Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd].C(O)C>[F:39][C:36]([F:37])([F:38])[C:28]1[CH:27]=[C:26]([CH2:25][O:24][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:15][C@H:14]3[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=1
Reactant: O=C([C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1)N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C([C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-piperidinylcarbonyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 120; 100 mg, 0.16 mmol), 10% palladium on charcoal (180 mg) and ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified chromatography on silica gel to give the title compound (83 mg, 90%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:4]=1[NH:13][NH2:14].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)=[C:23]([CH3:32])[CH:22]=1)=O>>[F:2][C:3]1[CH:8]=[C:7]([S:9]([NH2:10])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[N:13]1[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[CH:29][S:30][CH:31]=3)=[C:23]([CH3:32])[CH:22]=2)=[CH:18][C:17]([C:16]([F:35])([F:34])[F:15])=[N:14]1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Reactant: NNc1ccc(S(N)(=O)=O)cc1F
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2F)ccc1-c1cscn1

Procedure:
The title compound was prepared according to the procedure of Example 60 using 2-fluoro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[3-methyl-4-(4-thiazolyl)phenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br>CC(C)=O>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccccc1CBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1COc1ccc(C#N)cc1F
Yield: 90 %

Procedure:
To a solution of 3-fluoro-4-hydroxy-benzonitrile (1.2 g, 8.7 mmol; CAS Reg. No. 405-04-9) in acetone (20 ml) was added cesium carbonate (4.2 g, 13.05 mmol) and 2-bromomethyl-benzoic acid methyl ester (2 g, 8.7 mmol; CAS Reg. No. 2417-73-4) and the resulting solution was heated to reflux for 12 h. The reaction mixture was filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel (8-10% ethyl acetate/n-hexane) to give the desired product as a yellow sticky solid (90%). MS (Turbo Spray): m/z=286.1 (M+H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12]O)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:29])=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:29][CH2:12][CH:10]1[CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:26])[C:9]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1N(C2CCCCC2)CC(CO)C1(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1N(C2CCCCC2)CC(CCl)C1(c1ccccc1)c1ccccc1
Yield: 55 %

Procedure:
To 60.0 g. (0.17 mole) of 1-cyclohexyl-4-hydroxymethyl-3,3-diphenyl-2-pyrrolidinone in 400 ml. of chloroform was added 48.0 g. (0.40 mole) of thionylchloride with stirring. To this solution was added dropwise with ice bath cooling 40 g. (0.52 mole) of dry pyridine and the solution was refluxed for 2 hours. After concentrating in vacuo the residue was dissolved in chloroform and washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide solution. The chloroform solution was dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was recrystallized from isopropyl ether and after drying weighed 34.5 g. (55% yield) and melted at 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CSc1cccc(N=C=O)c1
Product: CSc1cccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1

Procedure:
Example 18 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-3-(methylthio)benzene (18.8 μl) to give the title compound (0.0352 g). LC-MS (System A): Rt 2.41 mins, Mass Spectrum m/z 440 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][C@@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][C@@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: C[C@H](N)CC(=O)OC(C)(C)C
Product: C[C@@H](CC(=O)OC(C)(C)C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1,1-dimethylethyl (3S)-3-aminobutanoate using methods similar to Example 563 to provide an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25 (d, J=6.74 Hz, 3 H), 1.39 (s, 9 H), 1.52-1.67 (m, 4 H), 1.99-2.11 (m, 2 H), 2.52-2.58 (m, 2 H), 3.19-3.30 (m, 2 H), 3.49 (t, J=6.84 Hz, 2 H), 4.16 (s, 2 H), 4.35-4.42 (m, 3 H), 7.11-7.17 (m, 2 H), 7.41 (m, 2 H), 8.20 (d, J=1.47 Hz, 1 H), 8.57 (d, J=1.68 Hz, 1 H), 10.41 (d, J=8.21 Hz, 1 H), 17.06 (d, J=5.26 Hz, 1 H); ES+ MS: 581 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.CN.[CH3:28][N:29](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC)ccc21
Yield: 49.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid methylamide (77.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), methylamine (2.0 M solution in THF, 1.0 mL), HBTU (190 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 387; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, br. s), 8.08 (1H, br. s), 7.95 (1H, m), 7.73 (2H, m), 7.51 (1H, m), 7.41-7.38 (1H, m), 4.21 (1H, bs. s), 2.82-2.80 (3H, d), 1.34-1.30 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: CS(O[CH:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][N:8]([CH3:18])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=O)=O.[NH:25]1[CH2:30][CH2:29][C:28]2([CH2:34][S:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]2=3)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:18][N:8]([CH2:7][CH:6]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[N:25]1[CH2:30][CH2:29][C:28]2([CH2:34][S:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]2=3)[CH2:27][CH2:26]1)[S:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: CN(CC(OS(C)(=O)=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: c1ccc2c(c1)SCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC(c1ccccc1)N1CCC2(CC1)CSc1ccccc12)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 62.2 %

Procedure:
N-(2-Methanesulfonyloxy-2-phenylethyl)-N-methylbenzenesulfonamide (128 mg, 0.346 mmol), spiro(benzo[b]thiophene-3(2H),4'-piperidine) (142 mg, 0.693 mmol), and sodium carbonate (167 mg, 1.04 mmol) were combined in 1.0 mL of dry DMF. The mixture was stirred under nitrogen 1 h at room temperature and 1.5 h at 40° C., then slowly warmed to 65° C. and maintained at that temperature for 5 h. After cooling to room temperature and stirring overnight, the mixture was partitioned between 50 mL of ethyl acetate and 25 mL of saturated aqueous sodium bicarbonate. The organic layer was washed with 25 mL of brine, dried over sodium sulfate and concentrated. Purification by preparative TLC, eluting with 5% ethyl ether in dichloromethane, gave 103 mg of the title compound as a viscous oil. 1NMR (400 MHz, CDCl3): δ 7.77 (d, 2H, J=8 Hz), 7.58 (tt, 1H, J=8, 1 Hz), 7.51 (t, 2H, J=8 Hz), 7.39-7.28 (m, 3H), 7.23 (d, 2H, J=8 Hz), 7.17-7.03 (m, 4H), 3.77 (t, 1H, J=7 Hz), 3.71 (dd, 1H, J=13, 7 Hz), 3.30 (dd, 1H, J=13, 7 Hz), 3.12 (d, 1H, J=11 Hz), 3.08 (d, 1H, J=11 Hz), 2.94 (bd, 1H, J=12 Hz), 2.84 (bd, 1H, J=12 Hz), 2.65 (s, 3H), 2.34 (td, 1H, J=12, 3 Hz), 1.99 (td, 1H, J=12, 3 Hz), 1.96-1.73 (m, 4H). Mass spectrum (ESE): m/z=479 (M+1).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:45]([S:52][CH:53]([CH:56]([O:59][CH3:60])[O:57][CH3:58])[CH2:54][NH2:55])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[CH2:45]([S:52][CH:53]([CH:56]([O:57][CH3:58])[O:59][CH3:60])[CH2:54][NH:55][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)C(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
To a solution of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.662 g) in N,N-dimethylformamide (20 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.414 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.292 g) and 2-(benzylthio)-3,3-dimethoxypropan-1-amine (0.500 g), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-60:40) to give the title compound (0.776 g, yield 70%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][O:25]S(C)(=O)=O)[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1.[CH3:32][O-].[Na+]>CO>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][O:25][CH3:32])[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1
Reactant: C[O-]
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)cn2)n1
Agent: [Na+]
Solvent: CO
Product: COC[C@H]1CN(c2ccc(-c3ccc(-c4nnn(C)n4)nc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-one prepared in the secondary step of the Example 24. The solution was added with 90 mg of sodiummethoxide at room temperature and then stirred for one day at room temperature. The solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered, concentrated in vacuo and purified by column chromatography to provide the title compound 200 mg. Yield 58%.
Reaction SMILES: [N:1]1[N:2]([C:6]2[C:7]([C:16]([O:18]CC)=[O:17])=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=[CH:4][CH:5]=1.[OH-].[Na+].Cl>CO>[N:1]1[N:2]([C:6]2[C:7]([C:16]([OH:18])=[O:17])=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1nc2ccccc2cc1-n1nccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc2ccccc2cc1-n1nccn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To the title compound of Step A (134 mg, 0.5 mmol) in MeOH (1 mL) was added aqueous 2M NaOH (1 mL). After 1 h at rt, the reaction was heated to 50° C. for 1 h, cooled to rt, acidified with 1N HCl, concentrated and used in subsequent steps without further purification. MS (ESI) mass calcd. for C12H8N4O2, 240.2; m/z found 241.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]4[CH2:20][O:21][C:22](=[O:23])[C:12]3=4)[CH:9]=2)[NH:4][N:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[CH3:19][C:15]1[NH:14][C:13]2[CH2:20][O:21][C:22](=[O:23])[C:12]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)[C:16]=1[C:17]#[N:18]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(Br)c3c2)C2=C(COC2=O)N1
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: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(-c4cccc(C(F)(F)F)c4)c3c2)C2=C(COC2=O)N1
Temperature: 95 °C
Reaction time: 12 h
Yield: 4.3 %

Procedure:
To a degassed solution of 120 mg (0.323 mmol) 4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile (Example 24) and 73.7 mg (0.388 mmol) [3-(trifluoromethyl)phenyl]boronic acid in anhydrous 1,4-dioxane (4.8 ml) were added under argon atmosphere 37.4 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution (2 M, 0.77 ml). The resulting mixture was stirred at 95° C. for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was subsequently washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (first run: acetonitrile/water gradient, final mixture 95:5 v/v; second run: methanol/water isocratic 75:25 v/v) to yield the title compound as a white solid (6 mg, 4% of th.).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([O:42][CH2:43][CH3:44])=[N:40][CH:41]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([O:42][CH2:43][CH3:44])=[N:40][CH:41]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: CCOc1ncc(Br)cn1
Product: CCOc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1
Yield: 62 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 62% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)chroman-3-amine and 5-bromo-2-ethoxypyrimidine. The reaction mixture was irradiated in a microwave at 140° C. for 20 min; MS (ESI) m/z 452[M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][C:30]=4[F:32])[N:17]=[N:18][CH:19]=3)[CH:11]=[CH:10][C:9]=2[F:22])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CSc1nncc(-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)n1
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F
Yield: 69.4 %

Procedure:
4,2′-Difluoro-5′-(3-methylsulfanyl-[1,2,4]triazin-5-yl)biphenyl-2-carbonitrile (0.15 g, 0.44 mmol) was coupled to 2,4-difluorobenzeneboronic acid (0.135 g, 0.97 mmol) by the method of Example 2 to give the title product as a pale yellow solid (124 mg): δH (400 MHz, CDCl3) 6.99-7.11 (2H, m), 7.44-7.48 (2H, m), 7.54-7.59 (2H, m), 8.32-8.39 (3H, m) 9.65 (1H, s); m/z (ES+) 407 (M++H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:23])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][CH:7]=1)=O.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH:24]1([N:30]2[C:4]([C:6]3[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][CH:7]=3)=[C:3]([CH3:23])[NH:2][C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCCCCCCCOc1ccc(C(=O)C(C)N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCOc1ccc(-c2c(C)[nH]c(=O)n2C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
2-Amino-4'-decyloxypropiophenone hydrochloride (500 mg, 1.46 mmol) was suspended in acetone (180 ml) under ice-cooling, and cyclohexyl isocyanate (201 mg, 1.61 mmol) was added thereto. Triethylamine (590 mg, 5.84 mmol) was added, and the mixture was stirred for one hour under ice-cooling. After addition of trifluoroacetic acid (2 ml), the mixture was stirred overnight at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with ethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a crude product, which was then purified by column chromatography (chloroform/ethanol=50/1 (v/v)) to give the title compound. Yield: 235 mg (39%), m.p. 137°-138° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1)(=[O:21])=[O:20]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28]([O:10][CH2:9][C:7]2[O:8][C:4]([CH2:3][NH:2][CH3:1])=[CH:5][CH:6]=2)=[N:27][CH:26]=[CH:25][N:24]=1)(=[O:20])=[O:21]
Reactant: CNCc1ccc(CO)o1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Product: CNCc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 28 using (5-methylaminomethyl-2-furanyl)methanol (0.2 g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.4 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.12 g.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>>[CH3:1][N:2]([CH3:23])[C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=3)([N:38]([C:39]3[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:43][CH:44]=3)[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[CH:37][CH:36]=3)[O:9][C:8]2=[O:10])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Yield: 87.6 %

Procedure:
Following a procedure similar to that described in Example 1 but employing 15.6 g of 5-(dimethylamino)-2-[4-(dimethylamino)benzoyl]benzoic acid and 19.6 g of 4,4'-dioctyldiphenylamine there was obtained 30.0 g of 6-(dimethylamino)-3-[4-(dimethylamino)phenyl]-3-[bis(4-octylphenyl)amino]phthalide, m.p. 208°-210° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange-colored image which changed to green on the clay after fluoroescent light exposure.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[Si:17]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1C=CCCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1C=CCCC1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 5.0 g of 2-cyclohexen-1-ol, 7.6 g of imidazole and 14.6 ml of tert-butylchlorodiphenylsilane in 100 ml of N,N-dimethylformamide was stirred at room temperature for 16 hrs. The mixture was then partitioned between 100 ml of saturated brine and 250 ml of ether. The layers were separated and the organic layer was washed with 100 ml of water and dried over magnesium sulfate and the solvent was evaporated in vacuo to give 3-(tert-butyldiphenylsilyloxy)cyclohexene as a viscous oil which was used without further purification. 1H NMR (CDCl3) δ 1.05 (s, 9H); 4.10 (m, 1H); 5.50 (br s, 2H); 7.20-7.70 (m, 10H).