Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:20][CH2:21][N:22]=2)[N:9]=[N:8]1>[Pd]>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:20]=[CH:21][N:22]=2)[N:9]=[N:8]1
Reactant: FC(F)(F)c1cc(Cn2nnc(C3=NCCN3Cc3ccccc3Cl)c2-c2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd]
Product: FC(F)(F)c1cc(Cn2nnc(-c3nccn3Cc3ccccc3Cl)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 137 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-4-[1-(2-chloro-benzyl)-4,5-dihydro-1H-imidazol-2-yl]-5-phenyl-1H-[1,2,3]triazole (300 mg, 0.53 mmol) in xylenes (2.66 mL) add 10% Pd/C (300 mg). Heat to 137° C. After 72 hours, cool reaction, filter, and concentrate. Purify by chromatography using a gradient of 50:1 to 10:1 CHCl3/MeOH to afford the title compound: MS (IS) 562.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[C:29](N=C(N(C)C)N(C)C)([CH3:32])([CH3:31])[CH3:30]>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:30][CH:29]([CH3:32])[CH3:31])[C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C(C)C)cn2)cc1
Yield: 17.1 %

Procedure:
The title compound (7.6 mg) was prepared from 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (39 mg, 0.097 mmol) and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.020 mL, 0.097 mmol) in acetonitrile (2 mL), following the procedure described for Example 1. LCMS (2 min, formic) Rt 1.37 min, m/z (ES+) 458 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]1([C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CS(C)=O.C(OCC)(=O)C>O>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:31]1[CH:32]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]=[CH:30]1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: c1ccc(-c2c[nH]cn2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(-c4ccccc4)c3)cc2c1=O
Temperature: 120 °C
Yield: 76.8 %

Procedure:
A mixture of 50 mg (0.156 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 139 mg (0.936 mmol) of 4-phenyl-1H-imidazole and 0.25 ml of DMSO is heated to 120° C. for 3.5 hours. After cooling to room temperature, the reaction mixture is distributed between ethyl acetate and water, the organic phase is separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using tetrahydrofuran-hexane (80:20) and the fractions containing the desired product are combined and evaporated giving 53 mg (77%) of the title compound. MS (ES−): m/e=441 (M−1−).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][O:15][CH2:16][CH:9]1[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12]2)C1C=CC=CC=1.[H][H]>CCO.CO.[Pd]>[C:20]1([S:17]([N:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][O:15][CH2:16]3)[CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Yield: 89 %

Procedure:
To a solution of 112e (3.0 g, 8.37 mmol) in EtOH (100 ml) was added Pd/C (0.5 g) in MeOH (30 ml). The reaction mixture was hydrogenated at atmospheric hydrogen at 50° C. for overnight. Then, the catalyst was filtered off, washed with ethanol, and the solvent was evaporated to give 112f as a colorless solid (2.0 g, 90%) MS: [M+H]+: 268
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH2:38]([NH2:40])[CH3:39]>C1COCC1>[CH2:38]([NH:40][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.413 g, 0.770 mmol) and 2.0 M ethylamine in THF (10 mL, 20 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 20 minutes to give ethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a dark yellow solid (0.292 g, 92.7%). This was dissolved in chloroform and methanol, and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a beige solid (0.227 g) MP 276-7° C.dec.; Mass Spectrum (+EI, [M+H]+) m/z 410. 1HNMR (500 MHz, DMSO-d6): δ8.95 (s, br, 2H), 8.75 (d, 1H, J=8.79 Hz), 8.52 (dd, 1H, J=7.45 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.04 (d, 1H, J=7.57 Hz), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.36 (d, 1H, J=2.07 Hz), 7.22 (dd, 1H, J=9.15 Hz and 2.31 Hz), 4.30-4.33 (m, 2H), 4.05 (s, 3H), 3.33-3.34 (m, 2H), 2.99-3.05 (m, 2H), 1.19-1.23 ppm (m, 3H). Elemental Analysis for C22H23N3O3S.1.00 mol HCl.0.40 mol H2O: Calcd: C, 58.31; H, 5.52; N, 9.27; Found: C, 58.62; H, 5.54; N, 9.11.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>C/C(/O)=C/C(C)=O.C=C.C=C.[Rh].O1CCOCC1.O>[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][C:13]([C@@H:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1C=CCCC1
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC[C@@H](c2ccc(C(F)(F)F)cc2)C1
Temperature: 100 °C

Procedure:
To a 40 ml microwave flask containing dioxane/H2O (10/1) (22 mL) was added cyclohexen-1-one (1.35 g, 14.0 mmol), acetylacetonatobis(ethylene)rhodium(I) (0.36 g, 1.40 mmol), R-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (0.88 g, 1.40 mmol) and 4-(trifluoromethyl)-phenylboronic acid (5.0 g, 28.0 mmol). The mixture was heated in the microwave (Personal Chemistry) at 100° C. for 20 minutes. The material was transferred to a separatory funnel and extracted with ethyl acetate (150 mL). The resulting organic layer was washed with NaHCO3 (75 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The mixture was purified on SiO2 (hexane/ethyl acetate 4/1) to provide the title compound. [α]D=+13.62 c=1.0 (CH3OH). 1H NMR (CD3OD, 300 MHz); δ 1.72-2.20 (m, 5H), 2.35-2.73 (m, 3H), 3.06-3.15 (m, 1H), 7.40-7.42 (m, 2H), 7.46-7.63 (m, 2H). MS (+ESI)m/z 242 (M+NH4—H2O)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[N:15]=[CH:16][N:17]([C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:38]([O:40][CH3:41])=[O:39].[Br:42]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:42][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[N:15]=[CH:16][N:17]([C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:18]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1CBr
Yield: 108.2 %

Procedure:
Methyl 1-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthoate (20.7 g) was suspended in carbon tetrachloride (400 mL) and N-bromosuccinimide (7.5 g) and 2,2′-azobisisobutyronitrile (0.58 g) were added. The reaction mixture was heated under reflux for 5 hrs. and concentrated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a crude title compound (25.7 g) as a brown amorphous solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH2:31]1[CH2:35][O:34][CH2:33][CH2:32]1>>[O:30]=[C:4]1[C:3](=[CH:2][NH:20][C:16]2[CH:17]=[CH:32][C:33]([O:34][CH2:35][CH2:31][N:5]3[CH2:6][CH2:11][CH2:3][CH2:4]3)=[CH:14][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: C1CCOC1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(OCCN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 121 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine1 (67.7 mg, 0.329 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture, and the resulting suspension was filtered. The filtrate then was concentrated in vacuo. The residue was redissolved into EtOAc then diluted with Hexanes causing a precipitate to form. This precipitate was filtered and washed with ˜1 mL of i-prOH yielding 62% (0.109 g, 0.185 mmol) of the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](F)[CH:4]=[C:3]([CH2:8][CH:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1.N[C@H](C(O)=[O:24])CC1C=CC=CC=1>>[CH:1]1[CH:6]=[C:5]([OH:24])[CH:4]=[C:3]([CH2:8][C@H:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC(Cc1cccc(F)c1)C(=O)O
Product: N[C@@H](Cc1cccc(O)c1)C(=O)O

Procedure:
DL-3-fluorophenylalanine and L-phenylalanine were purchased from Sigma (UK).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[SH2:17]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8](=[S:17])[NH2:9]
Reactant: Cc1ccncc1C#N
Reactant: S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccncc1C(N)=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of compound (14)(9.2 g, 77.9 mmol) in dimethylformamide (500 ml) was added triethylamine (800 mg, 7.79 mmol; 10 mol %), and the mixture was stirred at room temperature for 16 hrs. while introducing hydrogen sulfide gas. The solvent was concentrated and the obtained residue was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane. The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from a small amount of ethyl acetate to give the title compound (10.2 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)[N:8]=2)[CH:7]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Yield: 99.9 %

Procedure:
A solution of 5-chloropyrazin-2-amine (0.336 g, 2.6 mmol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (0.811 g, 2.6 mmol) in acetonitrile (15 mL) is stirred at 100° C. for 18 hr. The mixture is concentrated to give the title compound (890 mg), which is used without further purification. LCMS m/z=343.3 [M+H]+, tR=2.65 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6](=[O:7])[C:5]2=[CH:28][CH:29]=1.[C:30]([O:47][CH:48]([CH2:56][O:57][C:58](=[O:74])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:49][S:50][CH2:51][CH2:52][C:53](O)=[O:54])(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:30]([O:47][CH:48]([CH2:56][O:57][C:58](=[O:74])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:49][S:50][CH2:51][CH2:52][C:53]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:6](=[O:7])[C:5]2=[CH:28][CH:29]=1)=[O:54])(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CC(C)(C)OC(=O)CCC(C(=O)OC(C)(C)C)N1C(=O)c2ccc(N)cc2C1=O
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc2c(c1)C(=O)N(C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2=O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4-amino-N-(1,3-bis-(t-butyloxycarbonyl)propyl)phthalimide (178 mg) in pyridine (2.3 ml), phosphorus trichloride (0.020 ml) was added, followed by stirring at room temperature for 2 hours. To this mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 24 (150 mg) was added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:acetone=3:1) to yield the title compound (190 mg, yield 80%) as a wax-like substance.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[CH3:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
Phenol (28.5 g, 0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a golden oil (48.5 g, 83%) 1H NMR (250 MHz, CDCl3): δ 7.31 (d, 2H, J=7.8), 7.02 (t, 1H, J=7.9), 6.93 (d, 2H, J=7.8), 4.79 (q, 1H, J=6.1), 4.26 (q, 2H, J=7.2), 1.66 (d, 3H, J=6.1), 1.24 (t, 3H, J=7.2). MS [EI+] 195 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.ClC1C=CC(C2C3CCNCCC=3NN2C2CCOCC2)=CC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClC1CCOCC1
Agent: Clc1ccc(C2C3=C(CCNCC3)NN2C2CCOCC2)cc1
Product: Clc1ccc(-c2nn(C3CCOCC3)c3c2CCNCC3)cc1

Procedure:
The title compound was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) using 4-chloro-tetrahydro-pyran (1.5 mmol) in place of chloro-cyclobutane. The title compound was obtained as a 2:1 mixture (10 mg) with 3-(4-chloro-phenyl)-2-(tetrahydro-pyran-4-yl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. Data for the mixture: MS (ESI): exact mass calculated for C18H22ClN3O, 331.15; found, m/z 332.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.42 (m, 1H), 7.36-7.30 (m, 4H), 7.20-7.18 (m, 1H), 4.36-4.33 (m, 1H), 3.97-3.94 (m, 3H), 3.87-3.86 (m, 1H), 3.51-3.49 (m, 3H), 3.28-3.25 (m, 1H), 2.90-2.75 (m, 8H), 2.66-2.64 (m, 2H), 2.39-2.37 (m, 1H), 2.19-2.10 (m, 3H), 1.74-1.71 (m, 2H), 1.65-1.62 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[O:20]C)[N:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CC(F)(F)F)ccc1Oc1cccc(F)n1
Agent: BrB(Br)Br
Product: Oc1cc(CC(F)(F)F)ccc1Oc1cccc(F)n1
Yield: 75 %

Procedure:
According to the procedure of example 5 (b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by 2-fluoro-6-[2-methoxy-4-(2,2,2-trifluoroethyl)phenoxy]pyridine (0.14 mmol; 43 mg) and adding 3.5 equivalents (0.5 mmol; 500 μl) of boron tribromide, the title compound was prepared in 75% yield (0.11 mmol; 30 mg) after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[CH3:19][NH:20][C:21]([NH2:23])=[S:22].O>C(O)C>[CH3:19][NH:20][C:21]1[S:22][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:23]=1
Reactant: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CNC(N)=S
Solvent: CCO
Solvent: O
Product: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 80.9 %

Procedure:
A solution containing 32.4 g (0.10 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide and 11.3 g (0.13 mole) of N-methylthiourea in 250 ml of ethanol was refluxed for four hours. The reaction mixture was poured into 700 ml of water and ethanol was added. A small quantity of insoluble material was removed by filtration and the filtrate was made strongly alkaline by the addition of ammonium hydroxide. The solution was cooled and an additional 400 ml of water was added. The precipitated solid was collected and dried in an oven. There was obtained 25.5 g (81%) of product, m.p. 153°-55°, N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.8-2.9 (CH3, doublet), 3.5 (CH2), 6.3 (hetero-aromatic), 7.3-8.1 (aromatic, NH), 10.4 (HNC=O).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]2[NH:20][C:19](=[O:21])[CH2:18][S:17]2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].O=C1CSC(C[CH2:29][CH2:30][C:31]2[CH:41]=[CH:40][C:34](C(OCC)=O)=[CH:33][CH:32]=2)N1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]2[N:20]([CH2:29][CH2:30][C:31]3[CH2:41][CH2:40][CH2:34][CH2:33][CH:32]=3)[C:19](=[O:21])[CH2:18][S:17]2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(CCCC2NC(=O)CS2)cc1Cl
Reactant: CCOC(=O)c1ccc(CCCC2NC(=O)CS2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1Cl

Procedure:
This compound is prepared by the method described in Example 4, Step B, except that an equivalent quantity of ethyl 2-chloro-4-[3-(4-oxo-2-thiazolidinyl)propyl]benzoate is substituted for the ethyl 4-[3-(4-oxo-2-thiazolidinyl)propyl]benzoate of Example 4, Step B. The title compound is obtained as an oil by column chromatography on silica gel with 2% methanol in chloroform as eluant.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].[Cl:10][C:11]1[C:12]([F:23])=[C:13]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:14](Cl)=[O:15]>>[Cl:10][C:11]1[C:12]([F:23])=[C:13]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:14]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:15]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1c(F)c(F)c(Cl)c(F)c1C(=O)Cl
Product: CCOC(=O)CC(=O)C(=O)c1c(C)c(F)c(F)c(Cl)c1F

Procedure:
The procedure outlined for Example H was used to prepare the title compound from the dianion of malonic acid monoethyl ester and 3-chloro-2,4,5-trifluoro-6-methylbenzoyl chloride. The crude product was also chromatographed on silica gel to give the desired product as an orange oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1.[Ni]>[CH3:13][CH:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]([CH3:16])[CH3:17])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: O=Cc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@@H](N)Cc1ccccc1
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](Cc1ccccc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.37 h
Yield: 21 %

Procedure:
A solution of (S)-α-amino-N-[2,6-bis(1-Methylethyl)phenyl]benzenepropanamide (1.0 g, 3.1 mmol) and benzaldehyde (0.33 g, 3.1 mmol) in toluene (100 mL) was heated under reflux for 1 hour with the azeotropic removal of water then cooled (25° C.). To the resulting solution was added one equivalent of Raney nickel, and the resulting slurry was shaken vigorously under hydrogen (53 psi, 82 min 25° C.). The resulting slurry was filtered, and the filtrate was concentrated. The resulting oil was triturated with ether/hexane (1:1), and the resulting precipitate was collected by filtration to yield 0.27 g (21%) of the title compound, mp 120°-124° C.