Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@:16]2([CH3:17])[N:12](/[C:13](=[N:18]/[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[C:20]=3[CH3:28])/[O:14][CH2:15]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.O[C@H]1[C@@H]2N(/C(=N/C3C=CC(C#N)=C(Cl)C=3C)/OC2)CC1>>[OH:8][C@@H:9]1[C@:16]2([CH3:17])[N:12](/[C:13](=[N:18]/[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[C:20]=3[CH3:28])/[O:14][CH2:15]2)[CH2:11][CH2:10]1
Reactant: Cc1c(/N=C2\OC[C@]3(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Agent: Cc1c(/N=C2\OC[C@@H]3[C@H](O)CCN23)ccc(C#N)c1Cl
Product: Cc1c(/N=C2\OC[C@]3(C)[C@@H](O)CCN23)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 4E following the procedure found in Example 1 for the preparation of compound 1J. LCMS: m/z 306 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][O:29][CH2:30][CH:31]([NH:33][C:34]1[NH:38][C:37]([CH3:39])=[N:36][N:35]=1)[CH3:32]>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:33]([CH:31]([CH3:32])[CH2:30][O:29][CH3:28])[C:34]2[N:35]([N:36]=[C:37]([CH3:39])[N:38]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: COCC(C)Nc1nnc(C)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C(C)COC)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) and N-(2-methoxy-1-methylethyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.28 g, 40%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:23]3[C:24](=C=O)[O:25][CH2:26][CH2:27][CH:28]=3)[NH:16]OC(C3CC3)C)[C@H:4]2[S:3]1>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:23]3[CH2:24][O:25][CH2:26][CH2:27][CH:28]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NOC(C)C3CC3)C3=CCCOC3=C=O)[C@H]2S1
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)C3=CCCOC3)[C@H]2S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
A mixture of 2-methyl-7-[N-(Cl-cyclopropylethoxy)-carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid (3.0 g) and formic acid (20 ml) was stirred for 3 hours at room temperature. After the reaction was completed, formic acid was removed from the reaction mixture under reduced pressure at room temperature. The residue was pulverized with acetonitrile and the powder was collected by filtration. The powder was in turn washed with acetonitrile and water, and dried to give 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid (2.20 g), mp 125° to 128° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][N:4]=1.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:13][C:14]([S:17](/[N:19]=[CH:7]/[C:6]1[CH:5]=[N:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:10][CH:9]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)S(=O)/N=C/c1ccc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 107.4 %

Procedure:
To a solution of 6-(trifluoromethyl)nicotinaldehyde (45.0 g, 257 mmol) in dichloroethane (640 mL) were added (S)-(−)-2-methyl-2-propanesulfinamide (34.3 g, 283 mmol) and anhydrous copper(II) sulfate (82 g, 514 mmol). The mixture was stirred at 50° C. After 48 h, the mixture cooled to ambient temperature. The reaction mixture was filtered through Celite. The filtered cake was washed with dichloromethane and the filtrate was concentrated to give the title compound (76.8 g). MS 223.1 (M-tert-butyl+1)
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11]S(C)(=O)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Na+].[I-:17]>CC(C)=O>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][I:17])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(/C=C/CS(C)(=O)=O)CCOCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC1(/C=C/CI)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a 0° C. solution in acetone of 4-methoxy-4-(3-methanesulfonyl-trans-prop-1-enyl)tetrahydropyran (730 mg, 2.92 mmol), prepared as in step 5, was added NaI (5.84 mmol, 875 mg). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then concentrated and the residue partitioned between ether and H2O. The organic phase was washed twice with brine, dried over MgSO4, decolorized with activatedcarbon, filtered, through a pad of celite and concentrated in vacuo. The 4-methoxy-4-(3-iodo-trans -prop-1-enyl)tetrahydropyran (800 mg) so obtained was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10].[CH2:12](N)[CH2:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]1[NH:14][CH2:13][CH2:12][N:10]=1)[CH3:11]
Reactant: NCCN
Reactant: CC(C#N)c1ccccc1Br
Product: CC(C1=NCCN1)c1ccccc1Br

Procedure:
rac-2-[1-(2-Bromo-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-bromo-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): off-white solid; MS (EI): 251.0 and 253.0 (M+.), 173.1 (((M-Br)+.), 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[NH2:13])[CH3:2].C([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=O)(=O)C.O=P(Cl)(Cl)Cl>>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[NH:13][C:18]1[NH:19][CH2:20][CH2:21][N:17]=1)[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: CCc1ccc2ccccc2c1N
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc2ccccc2c1NC1=NCCN1

Procedure:
2-Ethylnaphthyl amine is reacted with N-acetyl-2imidazolidinone in the presence of POCl3 to produce the imidazoline intermediate. This intermediate is treated with sodium hydroxide and water to remove the aceto group and yield the name compound (VIII).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH2:10]Br)=[O:4].[CH3:16][NH:17][CH3:18].C1COCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH2:10][N:17]([CH3:18])[CH3:16])=[O:4]
Reactant: CNC
Reactant: COC(=O)c1oc2ccccc2c1CBr
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1oc2ccccc2c1CN(C)C
Reaction time: 1.5 h
Yield: 56.2 %

Procedure:
3-Bromomethylbenzofuran-2-carboxylic acid methyl ester (269 mg, 1 mmol) was dissolved in anhydrous DMF and added 2M dimethylamine/THF solution (1.5 ml, 3 mmol). After 1-2 h, the reaction was diluted with EtOAc and washed twice with saturated NaHCO3 (aq.) and brine. The organic extract over was dried over Na2SO4 and then concentrated in vacuo. The crude was purified on a silica gel column (5% MeOH in dichloromethane) to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid methyl ester (131 mg).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@@H:13]3[CH3:25])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C@@H:13]3[CH3:25])[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
To a mixed solution of tert-butyl(3S)-4-(1-(diphenylmethyl)azetidin-3-yl)-3-methylpiperazine-1-carboxylate (493 mg, 1.17 mmol) described in Production Example 6-1 and THF (10.0 mL) was added lithium aluminum hydride (178 mg, 4.68 mmol) at 0° C. The resultant mixture was stirred under reflux for 5 hours and 10 minutes. The reaction mixture was cooled to 0° C., then water (178 μL) and a 5 N aqueous sodium hydroxide solution (178 μL) were added thereto, and water (534 μL) was further added thereto. The reaction mixture was filtrated using Celite and then washed with ethyl acetate. A filtrate was concentrated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to give the title compound (321 mg, yield: 82%).
Reaction SMILES: [Na].[CH2:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=2)=[C:6]([O:18][CH3:19])[CH:5]=1)[CH3:3].[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([CH2:2][CH3:3])=[CH:5][C:6]=2[O:18][CH3:19])[N:10]=1)[CH3:21]
Reactant: CCO
Reactant: CCc1ccc(Oc2cccc(F)n2)c(OC)c1
Agent: [Na]
Product: CCOc1cccc(Oc2ccc(CC)cc2OC)n1
Temperature: 80 °C
Reaction time: 26 h

Procedure:
To a solution of sodium (55 mg; 2.39 mmol), under argon, in ethanol (2 mL), was added 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (82 mg; 0.33 mmol). The reaction was heated to 80° C. for 16 hours then to 90° C. for 26 hours. The mixture was concentrated in vacuo. After quenching with saturated NaHCO3 (10 mL), extractions with ethyl acetate (3*5 mL), the organic phase was dried over NaSO4, and concentrated in vacuo to give the desired product as a light brown oil used without further purification (82 mg; 0.30 mmol; 90%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[N:41]=[C:40](Cl)[CH:39]=[CH:38][N:37]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:38]5[CH:39]=[CH:40][N:41]=[C:36]([Cl:35])[N:37]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccnc(Cl)n4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (45.9 mg) in DMF (2 mL) was added diisopropylethylamine (73 μL) followed by 2,4-dichloropyrimidine (24.9 mg). The resulting solution was heated to 100° C. for 16 h then the mixture concentrated in vacuo. This crude was purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 18.3 mg of 2-((S)-1-phenylethylamino)-4-(5-(2-chloropyrimidin-4-yl)aminobenzimidazol-1-yl)pyrimidine (L-860,182). 1H NMR (500 MHz, CDCl3, partial): δ 8.51 (br s, 1H); 8.42 (d, J=5.5 Hz, 1H); 8.13 (d, J=5.9 Hz, 1H); 7.75 (s, 1H); 7.45 (d, J=7.3 Hz, 2H); 7.40 t, J=7.7 Hz, 2H); 6.77 (d, J=5.3 Hz, 1H); 6.56 (d, J=6.0 Hz, IH); 1.66 (d, J=6.9 Hz, 3H). Mass spectrum (ESI) 443.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)NC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (180 mg, 527 μmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (302 mg, 790 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (77.1 mg, 105 μmol), cesium carbonate (686 mg, 2107 mol) in DMF (2 mL) and water (0.4 mL) was first sparged with argon for 5 min then heated to 100° C. with stirring. 2:20 pm After 10 min, LCMS suggests >95% conversion. Reaction then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (5 mL). Organic then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with isocratic 4% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass for C29H29ClN6O4: 560.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-:24][CH2:25][CH3:26].[Na+]>C(O)C>[CH2:25]([O:24][C:2]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:26]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N2CCN(CC)CC2)cnc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(S(=O)(=O)N2CCN(CC)CC2)cnc1OCC
Temperature: 40 °C
Yield: 33.9 %

Procedure:
A solution of Ethyl 2-chloro-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate (36.1 g, 0.1 mol) in ethanol (180 mL) was cooled to 10° C. with stirring. Sodium ethoxide (10.2 g, 0.15 mol) was added portionwise keeping the temperature below 20° C. The reaction mixture was then stirred at ambient temperature for 18 hours. The precipitate was filtered off and water (180 mL) added to the filtrate. The filtrate was then heated to 40° C. for 1 hour. Ethanol (180 mL) was then distilled off at ambient pressure and the remaining aqueous solution allowed to cool to ambient temperature. The precipitated product was then filtered off, washed with water and dried under vacuo at 50° C. to afford the title compound (12.6 g, 34%) as a light brown solid. M.p. 66-68° C. δ (CDCl3): 1.04 (3H, t), 1.39 (3H, t), 1.45 (3H, t), 2.41 (2H, q), 2.52 (4H, m), 3.08 (4H, m), 4.38 (2H, q), 2.57 (2H, q), 8.38 (1H, d), 8.61 (1H, d). m/z (Found: 372 [M+H]+, 100%. C16H26N3O5S requires 372.46).
Reaction SMILES: [CH2:1]([B:8]([Cl:10])Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C#C.C(=O)=O.[CH3:16][C:17](C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:10][B:8]1[CH:17]=[CH:16][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: ClB(Cl)Cc1ccccc1
Reactant: CC(C)=O
Agent: C#C
Agent: O=C=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: ClB1C=Cc2ccccc2C1
Reaction time: 3 h
Yield: 95 %

Procedure:
About 10.0 ml (11.51 grams, 66.6 mmoles) of benzyl dichloroborane is dissolved in 100 ml of toluene in a 500 ml three-neck flask. Research grade acetylene is passed at a rate of 100 ml STP/min through two dry ice/acetone traps and a column (10 inches long ×1 inch ID) of activated basic alumina. The acetylene is introduced into the stirring solution through a needle below the surface of the liquid. The flask is vented to a scrubber containing 2.7 grams of NaOH in 1500 ml of water. The reaction is allowed to proceed for 3 hours. The acetylene flow is stopped and the volatiles in the reaction flask are evaporated under vacuum. 10.37 grams of colorless product are recovered. This is identified as 2-chloro-1,2-dihydro-2-boranaphthalene by NMR. This product is used in subsequent steps without further purification. The yield is 95 %.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:45][CH2:46][NH2:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:47][CH2:46][CH2:45][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[C:15]1=[O:38]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 2-(4-morpholinyl)ethanamine (0.008 mL, 0.061 mmol) for 30 min.@150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional equivalent (0.008 mL) of the amine, cooled to ambient temperature, and the resulting suspension was filtered, washed with EtOH and then thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.26-2.34 (m, 6 H), 3.33-3.37 (m, 2 H), 3.48-3.54 (m, 4 H), 3.91 (t, J=5.69 Hz, 2 H), 4.13 (s, 2 H), 4.56 (t, J=5.62 Hz, 2 H), 7.10-7.17 (m, 2 H), 7.33-7.40 (m, 2 H), 7.82 (s, 4 H), 8.16 (d, J=1.12 Hz, 1 H), 8.53 (d, J=0.84 Hz, 1 H), 10.04 (t, J=6.18 Hz, 1 H); ES+ MS: 600 (N+H+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][CH:8]=1
Reactant: Brc1ccc(C2CCCN2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a suspension of 2-(4-bromophenyl)pyrrolidine hydrogen chloride (250 mg, 0.952 mmol) in anhydrous methylene chloride (5 mL) was added triethylamine (0.66 mL, 4.76 mmol) under N2. The mixture was stirred at room temperature for 15 min. under N2. After 15 min., methanesulfonyl chloride (0.31 g, 2.72 mmol) was added and the mixture was stirred at room temperature under N2 overnight. Additional methanesulfonyl chloride (0.29 g, 2.54 mmol) and triethylamine (0.35 mL, 2.38 mmol) were added and stirred at room temperature for 4 h. The reaction was concentrated, and to the residue was added water (20 mL) and methylene chloride (18 mL), and the organic phase was washed with water (10 mL×3), brine (15 mL×1), dried over sodium sulfate and concentrated to afford the desired product (240 mg, 85.2% yield) which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C1CCC1
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (1.0 equiv.) in THF (0.26 M) under Ar was added Mg turnings (1.6 equiv.). A reflux condenser was attached and the solution was submerged in a 90° C. oil bath and refluxed for two hours. The cyclobutanone (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar for 5 hrs. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 1-(3,5-difluorophenyl)cyclobutanol in 54% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.83 (m, 1 H), 2.03-2.13 (m, 1 H), 2.31-2.43 (m, 2 H), 2.45-2.56 (m, 2 H), 6.71 (tt, J=8.80, 2.35 Hz, 1 H), 6.98-7.07 (m, 2 H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:19]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:6]([CH2:4][OH:3])[CH2:7]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3SR,4RS) 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (3.6 g, 0.01 mol) were dissolved in THF (70 mL). At 0° C. LiAlH4 (0.38 g, 0.01 mol) was added portion wise. After stirring at 0° C. for 4 h water (3 mL), then 5N NaOH (3 mL) and additional water (9 mL) was added. After stirring at ambient temperature for 30 min the mixture was extracted with ethyl acetate (3×10 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a light yellow oil (3.0 g, 94%) and directly used in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:22]=[C:17]([C:15]([NH:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:16])[CH:18]=[N:19][C:20]=2[O:30][CH2:31][C:32]([F:34])([F:33])[F:35])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
4-{[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-amino}-piperazine-1-carboxylic acid tert-butyl ester (1.047 g, 2.03 mmol) was combined with dichloromethane (25 mL) to give a white suspension. Subsequently trifluoroacetic acid (7.4 g, 5 ml, 64.9 mmol) was added at 0° C. and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from ethyl acetate and n-heptane to afford the title compound (1.0 g, quant.) as white solid.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].B(Cl)(Cl)Cl>>[OH:2][C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(C#N)c(OC)c1
Agent: ClB(Cl)Cl
Product: N#Cc1ccc(O)cc1O

Procedure:
2,4-Dimethoxybenzoic acid is reacted with hydroxylamine to form 2,4-dimethoxybenzaldoxime. 2,4-Dimethoxybenzaldoxime is reacted with diphosphorus pentoxide to form 2,4-dimethoxybenzonitrile. 2,4-Dimethoxybenzonitrile is reacted with boron trichloride to form 2,4-dihydroxybenzonitrile.