Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:35][C@@H:36]([C:38]([NH2:40])=[O:39])[CH3:37]>CC(O)C.O>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:35][C@@H:36]([C:38]([NH2:40])=[O:39])[CH3:37])=[O:5]
Reactant: C[C@@H](N)C(N)=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC(C)O
Product: C[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(N)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of Cbz-Pro-OH (10.1 gm) in 2-propanol (IPA, 100 mL) was cooled to -5° C., and NMM (4.4 mL) was added with additional cooling to -10° C. iso-Butyl chloroformate (5.2 mL) was added dropwise while maintaining the temperature at -10° to -15° C. After the addition was complete, a solution of HCl.D-Ala-NH2 (5.0 gm) and NMM (4.4 mL) in water (50 mL) was added and the mixture was stirred at -10° C. for another 30 minutes. The cooling bath was then removed and the solution stirred another three hours. The reaction was quenched in a mixture of EtOAc (200 mL) and water (100 mL) containing NaHCO3 (5 gm) and NaCl (5 gm). The layers were separated and the aqueous layer extracted with EtOAc (2×100 mL). The organic layers were combined and washed with water (2×50 mL) and then concentrated in vacuo to dryness. The residue was taken up in EtOAc (250 mL) and the solution washed with water (2×50 mL) to remove any residual IPA. The organic solution was concentrated in vacuo to about 50 mL and treated with EtOAc (50 mL) and heptane (50 mL) and the product crystallized. The solids were filtered, washed on the filter with heptane and dried in vacuo to yield 8.2 gm Cbz-Pro-D-Ala-NH2. HPLC: 99.2 pa %, [α]D =-11.2 (CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]2[CH2:11][CH:6]([C:7](Br)(Br)[CH:8]=1)[CH2:5][CH2:4]2.C(#N)C.S(=O)(=O)(O)[OH:16].[OH-].[Na+]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:3]2[CH2:11][CH:6]([CH2:5][CH2:4]2)[C:7](=[O:16])[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: BrC1=CC(Br)(Br)C2CCC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CC#N
Product: O=C1C=C(Br)C2CCC1C2
Reaction time: 0.83 h
Yield: 6.3 %

Procedure:
To a solution of 89.9 g (7.9% w/w, 100%=7.1 g, 20.6 mmol) of 2,4,4-tribromobicyclo[3.2.1]oct-2-ene in chlorobenzene there are added 100 ml of acetonitrile and 100 ml of 10% sulfuric acid and stirring is carried out for 50 minutes at ambient temperature. The pH is then adjusted to 7 using aqueous sodium hydroxide solution and the aqueous phase is separated off. The organic phase is washed with 50 ml of water and then dried using magnesium sulfate. After filtration and removal of the acetonitrile using a rotary evaporator, 57.8 g (88% of theory) of 4-bromo-bicyclo[3.2.1]oct-3-en-2-one are obtained as a 6.3% solution in chlorobenzene.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]=[C:11]=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:15]([N:14]([CH3:13])[C:11]([NH:10][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=1)=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCNC
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: c1ccccc1
Product: CCCCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 90 %

Procedure:
To a suspension of 5-t-butyl-3-isoxazolyl isocyanate (1.99 g) in benzene (120 ml), N-methylbutylamine (1.15 g) is added, and the resultant mixture is refluxed for 3 hours. After cooling, the reaction mixture is evaporated to remove the solvent, and the residue is chromatographed on a plate of silica gel to give 1-butyl-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (2.73 g). This substance is recrystallized from hexane to give crystals melting at 65.5° to 66.5° C. The yield is 89.8%.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Br[C:24]1[N:29]=[C:28](/[CH:30]=[C:31]2/[C:32](=[O:37])[NH:33][C:34](=[O:36])[S:35]/2)[CH:27]=[CH:26][CH:25]=1>CS(C)=O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:24]3[N:29]=[C:28](/[CH:30]=[C:31]4/[C:32](=[O:37])[NH:33][C:34](=[O:36])[S:35]/4)[CH:27]=[CH:26][CH:25]=3)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Reactant: Cc1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(c3cccc(/C=C4\SC(=O)NC4=O)n3)CC2)cc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
An 8 mL round bottomed vial was charged with 1-(p-tolyl)piperazine (56 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 equiv.), (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixture was shaken for 48 h at 110° C. The reaction mixture was then partitioned between CH2Cl2 (10 mL) and sat. NaCl (20 mL). The aqueous layer was back extracted with CH2Cl2 (2×15 mL) and the combined organic layer was dried over xxx and concentrated under reduced pressure to provide an orange residue. The orange residue was triturated with ether (3×15 mL) to provide (Z)-5-((6-(4-(p-tolyl)piperazin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione as an orange solid (65 mg, 122 mg theoretical, 53%). LC-MS m/z: 382 (M+1).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:15][N+:16]([O-:18])=[O:17])=[O:8])=O>ClCCl.CO>[OH:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:15][N+:16]([O-:18])=[O:17])=[O:8]
Reactant: O=COCCOC(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: O=C(OCCO)N1CCCSC1=C[N+](=O)[O-]
Yield: 61.2 %

Procedure:
The compound of Example 3 (2 g) was passed down a column of neutral alumina (200 g) using a dichloro methane/methanol mixture (95/5, v/v) as eluent at a flow rate of approximately 35 ml per minute. The eluted material was concentrated and purified by column chromatography on silica to afford the title compound (1.1 g) and recovered starting material (600 g). Melting point of the product was 59°-62° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=O)=[C:8]([CH3:25])[O:7][N:6]=1)=[N+]=[N-].CP(C)C>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]3=[C:8]([CH3:25])[O:7][N:6]=[C:5]3[CH2:4][N:1]=2)=[CH:19][CH:20]=1
Reactant: Cc1onc(CN=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CP(C)C
Solvent: Cc1ccccc1
Product: Cc1onc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone (47.2 mg, 0.144 mmol), DCM, and Et3N (40.1 μl, 0.288 mmol). The solution was cooled to 0° C. before addition of Ms-Cl (13.47 μl, 0.173 mmol). The reaction was stirred at 0° C. for 30 min before addition of water. The layers were separated and the aqueous was extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford crude (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate. To a round bottomed flask was added (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate (58.4 mg, 0.144 mmol), DMF, and sodium azide (28.1 mg, 0.432 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting the aqueous with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone. To a round bottomed flask was added (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (50.8 mg, 0.144 mmol), toluene (3 mL), and trimethylphosphine solution (216 μl, 1M in toluene, 0.216 mmol). The reaction was stirred at room temperature over 2 days before purifying via Biotage (EtOAc/hex) to afford 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepine. LC/MS m/z 309 [M+H]+; 1H NMR (400 MHz, Acetone) δ 7.70-7.76 (m, 1H), 7.63-7.70 (m, 1H), 7.32-7.49 (m, 6H), 5.10 (br. s, 1H), 4.10 (br. s, 1H), 2.68 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-dimethyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[NH:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([C:14](O)=[O:15])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:14](=[O:15])[C@@H:12]([NH:11][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:13]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(F)c(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)c(F)cc1N
Reaction time: 3 h

Procedure:
To the mixture of 1,2-diamino-4,5-difluorobenzene (2.00 g, 13.9 mmol) and Boc-L-Ala-OH (2.63 g, 13.9 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.85 g, 30.5 mmol) in DCM (139 mL) was added triethylamine (6.00 mL, 43.0 mmol) at rt and stirred for 3 h. The mixture was then concentrated in vacuo and absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (S)-tert-butyl 1-(2-amino-4,5-difluorophenylamino)-1-oxopropan-2-ylcarbamate as orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (1H, s), 7.21 (1H, dd, J=11.9, 8.8 Hz), 7.11 (1H, d, J=6.7 Hz), 6.65 (1H, dd, J=12.9, 8.0 Hz), 5.04 (2H, br. s.), 4.04-4.14 (1H, m), 1.39 (9H, s), 1.25 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 338.0 [M+Na]+ and m/z 314.0 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[CH:10]([C:31]#[N:32])[C:11]([C:13]2[C:14]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].N1C=CC=CC=1>CN(C)C=O>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[CH:10]([C:31]#[N:32])[C:11]([C:13]2[C:14]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC(C(=O)Nc1cccc(N)c1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccccc1-2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(NC(=O)C(C#N)C(=O)c2nn(-c3ccccc3)c3c2Cc2ccccc2-3)c1
Temperature: 0 °C

Procedure:
N-(3-Amino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide (1.8 g) dissolved in dimethylformamide (30 ml) is reacted with acetic anhydride (5 ml) in the presence of pyridine (5 ml) at 40° C. for 8 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water crystallization from dimethylformamide gives 1.2 g of N-(3-acetylamino-phenyl) -2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=Cc1ccc(-c2ccon2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ccon2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(3-isoxazolyl)benzaldehyde (prepared as described in Reference Example 74) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[S:12]([CH3:15])(=[NH:14])=[O:13]>C(O)C.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([S:12]([CH3:15])(=[NH:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(C)(=N)=O
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1S(C)(=N)=O

Procedure:
1.5 g (6.5 mmol) of (RS)—S-(2-methoxy-4-nitrophenyl)-S-methylsulfoximide in 100 ml of ethanol is mixed with 300 mg of palladium on carbon (10%×50% H2O) and hydrogenated for 45 minutes at room temperature and normal pressure. The batch is filtered and concentrated by evaporation. 1.0 g (5.1 mmol, corresponding to 79% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@@H:17]([CH2:32][OH:33])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C@@H:17]([CH2:32][O:33][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:19])(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(NC(=O)[C@H](CO)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)[C@H](COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (hereinafter referred to as mesyl chloride) (96 μl) was added to a solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (132 mg) in pyridine (2.5 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated saline solution, 1N HCl, and a saturated saline solution, and dried over Na2SO4. Then, the solvent was evaporated under reduced pressure to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (133 mg).
Reaction SMILES: C(C(CCCCCCCCCCCC)CN=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH:38](CCCCCCCCCC)CCCCCCCCCCCC)[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])CCCCCCCCC.[CH2:75]([CH:81]([CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])[CH2:82][CH2:83][NH2:84])[CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]>>[CH2:75]([CH:81]([CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])[CH2:82][CH2:83][N:84]=[C:14]([C:16]1[C:25]2[C:24]([C:26]([OH:28])=[O:27])=[C:23]([Br:29])[C:22]([Br:30])=[C:21]([C:31]([OH:33])=[O:32])[C:20]=2[C:19]([C:34](=[N:36][CH2:37][CH2:38][CH:81]([CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])[OH:35])=[C:18]([Br:61])[C:17]=1[Br:62])[OH:15])[CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]
Reactant: CCCCCCCCC(CCN)CCCCCC
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)CN=C(O)c1c(Br)c(Br)c(C(O)=NCC(CCCCCCCCCC)CCCCCCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Product: CCCCCCCCC(CCCCCC)CCN=C(O)c1c(Br)c(Br)c(C(O)=NCCC(CCCCCC)CCCCCCCC)c2c(C(=O)O)c(Br)c(Br)c(C(=O)O)c12
Yield: 31 %

Procedure:
The same synthetic method for compound 22 was used except using 3-hexylundecyl amine instead of 2-decyltetradecyl amine, and the yield was 31% (calculated based on TBNDA as a starting material).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([N:19]([CH:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C1COCC1.O.CCOC(C)=O>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:16][C:17]([N:19]([CH:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C(=O)CNc1ccccc1N)c1ccccc1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 40 g (385 mmol) of phenylenediamine is added 75 g (543 mmol, 1.4 equiv.) of potassium carbonate. The suspension is stirred at RT and a solution of 99 g (386.5 mmol, 1 equiv.) of 2-Bromo-N-isopropyl-N-phenyl acetamide in 15 mL THF is added dropwise. The resulting suspension is stirred at RT for 16 h and diluted with 1 L H2O and 1 L EtOAc. The Organics were washed with H2O (3×500 mL), brine (500 mL), dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 8/2 as eluent afforded 71 g of a yellow solid: mp. 110°-112° C.; 1H NMR (CDCl3, 300 MHz) δ7.48-7.44 (m, 4H), 7.18-7.15 (m, 2H), 6.69-6.59 (m, 3H), 6.21-6.19 (m, 1H), 5.11-4.98 (m, 1H), 3.4 (s, 2H), 1.09 (d, 6H, J=7).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCCCCBr
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Product: CCCCCN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide and bromopentane, reacted at 60° C. for 3 hours, the title compound was obtained as an amorphous white solid. δC (CDCl3, 62.9 MHz): 14.0, 22.3, 25.3, 28.4, 29.6, 48.1, 48.4, 62.2, 127.3, 127.6, 128.4, 129.0, 138.5, 139.4 and 145.2. δH (CDCl3, 250 MHz): 0.84 (3H, t, J 7.0), 1.24 (4H, m), 1.50 (6H, m), 2.06 (1H, s), 3.14 (4H, m), 3.62 (2H, t, J 5.95), 7.41 (3H, m), 7.56 (2H, d, J 7.94), 7.67 (2H, d, J 8.55) and 7.83 (2H, d, J 8.24).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.[OH-].[Na+]>>[CH3:1][C@H:2]1[C@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CNCC[C@H]1OC(=O)C(C)(C)C

Procedure:
The mother liquor of 17 from above is treated with 1N-NaOH to obtain the free base which is then crystallized with D-(+)-O,O′-Dibenzoyl tartaric acid as described above to give the antipode 20.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19]([O-])([O-])=O.[Na+].[Na+].IC>CN(C=O)C>[CH3:19][N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH3:12])=[N:8][C:7]=2[CH3:13])[C:2](=[O:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2c(C)nc(C)cc2c1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(C)nc(C)cc2c1=O
Temperature: 25 °C
Yield: 20.6 %

Procedure:
Ethyl 4-hydroxy-6,8-dimethyl-1,7-naphthyridine-3-carboxylate (Preparation 47, 460 mg) is dissolved in DMF (30 mL) and treated with Na2CO3 (396 mg). Iodomethane (0.3 mL) is slowly added to the mixture, and it is then heated to reflux for 1 h. The reaction mixture is cooled to room temperature, quenched with water (20 mL) and extracted with CH2Cl2 (50 mL). The organic layer is separated, dried (MgSO4), and concentrated in vacuo. The residue is purified by silica gel column chromatography (5% methanol/CH2Cl2) to give 100 mg (21%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 261 (M+H)+; 1H NMR (DMSO) δ 8.61, 7.78, 4.23, 4.18, 3.00, 2.56, 1.28.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:11][N:10]=1)(C)(C)C.[ClH:32]>CCOC(C)=O>[ClH:32].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:30])=[CH:11][N:10]=1
Reactant: COCCNC(=O)Cc1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCNC(=O)Cc1cnc(CN)c2cc(OC)c(OC)cc12
Yield: 100 %

Procedure:
As described in Example 1, 37 mg of {6,7-dimethoxy-4-[(2-methoxy-ethylcarbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 40 mg (>100%) of 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-N-(2-methoxy-ethyl)-acetamide hydrochloride. MS: APCI (M+H) calc'd for C17H23N3O4+H 334.3; found 334.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Br[C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=1.[OH-].[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Cl>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2].O.C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=2)=[CH:4][C:3]=1[F:11]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: Cc1ccc(Br)cc1CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)O
Reaction time: 0.17 h

Procedure:
Under argon, 33.5 g (192 mmol) of (4-chloro-3-fluorophenyl)boronic acid were added to a solution of 40.0 g (175 mmol) of (5-bromo-2-methylphenyl)acetic acid (EP 1791816 and WO 2006/29799) in a mixture of 437 ml (437 mmol) of degassed 1N aqueous sodium hydroxide solution, 160 ml of degassed water and 160 ml of degassed tetrahydrofuran. The mixture was stirred for 10 minutes, 507 mg (1.75 mmol) of tri-tert-butylphosphonium tetrafluoroborate and 532 mg (1.75 mmol) of palladium(II) acetylacetonate were added and the mixture was stirred at room temperature for 20 h. Toluene and water were then added, the pH was adjusted to 1-2 with concentrated aqueous hydrogen chloride solution, the mixture was stirred for 10 minutes, the phases were separated, the aqueous phase was extracted twice with toluene and the combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was stirred in 300 ml of a 6/1 mixture of n-hexane/tert-butyl methyl ether for 30 minutes, filtered off with suction, washed with n-hexane and dried under reduced pressure. This gave 38.0 g (78% of theory) of the title compound.