the residue in a mixture of ethanol (250 ml) with ethyl acetate (250 ml), adding Pd/C catalyst (10 g), agitating the mixture in hydrogen gas, filtering off the Pd/C, distilling off the solvent, and recrystallizing the residue from heptane (150 ml), to obtain (R)-4-(2'-hydroxy-1'-methyl)ethyloxy-4'-octyloxybiphenyl (m.p. 107.9° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH3:13])=[C:9](OC)[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[CH3:18][NH:19][CH3:20]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH3:13])=[C:9]([N:19]([CH3:20])[CH3:18])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: COc1c(C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: CNC
Solvent: O
Product: Cc1c(N(C)C)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: -78 °C

Procedure:
8-Chloro-3-methoxy-4-methyl-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.4 g) was treated with 100 mL of liquid dimethylamine chilled to -78° C. The mixture was sealed in a pressure vessel and warmed to 26° C. for 72 hours. The excess dimethylamine was evaporated to give an oil which was dissolved in water and extracted with ethyl acetate. The organic extracts were combined and concentrated to a brown oil. The oil was crystallized using ether to give a yellow solid. The solid was purified by chromatography, with ethyl acetate:hexane (1:1) as the eluent, to give the title compound; NMR: 2.95 (s,6), 2.28 (s,3); MS: m/z=265(M+1).