Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2].S([O-])([O-])(=O)=[O:17].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+].O>CC(C)=O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:17])[CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)cc2c1CCCC2
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(F)cc2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a-solution of the compound obtained in (6) above (9.46 gm) in 420 ml of acetone was added 42 ml of 15% aqueous solution of magnesium sulfate. After cooling to 0° C., 21.7 gm of potassium permanganate was added to the mixture, a bit at a time. The mixture was stirred for 50 minutes at 0° C. and for 1 hour at room temperature. Upon addition of 1 l of water, the reaction product was extracted 3 times with chloroform. The chloroform layer was washed with water and saturated brine in this order, and dried over anhydrous-sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (3:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 7.98 gm of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:50]1[CH2:55][CH2:54][CH2:53][C@@H:52]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:51]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:50]3[CH2:55][CH2:54][CH2:53][C@@H:52]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:51]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(O)[C@@H]1CCCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1Cl
Yield: 72.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z 379 (M+1); HRMS, calcd for C19H23ClN2O4: 378.1346, found 378.1340.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O[CH:14](OCC)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:19][CH:18]=1)C>C(Cl)(Cl)Cl>[O:9]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:22]=2)[NH:10]1
Reactant: NC(=O)c1ccccc1O
Reactant: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C(Cc2ccc(OCC3NC(=O)c4ccccc4O3)cc2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of polyphosphonate ethyl ester (PPE) (3.15 g, 7.29 mmol) in chloroform (4.0 mL) was added salicylamide (0.5 g, 3.65 mmol) followed by addition of a solution of 5-[4-[(2,2-diethoxy)ethoxy]phenyl methyl]thiazolidin-2,4-dione (1.36 g, 4.0 mmol) obtained in example 2, in chloroform (10 mL) dropwise at 25-30° C. The reaction mixture was immersed in a preheated oil bath and refluxed for 3 h. The reaction mixture was cooled to room temperature and CHCl3 was removed under reduced pressure. To the resultant residue aq. sat. NaHCO3 solution (25 mL) was added and stirred for 30 min. at 25-30° C. The precipitated brown coloured solid was filtered and purified by column chromatography using EtOAc:pet. ether (1:1) to yield the title compound (1.15 g, 81%). mp: 134° C.-138° C.
Reaction SMILES: CC1C(C)CCC(C)C1=[O:10].[CH3:11][C:12](=[CH:14][CH2:15][CH:16]=[C:17]([CH3:20])[C:18]#[CH:19])[CH3:13].CC(=CCCC(=C)C#C)C>O>[CH3:11][C:12]([CH3:13])=[CH:14][CH2:15][CH2:16][C:17]([OH:10])([C:18]#[CH:19])[CH3:20]
Reactant: C#CC(C)=CCC=C(C)C
Reactant: CC1CCC(C)C(C)C1=O
Agent: C#CC(=C)CCC=C(C)C
Solvent: O
Product: C#CC(C)(O)CCC=C(C)C

Procedure:
A mixture of 28 g of 2,3,6-trimethyl-cyclohexanone and 27 g of the isomer mixture consisting of 2,6-dimethyl-oct-2,5-dien-7-yne and 2-methyl-6-methylene-oct-2-en-7-yne, obtained by elimination of water from 2-dehydrolinalool, is added dropwise to a suspension of 35 g of KOH in 200 ml of toluene at 0° C. The reaction mixture is then kept for 6 hours at 0° C, whilst being stirred, after which water is added and the organic phase formed is dried and concentrated. Subsequent fractional distillation gives 12.3 g of unconverted trimethylcyclohexanone and 12 g of a mixture of 2,3,6-trimethyl-1-(3',7'-dimethyl-oct-1'-yn-3',6'-dien-1'-yl)-cyclohexanol and 2,3,6-trimethyl-1-(7'-methyl-3'-methylene-oct-1'-yn-6'-en-1'-yl)-cyclohexanol of boiling point 125°-127° C/0.4 mm Hg as a viscous oil. This corresponds to a yield of 39%, based on ketone converted. Fragrance note: faintly floral, spicy, minty.
Reaction SMILES: O1CCN(C[CH2:8][NH:9][C:10](=[O:56])[CH2:11][CH2:12][S:13][CH2:14][C:15]2[CH:16]=[C:17]([CH:53]=[CH:54][CH:55]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:22]=2[C:33]2[CH:34]=[C:35]([CH:50]=[CH:51][N:52]=2)[C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[O:37])=[O:19])CC1.[CH3:57][O:58][CH2:59]CN>>[CH3:57][O:58][CH2:59][CH2:8][NH:9][C:10](=[O:56])[CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:53]=[CH:54][CH:55]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:23][C:22]=1[C:33]1[CH:34]=[C:35]([CH:50]=[CH:51][N:52]=1)[C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=1)=[O:37])=[O:19]
Reactant: COCCN
Reactant: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCN1CCOCC1
Product: COCCNC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared using the procedure described for the preparation of 2-(2-(3-(((3-((2-morpholinoethyl)amino)-3-oxopropyl)thio)methyl)benzamido)-5-(piperidin-1-yl)-phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 4.16, using 2-methoxyethylamine in place of 2-morpholinoethylamine MS (ES, m/z): 734 [M+H]+
Reaction SMILES: [OH-].[Na+].Cl.C[O:5][C:6](=[O:23])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]=1[Cl:22]>O.CO>[ClH:13].[Cl:22][C:8]1[C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]([OH:23])=[O:5]
Reactant: COC(=O)c1c(Cl)ccc(OCCN2CCCC2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(Cl)ccc(OCCN2CCCC2)c1Cl
Temperature: 90 °C
Yield: 169.9 %

Procedure:
To a solution of NaOH (2.73 g, 68.25 mmol) in 80 ml of water and 40 ml of methanol was added in one portion 8 g (22.56 mmol) of 2,6-dichloro-3-(2-pyrrolidinoethoxy)benzoic acid methyl ester hydrochloride and the mixture was heated at 90° C. for 15 hours. The mixture was concentrated in vacuo to remove methanol, the aqueous layer was acidified with 20 ml of conc. HCl solution, and the white solid was filtered. The white solid was dissolved in hot water, filtered, and the filtrate was treated with 15 ml of conc. HCl solution. The solid product was recrystallized from methanol/ether to afford 6.53 g (85%) of 2,6-dichloro-3-(2-pyrrolidinoethoxy)benzoic acid hydrochloride (Formula III: Ar=2,6-Cl2 -3- (OCH2CH2 -1-pyrrolidinyl)phenyl) as a white crystalline solid, m.p. 257°-259° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Cl.Cl.[CH3:28][NH:29][CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1.N12CCCN=C1CCCCC2>C(#N)C>[F:19][C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[CH:13][C:18]=1[N:9]1[C:3]2[C:4](=[CH:5][C:6]([F:8])=[C:7]([N:33]3[CH2:34][CH2:35][O:36][CH:31]([CH2:30][NH:29][CH3:28])[CH2:32]3)[C:2]=2[F:1])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: CNCC1CNCCO1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
A solution of 710 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 487 mg of 2-(methylaminomethyl)morpholine dihydrochloride and 1035 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of acetonitrile is refluxed for 21 hours. The reaction mixture is concentrated under reduced pressure and to the residue is added 10 ml of methanol. The obtained crystals are collected by filtration and washed with methanol, water and then acetone to give 1-(2,4-difluorophenyl)-7-[2-(methylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 224°-227° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:18])[CH3:17])[CH2:12]1)[C:5]([OH:7])=O.[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:18])[CH3:17])[CH2:12]1)[C:5]([NH:29][C@H:27]([C:25]1[NH:24][C:23]2[CH:30]=[CH:31][C:20]([Cl:19])=[CH:21][C:22]=2[N:26]=1)[CH3:28])=[O:7]
Reactant: CN(C)C1CCN(c2ccc(C(=O)O)cc2Cl)C1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCC(N(C)C)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA in DMF.
Reaction SMILES: [OH:1][C@H:2]([CH3:16])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[C:11]=2[N:13]=O)[CH:6]=[N:5]1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][C:26](Cl)=O>O1CCCC1.CN(C)C1C=CN=CC=1.[Pd]>[CH3:23][O:24][CH2:25][C:26]1[O:15][C:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[N:5][N:4]([CH2:3][C@H:2]([OH:1])[CH3:16])[C:12]=3[C:11]=2[N:13]=1
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c(N=O)c21
Reactant: COCC(=O)Cl
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2c(ccc3cnn(C[C@@H](C)O)c32)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
A solution of the product from Step A (1.05 g, 4.75 mol) in tetrahydrofuran (50 mL) containing 10% palladium-on-carbon (0.1 g) was stirred under an atmosphere of hydrogen at room temperature for 18 hours. The reaction mixture was filtered, pyridine (1.0 mL, 12.3 mol) and methoxy acetyl chloride (0.43 mL, 4.75 mol) were added, and this mixture was stirred at room temperature. More pyridine (5.0 mL) was added and the reaction mixture was stirred at room temperature for 20 minutes followed by the addition of 4-dimethylaminopyridine (0.1 g); this mixture was heated at 60° C. for 3 hours followed by removal of solvents by heating at 220° C. for 30 minutes. The resulting dark liquid was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a yellow oil (200 mg, 16%): LC/MS m/z 262.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][C@H:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:18]([N:25]1[CH2:29][CH2:28][C@@H:27]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(C(C#N)c2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(C#N)(c2ccccc2)[C@@H]2CCN(Cc3ccccc3)C2)c1
Temperature: 80 °C
Yield: 77.3 %

Procedure:
To a stirred solution of (3-methoxyphenyl)phenylacetonitrile (5.2 g, 23 mmol; prepared as described in Preparation 6) in THF (100 mL) was added toluene-4-sulfonic acid (S)-1-benzylpyrrolidin-3-yl ester (7.2 g, 22 mmol), followed by the addition of potassium t-butoxide (4.0 g, 36 mmol). The mixture was heated to 80° C. for 1 hour, then allowed to cool and H2O (10 mL) was added. The mixture was filtered through a pad of Celite®. The mixture was washed with a saturated aqueous NaCl solution (100 mL) and the organic phase was separated, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography to afford the title compound (6.2 g, 17 mmol). MS m/z: {M+H+] calcd for C26H26N2O, 382.5; found 383.4.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([SiH2:22][CH2:23]Cl)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>CN(C)C=O.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([SiH2:22][CH2:23][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(C([SiH2]CCl)c2ccc(F)cc2)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(C([SiH2]Cn2cncn2)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
In this preparation 1.0 g of sodium 1,2,4-triazole is added to a solution of 3.1 g of bis(4-fluorophenyl)methylsilylmethyl chloride in 15 mL of dimethylformamide. The mixture is heated at about 80°-90° C. for two hours and then cooled to room temperature. The mixture is then diluted with 60 ml of water and extracted three times with 50 ml portions of ethyl ether. The extracts are combined, washed twice with 80 ml of water, then with 80 ml of aqueous saturated sodium chloride solution and dried over magnesium sulfate. The ethyl ether solvent is evaporated off affording an oil which is then purified by chromatography over silica gel solution with ethyl acetate, hexane, and mixture thereof.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:19]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccnc2N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(2-aminopyridin-3-yl)phenol (19.8 g), tert-butyldimethylchlorosilane (21.8 mL) and 1H-imidazol (8.69 g) in DMF (200 mL) was stirred at room temperature for 20 hr. To the mixture was added water, and the resulting precipitate was collected by filtration, and then washed with water to give the title compound (30.5 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28](B(O)O)=[CH:29][C:24]=2[CH:23]=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)=[CH:29][C:24]=2[CH:23]=[CH:22]1
Reactant: OB(O)c1ccc2occc2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4occc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in dioxane (5.0 mL) was added (1-benzofuran-5-yl)boronic acid (215.6 mg, 1.33 mmol), K3PO4 (280.6 mg, 1.33 mmol), Pd(PPh3)4 (25.56 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(1-benzofuran-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (105 mg, crude). LC/MS (ES, m/z): 376.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[N:10]1[C:14](=O)CC[C:11]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:10]([CH3:14])[CH3:11])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)Cc1cccc(Cl)n1

Procedure:
2-Chloro-6-methylpyridine (6.4 g, 0.05 mol) is refluxed with N-bromosuccinimide (8.9 g, 0.05 mol) in 50 ml of carbon tetrachloride with benzoyl peroxide (50 mg) until the N-bromosuccinimide has reacted completely (7-14 hours). The succinimide is removed by filtering and the filtrate is saturated with anhydrous dimethylamine. Dimethylamine hydrochloride is removed by filtration and the filtrate is concentrated in vacuo. The residual oil is taken up in hexane and extracted into dilute hydrochloric acid. After the acid extract is washed with ether it is made basic with sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This gives 2.2 g of 2-chloro-6-dimethylaminomethylpyridine as a pale yellow oil.
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[CH3:11][O:12][C:13]1C=CC=C2[C:14]=1CCCC2=O>>[CH3:11][O:12][C:13]1[CH:14]=[CH:2][CH:3]=[C:4]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[NH2:10]
Reactant: COc1cccc2c1CCCC2=O
Reactant: NC1CCCc2occc21
Product: COc1cccc2c1CCCC2N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.19, 7.05, 6.75, 4.00, 3.84, 2.76, 2.61, 1.97, 1.70; 13C NMR (100 MHz, CDCl3) δ 157.44, 142.83, 126.67, 126.02, 120.53, 108.09, 55.72, 49.75, 33.21, 23.57, 19.11; HRMS (FAB) calcd for C11H15NO+H 178.1232, found 178.1233.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:14](=[O:35])[C:13]1=[O:36])=O)(C)(C)C.[ClH:37]>C(OCC)(=O)C.O1CCOCC1>[ClH:37].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:14](=[O:35])[C:13]1=[O:36]
Reactant: CC(C)(C)OC(=O)NCCCN1CCN(CC(=O)OC(c2ccccc2)c2ccccc2)C(=O)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCCCN1CCN(CC(=O)OC(c2ccccc2)c2ccccc2)C(=O)C1=O

Procedure:
In 3 ml of ethyl acetate was dissolved 0.50 g of diphenylmethyl [4-[3-(tert-butoxycarbonylamino)-propyl]-2,3-dioxopiperazin-1-yl]acetate, followed by adding thereto 3.3 ml of a 1.5N solution of hydrochloric acid in dioxane, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 0.43 g of diphenylmethyl [4-(3-aminopropyl)-2,3-dioxopiperazin-1-yl]acetate hydrochloride as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]([O:15][CH3:16])=[O:14])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[O:21]=[S:22]1(=[O:38])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36]Br>C(Cl)Cl>[O:38]=[S:22]1(=[O:21])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36][N:10]1[CH2:11][CH2:12][C@@H:7]([N:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[NH:3][C:2]2=[O:1])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1
Reactant: COC(=O)[C@@H]1CNCC[C@H]1n1c(=O)[nH]c2ccccc21
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(CCCCN2C(=O)c3cc(Cl)ccc3S2(=O)=O)CC[C@H]1n1c(=O)[nH]c2ccccc21

Procedure:
From (±) cis/trans-4-(2-oxo-1-benzimidazolinyl)-3-methoxycarbonyl-piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1, Step 3, there was obtained a white solid from methylene chloride, melting point 170-176° C. Analysis calculated for C25H27ClN4O6S: C, 54.89; H, 4.98; N, 10.24; found: C, 54.65; H, 4.98; N, 10.22. The NMR was consistent with the structure.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:16]([O:20][CH2:21][CH:22]1[O:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH:22]([OH:24])[CH2:21][O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reactant: CC(C)(C)OCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)(C)OCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 78.3 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), t-butylglycidyl ether (1.56 g, 12 mmol) and ethyltriphenylphosphonium bromide (0.1 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 2.8 g (78%).
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][CH2:9][O:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].CNN>ClCCl>[C:1]([Si:5]([CH3:22])([CH3:23])[O:6][CH2:7][CH2:8][CH2:9][O:10][NH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCON
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A solution of 2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-isoindole-1,3-dione (26.3 g, 78.3 mmol) in dichloromethane (120 mL) was cooled to 0° C. and treated with methylhydrazine (16.1 g, 78.3 mmol). The reaction mixture was stirred for 30 min at 0° C. and filtered. The filtrate was concentrated under reduced pressure, redissolved in ether, and refrigerated (4° C.) overnight. The resultant crytalline material was removed by filtration and the filtrate was concentrated under reduced pressure to afford O-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-hydroxylamine (15.95 g, 99% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.69 (br s, 2 H), 3.74 (t, J=6.3 Hz, 2 H), 3.67 (t, J=6.3 Hz, 2 H), 1.78 (quintet, J=6.3 Hz, 2 H), 0.88 (s, 9 H), 0.00 (s, 6 H); MS (APCI+)=206.1. Anal. Calcd./Found for C9H23NO2Si: C, 52.64/52.22; H, 11.29/10.94; N, 6.82/6.46.