Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[C:9](=[O:18])[NH:10][C:11]2[C:16]/1=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[CH2:23]([O:22][C:20]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)/[C:8](=[CH:1]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)/[C:9]1=[O:18])=[O:21])[CH3:24]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\c2ccccc2)c2ccc(Cl)cc21
Yield: 104 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 5.87 mmol) was reacted with ethyl chloroformate (0.83 mL, 8.8 mmol) and triethylamine (1.64 mL, 12 mmol) in dichloromethane to give E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid (Yield 2.0 g, 100%).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]([CH3:19])[CH2:16][CH2:17]O)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1>CCOCC>[Br:2][CH2:17][CH2:16][CH:15]([C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1)[CH3:19]
Reactant: COc1cc(OC)cc(C(C)CCO)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)CCBr)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(3,5-dimethoxyphenyl)-1-butanol (30.0 g., 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice (200 g.) and the resulting mixture extracted with ether (3×50 ml.). The combined extracts are washed with 5% sodium hydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50 ml.) and dried (Na2SO4). Removal of the ether and vacuum distillation of the residue affords the title product; 25 g. (55% yield); b.p. 125°-132° C. at 0.4 mm.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:21][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[Br:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@H:10]4[CH2:21][C@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of (1aS,5aS)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.00 g, 2.87 mmol) in methanol (5 mL) and THF (5.00 mL) was added a 2.0 M aqueous solution of sodium hydroxide (2.87 mL, 5.74 mmol). The reaction was stirred at 23° C. for 2 h. The organic solvents were removed by distillation. The remaining aqueous solution was diluted with water (20 mL) then acidified to pH ˜2 by addition of 6 M aq. HCl. The resulting precipitate was collected by filtration, rinsed with water, then dried under vacuum to give the title compound (0.87 g) as a white solid. LCMS m/z=320.0 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C1C[O:24][CH2:23][CH2:22]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:23]([NH:2][C:3]([CH3:20])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5])(=[O:24])[CH3:22]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino2,3-dimethyl-N-(p-tolylsulfonyl) butyramide hydrochloride (45 g~0.4 mols) is completely dissolved in 160 mL of pyridine and 500 mL of THF is added. Acetic anhydride (45 mL) is then poured into the solution and the reaction mixture is heated at reflux for one hour. The solvents are removed under reduced pressure, and the oily residue is crystallized from EtOH/water affording 33.09 g of the title product having m.p. 198°-199° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C:29]4([CH2:28][CH2:27][O:26][CH3:25])[CH2:31][CH2:30]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COCCC1(N)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 200 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.65-0.73 (m, 2 H) 0.72-0.80 (m, 2 H) 1.86 (t, J=7.1 Hz, 2 H) 2.43 (s, 3 H) 3.21 (s, 3 H) 3.46 (t, J=6.9 Hz, 2 H) 7.64 (dd, J=8.1, 1.5 Hz, 1 H) 7.71 (s, 1 H) 7.80 (d, J=8.1 Hz, 1 H) 8.14 (s, 1 H) 8.38 (br. s., 2H) 8.83 (s, 1 H) 8.87 (t, J=1.5 Hz, 1 H) 13.17 (br. s., 1 H). MS m/z 418 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([OH:24])[CH2:11][N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:24][CH:10]([CH2:11][N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)CN(CC(O)CSc1ccc(Cl)cc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(CC(CSc1ccc(Cl)cc1)OC(C)=O)c1ccccc1
Reaction time: 20 h

Procedure:
After 200 mg (0.00054 moles) of 1-(p-chlorophenylthio)-3-(N-carbomethoxymethyl-N-phenylamino)-2-propanol and 1 g of acetic anhydride were dissolved in 3 ml of pyridine and left to stand at room temperature for 20 hr, the reaction mixture mixture was poured into iced water and extracted with ether. The ether layer was washed with 10% hydrochloric acid and water and dried. Evaporation or ether under reduced pressure gave 190 mg (86.5%) of an oily substance.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:11]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccsc1

Procedure:
The reaction was repeated on a 50 mmol scale with 2-bromobenzaldehyde (5.8 mL), thiophene-3-boronic acid (7.03 g, 0.0555 mol) in ethanol (55 mL), Pd(PPh3)4 (1.7 g, 3 mol %), 2 M aqueous Na2CO3 (55 mL) in toluene (275 mL) to yield crude 2-(3-thienyl)benzaldehyde as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH3:26]>C(#N)C>[CH2:25]([O:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH3:26]
Reactant: CCBr
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C
Temperature: 50 °C
Yield: 98.8 %

Procedure:
To a stirred solution of methyl 2-hydroxy-2′-methyl-1,1′-biphenyl-4-carboxylate (10 g, 41.2 mmol) in anhydrous ACN (100 mL) was added anhydrous potassium carbonate (17.1 g, 123.6 mmol) followed by ethyl bromide (15.4 mL, 206 mmol). The reaction mixture was heated at 50° C. for 48 hours, and then cooled to RT and filtered. The filtrate was concentrated under vacuum to afford of the title compound as brown liquid (11 g, 98%). 1H NMR (DMSO-d6, 400 MHz) δ 7.70 (1H, d), 7.62 (1H, s), 7.16-7.29 (5H, m), 4.09 (2H, q), 3.95 (3H, s), 2.15 (3H, s), 1.30 (3H, t).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 59.3 %

Procedure:
A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144° C.; 1H NMR (CDCl3) δ: 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) δ: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: Nc1ccccn1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C(C)(C)Nc3ccccn3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Yield: 1.7 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 120 mg, 0.317 mmol) and 2-aminopyridine (448 mg, 4.76 mmol) in 5 mL of DCM at 0° C. was added 244 μL (3.17 mmol) of TFA. The mixture was allowed to warm to room temperature, at which time it was cooled in an ice bath and filtered. The filtrate was concentrated in vacuo with MeOH (10 mL) and purified by preparative thin layer chromatography ((2×) with 10% MeOH—CHCl3) to afford 2.5 mg (2%) of the title compound as a white solid. 1H-NMR (CDCl3-CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.6 Hz), 7.88 (m, 1H), 7.64 (s, 1H), 7.29 (m, 1H), 7.18 (d, 1H, J=2.0 Hz), 7.16-7.11 (m, 1H), 7.47-7.44 (m, 1H), 5.81 (d, 1H, J=8.6 Hz), 5.66 (m, 1H), 2.16-2.13 (m, 2H), 1.99 (m, 2H), 1.59 (s, 6H), 1.52-1.44 (m, 2H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H30N6O 455.2 (M+H). found 455.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
(6-Bromo-pyridin-2-yl)-methanol (2949 mg, 15.68 mmol), phthalimide (3000 mg, 20.39 mmol), triphenylphosphine (5348 mg, 20.39 mmol) and 1,1-(azodicarbonyl)-dipiperidine) 5144, 20.39 mmol) were dissolved in THF (150 mL) and stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and the resulting precipitate was removed via filtration. A saturated aqueous sodium bicarbonate solution was added to the filtrate and the solution was extracted several times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and condensed under reduced pressure. The crude residue was purified by column chromatography with a gradient of 10 to 75% AcOEt/hexanes to give 2-(6-Bromo-pyridin-2-ylmethyl)-isoindole-1,3-dione as a white solid (4000 mg, 80%) MS ES (MH+317.2/319.1).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:54][O:55][C:56](=[O:72])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:20][S:21][CH2:22][CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:30]2)=[O:25])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>FC(F)(F)C(O)=O>[C:1]([O:18][CH:19]([CH2:54][O:55][C:56](=[O:72])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:20][S:21][CH2:22][CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]([C:47]([OH:49])=[O:48])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH2:30]2)=[O:25])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)CN(C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2=O)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)CN(C(CCC(=O)O)C(=O)O)C2=O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 5-(6,7-bis(palmitoyloxy)-4-thiaheptanoyl)amino-2-(1,3-bis(t-butyloxycarbonyl)propyl)isoindolin-1-one as obtained in Example 62 (208 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 4 hours, followed by concentration, to yield the title compound (191 mg, yield 100%) as a colorless crystal.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]([C:22]2[CH:23]=[CH:24][C:25](=[O:31])[N:26]([CH:28]([CH3:30])[CH3:29])[N:27]=2)=[N:16][C:17]=1S(C)(=O)=O.Cl>CC(N(C)C)=O>[NH2:11][C:12]1[N:13]=[C:14]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:15]([C:22]2[CH:23]=[CH:24][C:25](=[O:31])[N:26]([CH:28]([CH3:30])[CH3:29])[N:27]=2)=[N:16][C:17]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)n1nc(-c2nc(Oc3ccc(F)cc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in DMA (0.6 ml) was added 4-fluorophenol (87.3 mg) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6-[5-amino-6-(4-fluorophenoxy)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (70 mg)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([O:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[N:16]1[CH2:22][C:23]#[C:24][CH2:25][O:26][CH2:27][C:28]#[N:29])C)C>C(Cl)Cl>[OH:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[N:16]1[CH2:22][C:23]#[C:24][CH2:25][O:26][CH2:27][C:28]#[N:29]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOCC#CCN1C(=O)CCC[C@@H]1CO
Reaction time: 1 h
Yield: 53.1 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.5 mmol) was added to a solution of {4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetonitrile (290 mg, 0.94 mmol) in CH2Cl2 (3 mL). After 1 h at rt, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 118 mg (53%) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[N:10]/[CH3:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:22]/[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])/[C:20]#[N:21])=[C:15]([F:28])[CH:14]=1.[OH-].[K+]>CS(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:20]#[N:21])[CH:22]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:11][NH:10][CH:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[C:15]([F:28])[CH:14]=1
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Reactant: C/N=C/c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2Cl)C1(C#N)c1ccc(Cl)cc1F
Yield: 17.7 %

Procedure:
In a manner similar to the method described in Example 3a, [1-(2,3-dichloro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.76 g, 20.00 mmol) reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (5.03 g, 20.00 mmol) in DMSO (30 mL) in the presence of KOH powder (5.72 g, 56.11 mmol) to give rac-(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (1.56 g 17.7%). HRMS (ES+) m/z Calcd for C22H22Cl3FN2+H [(M+H)+]: 439.0906, found: 439.0905.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:21]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 97802.9 %

Procedure:
To a cooled solution of 10.8 g (0.1 mol) anisole in 100 ml anhydrous toluene 13.3 g (0.1 mol) aluminium trichloride was added in portions over 15 minutes at −10° C. then 15.5 g (12.3 ml, 0.1 mmol) 4-chloro-butyryl chloride were added over 15 minutes keeping the temperature at −10° C. After stirring for additional 30 minutes at −10° C. the reaction mixture was hydrolyzed and the layers were separated. The aqueous layer was extracted with toluene (three times 100 ml) and the combined organic layers were dried and evaporated to yield 20.8 g (97%) 4-chloro-1-(4-methoxy-phenyl)-butan-1-one as a light beige liquid that solidified on standing. The product was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH3:17].O>C(O)C>[CH2:14]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc2ccccc2c1
Yield: 84.9 %

Procedure:
In 100 g of ethanol were dissolved 50 g (0.347 mol) of 2-naphthol and 14.6 g (0.364 mol) of sodium hydroxide. Under reflux, 50 g (0.364 mol) of n-butyl bromide was added to the solution, which was refluxed for a further 4 hours. To the reaction solution were added 200 g of water and 4 g of sodium hydroxide. The organic layer thus separated, 75 g, was distilled in vacuo, obtaining 59 g of 2-n-butoxynaphthalene. The distillate (liquid) solidified when allowed to stand at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:33]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14](=[O:32])[N:15]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>ClCCl>[NH2:33][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=1)[C:14]([N:15]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=1)=[O:32]
Reactant: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 95.4 %

Procedure:
To a mixed solution of 9H-fluoren-9-ylmethyl N-((1S)-2-(4-(tert-butoxy)phenyl)-1-((2,2-diethoxyethyl)((6-fluoropyridin-2-yl)methyl)carbamoyl)ethyl)carbamate (1.37 g, 2.00 mmol) described in Production Example 2-1 and dichloromethane (7.0 mL) was added piperidine (7.0 mL) at room temperature. The resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate) to give the title compound (881 mg, yield: 95%).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=3)[CH2:12]1)[C:8](=[O:37])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[CH3:36][O:35][C:29]1[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:37])[CH2:23]4)[CH2:12]2)[CH:32]=[C:31]([O:33][CH3:34])[N:30]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(OC)nc(OC)n3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(OC)n1
Yield: 99.1 %

Procedure:
A solution of the ethyl ester 18f (0.33 g, 0.64 mmol) in THF/MeOH 1:1 (20 ml) was treated with a 1M solution of LiOH (10 ml) as described in Example 13 step d. Purification by column chromatography on silica gel eluted with DCM-MeOH gave the title compound, (0.31 g, 99%), (M+H)+489.