Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH2:10]([CH:12]1[O:17][C:16]2[CH:18]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:20]=[CH:21][C:15]=2[NH:14][CH2:13]1)[CH3:11].Br[C:32]1[CH:33]=[N:34][C:35]([N:38]2[CH2:42][CH2:41][CH:40]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]2)=[N:36][CH:37]=1>O.O1CCOCC1>[CH2:10]([CH:12]1[O:17][C:16]2[CH:18]=[C:19]([C:32]3[CH:33]=[N:34][C:35]([N:38]4[CH2:42][CH2:41][CH:40]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]4)=[N:36][CH:37]=3)[CH:20]=[CH:21][C:15]=2[NH:14][CH2:13]1)[CH3:11]
Reactant: CC(C)(C)OC(=O)CC1CCN(c2ncc(Br)cn2)C1
Reactant: CCC1CNc2ccc(B3OC(C)(C)C(C)(C)O3)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCC1CNc2ccc(-c3cnc(N4CCC(CC(=O)OC(C)(C)C)C4)nc3)cc2O1
Reaction time: 12 h
Yield: 60 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20.4 mg, 0.025 mmol), potassium carbonate (174.7 mg, 1.258 mmol), 2-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (prepared according to the procedure indicated in Scheme A1, 160.0 mg, 0.553 mmol) and tert-butyl 2-(1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)acetate B-6 (172.1 mg, 0.503 mmol) were mixed in a 4:1 dioxane:water mixture (5.55 mL) at room temperature. The reaction mixture was degassed several times under reduced pressure and stirred for 12 h under an atmosphere of argon. The mixture was then filtered through a celite pad, washed with ethyl acetate (30 mL) and concentrated to dryness under reduced pressure. The residue was adsorbed on silica (1.0 g) and purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give tert-butyl 2-(1-(5-(2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidin-3-yl)acetate B-7 as a light yellow oil (140.0 mg; Yield=60%). MS (ESI) [M+1]+ 425.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.O>S(=O)(=O)(O)O>[N+:1]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:5])[CH:15]=[CH:14]2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Nitric acid (70%), 2.3 mL, was added dropwise to a stirred mixture of 2-hydroxyquinoline (available commercially or by one of the methods described in Beilstein 21, 77) 3.5 g (0.024 mole), in 20 mL of concentrated sulfuric acid at 0° C. The reaction mixture was stirred for 2 hours at room temperature and then poured into ice and water. The resulting solid was collected by filtration, washed with cold water and then digested twice with hot methanol to yield 3 g (67%) of 6-nitrocarbostyril as crystals; m.p. 280°-282° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc([C@H]2CNCCO2)cc1
Yield: 95.8 %

Procedure:
A suspension of (2S)-2-(4-fluorophenyl)-4-(benzyl)morpholine (250 mg) and 5% Pd—C (0.106 g) in ethanol (5 mL) was treated with hydrogen for 1 hr at 33-35° C. The suspension was filtered through celite and washed with ethanol. The solvent was evaporated to give (2S)-2-(4-fluorophenyl)morpholine (160 mg, 94%) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl.C(OCC)C>[C:18]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: CC(C)Oc1ccccc1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-isopropoxyphenol (1.53 g, 10 mmol) in CH2Cl2 at 0° C., was added pyridine (1.76 mL, 22 mmol) followed by acetyl chloride (0.79 mL, 1.1 eq). The mixture was stirred at 0° C. for 1.0 h, diluted with diethyl ether, washed with 5% citric acid and brine. The organic extract was dried over Na2SO4, evaporated to give 2-isopropoxyphenyl acetate as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH:9]1[CH:14]=[CH:13][C:12]([P-:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[K+]>C1COCC1>[C:16]1([P:15]([C:12]2[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=2)[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 140 mg (0.15 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 1.27 g (10.0 mmol) of 4-chlorotoluene, and 10.0 mmol of KPPh2 in 30.0 mL of THF. The resulting mixture was refluxed for 17 h before the reaction was cooled to room temperature, quenched with with 20 mL of H2O. The phosphorus-31 NMR spectrum of the reaction mixture at this point showed the δ32.1 [˜10%, Ph2PH(O)] and −5.0 (˜90%, MeC6H4-PPh2) resonances.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)=[O:27]>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[O:27])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: O=C(O)c1ccccn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccccn1
Yield: 39.9 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and pyridine-2-carboxylic acid (41 mg, 0.33 mmol) as starting materials. The title compound (50 mg, 36.2%) was isolated as off white solid; MS (ESI): 380 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Si:8]([O:15][CH2:16][CH:17]=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH2:19](Cl)Cl>S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:11]([CH3:14])([Si:8]([CH3:10])([CH3:9])[O:15][CH2:16][CH2:17]/[CH:19]=[N:7]/[S+:5]([O-:6])[C:2]([CH3:4])([CH3:3])[CH3:1])[CH3:13]
Reactant: ClCCl
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: CC(C)(C)[S+]([O-])/N=C/CCO[Si](C)(C)C(C)(C)C

Procedure:
A three necked round bottom flask fitted with a mechanical stirrer, nitrogen inlet and temperature probe was charged with (S)-(−)-2-methyl-2-propanesulfinamide (113 g, 0.929 mol) and DCM (2.0 L) at room temperature (endotherm to 9° C.). Copper(II) sulfate (309 g, 1.94 mol) was then added followed by (tert-butyldimethylsilyl-oxy)acetaldehyde (150 g, 0.774 mol). After 36 hours the reaction mixture was filtered through a plug of Celite, the plug rinsed with DCM (3×200 mL), and the filtrate concentrated to provide the title compound as a light yellow syrup. The crude product was carried forward into the next step without further purification. 1H NMR (CDCl3) δ 8.08 (1H, s), 4.56 (2H, s), 1.22 (9H, s), 0.95 (9H, s), 0.12 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](NC2N=CN=C(NC(C3CC3)=O)C=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.FC1C=C(C=CC=1)C=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](=[O:21])[N:4]2[CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[NH:23][C:24](=[O:25])[C:3]=12
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: O=Cc1cccc(F)c1
Solvent: CC#N
Product: O=C1NC(c2cccc(F)c2)n2c1c(Cl)ccc2=O
Temperature: 85 °C

Procedure:
To a suspension of 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.5 g, 1.99 mmol) in acetonitrile (15 mL), 3-fluorobenzaldehyde (0.86 g, 6.96 mmol) and ferric chloride (2.25 g, 13.92 mmol) were added in a vial. The vial was sealed and heated the reaction mass to 85° C. for 16 h. After completion, the reaction mass was cooled to room temperature, filtered through celite bed, washed with 5% methanol in dichloromethane followed by concentration to get crude. The crude was then purified by column chromatography eluting with 5% methanol in dichloromethane to afford 8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione as white solid. Yield: 0.45 g, 63%; MS (ESI) m/z 256.17 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](NCC)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH3:35][O:36]C1N=C(C(O)=O)C=C(C)N=1>>[CH3:35][O:36][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: COc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Product: COc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-Methoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-methoxy-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimioyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.84 min; [M+H]+=444.19.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[CH3:17][N:18]([CH3:19])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccccc1Oc1ccccc1

Procedure:
A solution of 7.7 parts of 2-phenoxybenzoyl chloride in 50 parts of methylene chloride was added slowly to a cold (0°) vigorously stirred mixture of 50 parts of methylene chloride and 40 parts of 25% aqueous dimethyl amine. After 8 hours the methylene chloride layer was separated. The organic layer was washed with water and dried over magnesium sulfate. Removal of the magnesium sulfate by filtration and the methylene chloride under vacuum gave 5.1 parts of N,N dimethyl-2-phenoxybenzamide as a viscous oil. NMR (CDCl3) 2.9δ(S,3H,N--CH3), 3δ(S,3H,N--CH3), 7.2δ(m,9H,Aromatic H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([N:17]1[CH:21]=NC=N1)(N1C=NC=N1)=[S:11].NC1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[N:33]=[N:34][S:35][CH:36]=2)=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[S:11])[NH:17][C:21]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[N:33]=[N:34][S:35][CH:36]=3)=[O:31])=[CH:25][CH:24]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1ccc(NC(=O)c2csnn2)cc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: S=C(n1cncn1)n1cncn1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(NC(=S)Nc2cc(Cl)cc(Cl)c2)cc1)c1csnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is added freshly prepared 1,1′-thiocarbonyl-di-(1,2,4)-triazole (0.20 g) and the mixture is stirred for approximately 30 minutes at room temperature. [1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask and the mixture is stirred for approximately 6 hours. The solvent is then removed by evaporation under reduced pressure and warm acetonitrile (3 mL) is added. After 15 hours the mixture is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, and air dried to provide the desired product as a white powder. [M+H]424.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O-:16])=[O:15])=[C:12](C)[CH:11]=1.[CH3:20][Si](C)(C)N[Si](C)(C)C>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[O:8]=[C:3]1[N:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:20])=[O:15])=[CH:12][CH:11]=2)[CH2:6][O:1][NH:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cc1cc(N)ccc1C(=O)[O-]
Reactant: O=C1CONC(=O)N1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC2=NC(=O)NOC2)cc1
Yield: 63 %

Procedure:
A solution of 1.16 g (0.010 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 5 mg ammonium sulfate, 1.80 g (0.012 mole) of p-amino-methylbenzoate and 20 ml hexamethyldisilazane in 40 ml freshly distilled dry dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 1.56 g (63 percent) of 4-((3,6-dihydro-3-oxo-2H-1,2,4-oxadiazin-5-yl)amino)benzoic acid, methyl ester.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[CH3:28][NH2:29]>CO>[C:21]1([S:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[C:8]([CH2:7][NH:6][CH2:5][C:4]([NH:29][CH3:28])=[O:3])=[CH:9][CH:10]=[CH:11]3)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN
Reactant: CCOC(=O)CNCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Solvent: CO
Product: CNC(=O)CNCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
[(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-acetic acid ethyl ester is added to methylamine in methanol, and the solution is stirred at room temperature, then concentrated under reduced pressure. The oil is dissolved in ethanol and 1N HCl in diethyl ether is added to precipitate 2-[(6-benzenesulfonyl-naphthalen-1-ylmethyl)-amino]-N-methyl-acetamide as a hydrochloride salt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[O:10])=[O:7].[C:11]([CH:13]1[CH2:15][NH:14]1)#[N:12]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]([N:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[O:10])=[O:7]
Reactant: N#CC1CN1
Reactant: O=C=NC(=O)c1cccs1
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)c1cccs1
Reaction time: 1 h

Procedure:
2.76 g. Thiophene-2-carbonyl isocyanate are dissolved in 45 ml. anhydrous toluene and mixed dropwise, while stirring, at 20° to 30° C. with a solution of 1.22 g. 2-cyanoaziridine in 30 ml. toluene. Stirring is continued for 1 hour at ambient temperature and the precipitate obtained is filtered off with suction, washed with toluene and subsequently triturated with diethyl ether. There are thus obtained 3.4 g. 1-(N-2-thiophene-carbonyl-carbamoyl)-2-cyanoaziridine; m.p. 156°-160° C., which still contains a little thiophene-2-carboxylic acid amide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[OH:5].C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.C(C1C=CC=CN=1)(=O)C>>[CH3:1][NH:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[OH:5]
Reactant: CNC[C@@H](O)c1ccccn1
Agent: CC(=O)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Product: CNC[C@H](O)c1ccccn1

Procedure:
As described for the preparation of (1R)-2-(methylamino)-1-pyridin-2-ylethanol (Preparations 65-69), using (1S,2S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine in place of (1R,2R)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine, 2-acetylpyridine was converted to the title compound, isolated as an amber oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30]Cl)=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[O:40]([NH2:42])[CH3:41]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30][NH:42][O:40][CH3:41])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc(CCl)n2CC1CCOCC1
Reactant: CON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 50 °C
Reaction time: 40 h
Yield: 36.1 %

Procedure:
7-(Benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.3 g, 5.26 mmol) and triethylamine (1.6 g, 15.78 mmol) were added to a solution of methoxylamine hydrochloride (0.88 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (11 mL). The reaction was heated with stirring for 40 hours at 50° C., allowed to cool to ambient temperature, and partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with another portion of dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using a HORIZON HPFC system equipped with a FLASH 40+M silica cartridge eluting with dichloromethane:methanol in a gradient from 100:0 to 90:10. The resulting product (1.0 g) was recrystallized from acetonitrile, and the crystals were isolated by filtration, washed with acetonitrile, and dried overnight in a vacuum oven at 65° C. to provide 0.85 g of 7-(benzyloxy)-2-[(methoxyamino)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow, crystalline solid, mp 190-193° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23]COC)=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[C:13](/[CH3:20])=[CH:14]/[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[K+].O.Cl>C(O)C.O1CCCC1>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:23])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[C:13](/[CH3:20])=[CH:14]/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cccc2c(/C(C)=C/C(=O)O)cc(OC)c(O)c12
Yield: 74.6 %

Procedure:
470 mg of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoate was dissolved in 5 ml of ethanol and 5 ml of tetrahydrofuran, to which 350 mg of potassium hydroxide and 2 ml of water were added, followed by refluxing for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to obtain 280 mg of the titled compound as pale yellow crystals.
Reaction SMILES: [CH:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([NH:20][CH2:21][C:22]#[C:23][CH2:24]Cl)[CH3:19]>>[CH:12]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:11])[C:8]([O:10][CH2:24][C:23]#[C:22][CH2:21][NH:20][CH2:18][CH3:19])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Reactant: CCNCC#CCCl
Product: CCNCC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
by standard esterification technique, reacting cyclohexylphenyl glycolic acid with 4-ethylamino-2-butynyl chloride to produce 4-ethylamino-2-butynyl cyclohexylphenyl-glycolate (DEO).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[CH:17][C:16]=2[N+:30]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH3:23])=[CH:17][C:16]=2[NH2:30])=[CH:10][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Oc1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1)c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1)c1ccccc1
Yield: 31.9 %

Procedure:
A solution of the product from Example 216C (1.78 g, 3.80 mmol), iron powder (0.85 g, 15.3 mmol) and ammonium chloride (0.25 g, 4.57 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.53 g, 32%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12]([CH:15]([C:17]3C4C(C5C=CC=C[C:29]=5[CH:30]=3)=CC=CC=4)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[C:32](F)(F)[C:33](O)=O>C(Cl)Cl>[CH2:30]1[C:29]2[C:13]([C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:7]=2[CH:8]=[C:10]2[C:11]=3[C:33]3[CH:32]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]3[CH:2]=[CH:1][CH:14]=[CH:13][C:9]=32)=[CH:12][CH:15]=[CH:17]1
Reactant: OC(c1cc2ccccc2c2ccccc12)c1cc2ccccc2c2ccccc12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=CCc2c3c(c4ccccc4c2=C1)=c1c(c2ccccc2c2ccccc12)=C3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Di-phenanthen-9-yl-methanol (24.5 g, 63 mmol) was suspended in CH2Cl2 (100 ml). Trifluoroacetic acid (40 mL) was added dropwise under an atmosphere of nitrogen over a period of 10 minutes, forming a yellow suspension. This was stirred at room temperature under nitrogen for 20 minutes after which time excess solvent was removed in vacuo. The resulting yellow solid was suspended in CH2Cl2 (100 mL) and reconcentrated (5 times). The residue was then washed with diethyl ether to give 1H-tetrabenzo[a,c,g,i]fluorene as a bright yellow solid (16.4 g, 45 mmol, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2Cl)=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18].[OH-].[Na+]>CCO.Cl>[Cl:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH3:16])=[CH:20][CH:21]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:4][CH:3]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: Clc1coc2nc3ccccc3c(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1ccc(Nc2c3ccccc3nc3occ(Cl)c23)cc1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
To a solution of 3,4-dichlorofuro[2,3-b]quinoline (compound 12, 0.92 g, 3.86 mmol) and 4-aminoacetophenone (0.88 g, 6.52 mmol) in EtOH (40 mL), concentrated HCl was added until a pH of 6 was reached. The mixture was refluxed for 16 h and the solvent evaporated in vacuo to yield a residual solid, which was suspended in ice-water (80 mL) and neutralized with a 1N NaOH solution. The resultant precipitate was collected by filtration, washed with H2O, and then chromatographed on a column of silica gel using CH2Cl2—MeOH=10/1 to obtain the title compound 13 (0.99 g, 75% yield).