Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2OC(NC)=O)[CH2:3]1.C(OC1C=CC=CC=1[N+:28]([O-:30])=[O:29])C(=C)C>>[CH3:1][C:2]1([CH3:16])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([N+:28]([O-:30])=[O:29])[C:9]=2[O:10]1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: C=C(C)COc1ccccc1[N+](=O)[O-]
Product: CC1(C)Cc2cccc([N+](=O)[O-])c2O1

Procedure:
Carbofuran is a commercially available material. It is manufactured by the simultaneous thermal rearrangement and cyclization of 1-methallyloxy-2-nitrobenzene to form 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran, which is then reduced to the amine, then diazotized and converted to 2,3-dihydro-2,2-dimethylbenzofuran-7-ol, and then esterified with methyl isocyanate. In an alternative procedure, 2-methallyloxyphenol is thermally rearranged and cyclized to form 2,3-dihydro-2,2-dimethylbenzofuran-7-ol, which is then treated simultaneously with methyl isocyanate and triethylamine. The starting material 2-methallyloxyphenol can be prepared by reacting catechol with potassium carbonate and potassium iodide in dry acetone under a nitrogen atmosphere. Further particulars of each of these procedures will be readily apparent to those skilled in the art.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([OH:17])=[O:16].[C:24](O)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([O:17][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:16]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Benzenesulfonyl chloride (12.8 mL, 100 mmol) was added rapidly to a solution of 3-methyl-4-nitrobenzoic acid (9.06 g, 50 mmole) in dry pyridine (25 mL) at 40° C. The reaction was mildly exothermic. The cloudy, orange solution was stirred for 5 min, then t-butanol (4.7 mL, 50 mmole, 1 eq.) was added. After 1 h, the reddish-orange mixture was poured into ice/water (200 mL), and the resulting mixture was stirred briskly for 1 h. The solid was collected by suction filtration, washed with H2O, and dissolved in toluene (200 mL). The solution was dried (MgSO4) and filtered through a pad of silica gel eluting with toluene. Concentration gave the title compound as a yellow oil which crystallized under vacuum (9.67 g, 82%). TLC Rf 0.65 (4:1 toluene:hexane); 1H NMR (250 MHz, CDCl3) δ 7.85-8.10 (m, 3H), 2.61 (s, 3H), 1.60 (s, 9H); IR (CCl4) 1724, 1531, 1372, 1308, 1295, 1164, 1120, 843 cm-1 ; MS(ES) m/e 260.0 [M+Na]+, 238.0 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH3:17][O:18][C:19](Cl)=[O:20]>CN(C=O)C>[CH3:17][O:18][C:19]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8])=[O:20]
Reactant: CNCCOCC(=O)O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N(C)CCOCC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
[2-(Methylamino)ethoxy]acetic acid (Bull. Soc. Chim.; 1956, 1210) (130 mg, 0.98 mmol) was mixed with triethylamine (0.56 mL, 4 mmol) in dry DMF (2 mL). Methylchloroformate (185 mg, 1.95 mmol) was added and the mixture was stirred at room temperature for 20 minutes, then quenched with water. Aqueous HCl (2M) was added to adjust the pH to ˜2. Product was extracted with ethyl acetate, the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as an oil (100 mg), which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:42]1[CH:47]=[CH:46][C:45]([CH:48]=[CH:49][C:50](=[NH:52])[NH2:51])=[CH:44][CH:43]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:42]2[CH:47]=[CH:46][C:45]([CH:48]=[CH:49][C:50](=[NH:51])[NH2:52])=[CH:44][CH:43]=2)=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)C=Cc1ccc(OC(=O)[C@H]2CC[C@H](CNC(=O)OCc3ccccc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 5.0 g of trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylic acid in 50 ml of dried pyridine, while being cooled in ice, was added 4.2 g of DCC. After 30 minutes of stirring, to the mixture was added 4.4 g of 4-(β-amidinoethenyl)phenol methanesulfonate. The mixture was stirred overnight at room temperature. The DCU precipitated from the reaction mixture was separated by filtration and washed with pyridine. Ethyl ether was added to the combined filtrate to precipitate a white substance which was collected by filtration, washed with ethyl ether, and recrystallized from ethanol to yield 5.7 g of colorless needle crystals of 4-(β-amidinoethenyl)pnenyl trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylate methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH3:12]S(C)=O.CI.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25 g (0.159 mol) of 5-fluoro-2-nitrophenol are added to 125 ml of DMSO. 22.5 g (0.159 mol) of methyl iodide are then added, followed by dropwise addition, while keeping the temperature below 25° C., of 17.8 g of aqueous 50% potassium hydroxide solution. The mixture is stirred for one hour at ambient temperature and a further 22.5 g (0.159 mol) of methyl iodide are then added. After stirring for 24 hours, the reaction medium is poured into 125 ml of water and then extracted with 60 ml of dichloromethane. The organic phase is washed with 90 ml of aqueous sodium hydroxide solution (1N) and then with 60 ml of water. After drying over MgSO4, the organic phase is concentrated under reduced pressure. 20.59 g (76%) of 4-fluoro-2-methoxy-1-nitrobenzene (1) are thus recovered.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[CH:18]=[CH:17][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[N:16]1[CH:17]=[CH:18][C:14]([C@H:10]2[CH2:11][CH2:12][CH2:13][C@@H:9]2[OH:8])=[N:15]1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn(C3CCCCO3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: O[C@H]1CCC[C@@H]1c1ccn(C2CCCCO2)n1
Yield: 91.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 106b by using the 3-[(1R,2S)-2-(benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (403 mg, 1.23 mmol) prepared in Example 148d, palladium carbon (5%; 400 mg) and ethanol (20 mL) to yield the title compound (265 mg, 91%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:11]=1)(=O)OCC)C.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:11]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOP(=O)(Cc1cccc(Oc2cc(C)ccn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
[3-(4-Methyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (2.9 g, 8.6 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.03 mL, 0.17 mmol) were combined in THF (10 mL). Sodium hydride (381 mg, 60% dispersion in mineral oil, 9.51 mmol) was added. The reaction was stirred for 30 minutes and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.90 g, 9.51 mmol) in THF (10 mL) was added. After 16 hours, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30%, EtOAc:heptane) to afford the desired product (1.15 g, 35% yield) as a thick oil.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([O:41][CH2:42][CH2:43][O:44][CH3:45])[C:34]3[CH2:40][NH:39][CH2:38][CH2:37][C:35]=3[N:36]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([O:41][CH2:42][CH2:43][O:44][CH3:45])[C:34]3[CH2:40][N:39]([C:10]([C:3]4[CH:2]=[N:1][N:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=45)=[O:12])[CH2:38][CH2:37][C:35]=3[N:36]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1cnn2ccccc12
Reactant: COCCOc1nc(-c2ccc(Cl)nc2)nc2c1CNCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1nc(-c2ccc(Cl)nc2)nc2c1CN(C(=O)c1cnn3ccccc13)CC2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
A suspension of the pyrazolo[1,5-a]pyridine-3-carboxylic acid (9.45 g, 58.3 mmol) and N,N-dimethylformamide (0.451 mL, 5.83 mmol) in CH2Cl2 (600 mL) was cooled to 0° C. and treated slowly with oxalyl chloride (7.65 mL, 87 mmol). The mixture was removed from the cold bath and stirred at room temperature for 2.5 h. An LC-MS sample with added pyrrolidine indicated no residual starting material. The mixture was filtered through filter paper to remove undissolved precipitates and then concentrated in vacuo to afford the crude acid chloride as a tan solid. This tan solid was re-dissolved in CH2Cl2 (300 mL), and added via an addition funnel over two minutes to a stirring solution of 2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (16.08 g, 115 mmol) in CH2Cl2 (300 mL) at 0° C. The reaction mixture was removed from the cold bath and stirred for 30 min. The reaction mixture was diluted with CH2Cl2 (1.2 L) and washed with water (1.5 L) and sat. aq. NaHCO3 (1.5 L). The organic phase was washed with brine (1 L) and the aqueous phases were back-extracted with CH2Cl2 (0.5 L). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting orange amorphous foam was purified by gradient elution on silica gel 0 to 50% [10% MeOH in DCM] in DCM. The isolated amorphous material was diluted with EtOAc (600 mL) and crystallized out of solution at room temperature. The mixture was stirred at 60° C. for 45 min and concentrated to dryness to drive all of the amorphous material to the crystalline form. The now crystalline material was stirred with diethyl ether (1 L) for 30 min at room temperature and then triturated. The resulting white solid was washed with diethyl ether (3×100 mL) and dried to afford the title compound as a white crystalline solid (25.16 g, 94%). Data for O-2: 1H NMR (500 MHz, CDCl3) δ 9.16 (d, J=2.4, 1H), 8.61 (dd, J=8.3, 2.5 Hz, 1H), 8.53 (d, J=6.8, 1H), 8.18 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.35 (td, J=7.9, 1.0 Hz, 1H), 6.95 (td, J=7.0, 1.2 Hz, 1H), 4.89 (s, 2H), 4.68 (t, J=4.8 Hz, 2H), 4.10 (t, J=5.9 Hz, 2H), 3.80 (t, J=4.8 Hz, 2H), 3.44 (s, 3H), 3.11 (t, J=5.7, 2H); HRMS m/z (M+H) 465.1446 found, 465.1436 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(O)(c2cccc(OC)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of 3-(methyloxy)phenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1608 g, 0.877 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.2881 g, 92.9%). EI-MS m/z 354 (M+H+) Rt (1.46 min).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:21])=[C:12]3[CH:18]=[C:17]([CH2:19][OH:20])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:18]=[C:17]([CH2:19][OH:20])[S:16][C:13]=3[N:14]([CH3:24])[CH:15]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (0.955 g) from Example No. 34 in DMF (20 mL) is added potassium carbonate (0.567 g) followed by iodomethane (0.20 mL). The reaction is stirred at rt for 1 h. The reaction mixture is partitioned between water (50 mL) and CH2Cl2 (100 mL). The aqueous layer is extracted with CH2Cl2 (100 mL). The organic layer is removed in vacuo and insoluble material in the aqueous layer is filtered off. The resulting solid is recrystallized from ethanol to yield 0.825 g (83%) of the title compound as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([N+:20]#[C-])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([NH2:20])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: [C-]#[N+]C(Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reaction time: 0.05 h
Yield: 96.8 %

Procedure:
To a solution of 1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(trifluoromethyl)benzene (20 mg, 0.052 mmol) in MeOH (0.4 mL) was added 4 N HCl in dioxane (0.3 mL) and the reaction mixture was stirred for 3 minutes. The reaction solvent was evaporated under a stream of nitrogen. The residue was diluted with 1 N NaOH (5 mL) and the aqueous portion was extracted with Et2O (3×5 mL). The combined organic fractions were washed with sat. NaCl (5 mL), dried over Na2SO4, filtered and evaporated under vacuum to yield 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (19 mg, 97% yield) as a clear glass.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C@H:10]1[CH2:15][CH2:14][C@@H:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]1)(=[O:9])[CH3:8]>CO>[C:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: CC(=O)[C@H]1CC[C@@H](C(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H](C(C)(C)C)CC1

Procedure:
The cis isomer was epimerized in a refluxing solution of sodium carbonate in aqueous methanol to a 90%:10% mixture of trans:cis-1-acetyl-4-t-butylcyclohexane. The spectral data of this mixture was essentially identical with that obtained for the pure trans isomer.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][N:30]([CH3:39])[C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][N:30]([CH3:39])[C:31]([CH:33]1[CH2:34][CH2:35][N:36]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:37][CH2:38]1)=[O:32]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(C)C(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(=O)N(C)C)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 49.4 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and piperidine-4-carboxylic acid dimethylamide (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0, 95:5, 90:10, to 85:15) to afford 326 as a white solid (69 mg, 51%). LCMS (Method G): RT=5.48 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.19 (m, 1 H); 7.73-7.68 (m, 1 H); 7.29-7.25 (m, 2 H); 4.35 (m, 4 H); 3.91-3.83 (m, 7 H); 3.75 (s, 2 H); 3.06 (s, 3 H); 2.95 (s, 6 H); 2.54 (m, 1 H); 2.18 (m, 2 H); 1.92-1.79 (m, 2 H) and 1.71 (m, 4 H)
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[CH:12])[C:8](=[O:13])[CH2:7][CH2:6]1)=O.[BH4-].[Na+]>C(O)C>[OH:2][CH2:3][CH:5]1[N:9]([CH2:10][C:11]#[CH:12])[C:8](=[O:13])[CH2:7][CH2:6]1
Reactant: C#CCN1C(=O)CCC1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN1C(=O)CCC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-water chilled solution of 6.42 g of 5-methoxycarbonyl-1-(2-propynyl)-2-pyrrolidinone in absolute ethanol (60 ml), 1.55 g of powdered sodium borohydride was added. The mixture was stirred overnight at ambient temperature.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:46]1([CH2:49][O:50][C:51]2[CH:66]=[CH:65][C:54]3[CH2:55][CH:56]([C:58]4[N:63]=[CH:62][C:61](O)=[CH:60][CH:59]=4)[O:57][C:53]=3[CH:52]=2)[CH2:48][CH2:47]1>C1COCC1.C1(C)C=CC=CC=1>[CH:46]1([CH2:49][O:50][C:51]2[CH:66]=[CH:65][C:54]3[CH2:55][CH:56]([C:58]4[N:63]=[CH:62][C:61]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])=[CH:60][CH:59]=4)[O:57][C:53]=3[CH:52]=2)[CH2:47][CH2:48]1
Reactant: Oc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A toluene solution (1.9 M, 0.474 mL) of diisopropyl azodicarboxylate was added dropwise to a solution of tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (158 mg), triphenylphosphine (236 mg) and 6-[6-(cyclopropylmethoxy)-2,3-dihydro-1-benzofuran-2-yl]pyridin-3-ol (170 mg) in THF (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: BrC1C(F)=CC([N+]([O-])=O)=C2C=1N=C(Cl)C=C2.Cl.Br[C:19]1[C:20]([F:33])=[CH:21][C:22]([N+:30]([O-])=O)=[C:23]2[C:28]=1[NH:27][C:26](=[O:29])[CH:25]=[CH:24]2.C([O-])=O.[NH4+]>O.C(O)C.CC(O)=O>[NH2:30][C:22]1[CH:21]=[C:20]([F:33])[CH:19]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:29])[NH:27]2
Reactant: O=c1ccc2c([N+](=O)[O-])cc(F)c(Br)c2[nH]1
Agent: Cl
Agent: O=C[O-]
Agent: O=[N+]([O-])c1cc(F)c(Br)c2nc(Cl)ccc12
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(F)cc2[nH]c(=O)ccc12
Yield: 47 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene, the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:44])[CH2:21][NH:22][C:23]([CH3:43])([CH3:42])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=3[C:29]([CH2:39][CH3:40])([CH2:37][CH3:38])[O:28][C:27]2=[O:41])[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.Cl>>[CH2:39]([C:29]1([CH2:37][CH3:38])[O:28][C:27](=[O:41])[N:26]([CH2:25][CH2:24][C:23]([NH:22][CH2:21][CH:20]([OH:44])[C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)([CH3:42])[CH3:43])[C:31]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]1=2)[CH3:40]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c2cc(F)ccc21
Agent: Cl
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2cc(F)ccc21

Procedure:
The product is prepared analogously to Example 12b starting from 1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-3-methyl-butyl}-4,4-diethyl-7-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one. Yield: 170 mg (78%; hydrochloride); HPLC-MS: Rt=10.6 min. (method A); ESI-MS: [M+H]+=516.