Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.N1CCCCC1.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>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.[Cu]I.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:37]#[C:36][C:34]([OH:38])([C:30]4[S:29][CH:33]=[CH:32][N:31]=4)[CH3:35])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccs3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a sealed tube was added 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide (55%, 113 mg, 0.172 mmol), followed by piperidine (2 mL), tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol), copper(I) iodide (7 mg, 0.034 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (105 mg, 0.688 mmol). The reaction mixture was purged with nitrogen gas, capped and stirred at 60° C. for 1.5 hr. Reaction mixture was concentrated in vacuo. EtOAc (5 mL) added. Concentration in vacuo was repeated. The residue was purified using column chromatography (Biotage, 100% DCM to 10% MeOH/DCM) to give a brown solid. Trituration of the solid with DCM gave the title compound: 1H NMR (500 MHz, DMSO) delta 1.95 (3H, s), 3.12 (3H, s), 3.33 (3H, s), 7.12 (2H, s), 7.13-7.19 (2H, m), 7.42 (1H, dd, J=8.35, 1.42 Hz), 7.71 (1H, d, J=3.31 Hz), 7.80 (1H, d, J=3.15 Hz), 7.97-8.07 (1H, m), 8.35 (1 H, d, J=5.52 Hz), 8.94 (1H, s); LC-MS: m/z=+434.45 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40]O)[C:5]=2[N:4]=1.C[CH2:44][N:45](CC)[CH2:46]C.CS(Cl)(=O)=O.N(C)C>C1COCC1>[F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][CH2:39][CH2:40][N:45]([CH3:46])[CH3:44])[C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Reactant: CCN(CC)CC
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CCCOc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate from the previous step and 0.34 g (3.3 mmol) of Et3N in 20 mL of THF was cooled to 0° C. and 0.32 g (2.8 mmol) of methanesulfonyl chloride was added dropwise. After 1 hr, 6 g of 40% aqueous Me2NH was added, and the resulting mixture was stirred at room temperature for 36 hrs. The THF was removed under vacuum and the residue was diluted with water and extracted into CH2Cl2. Drying and removal of the solvent gave tert-butyl 4-[4-{2-(difluoromethyl)-4-[3-(dimethylamino)propoxy]-1H-benzimidazol-1-yl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.87 (dd, J=8.4. 0.6 Hz, 1H), δ 7.48 (t, JHF=53.5 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.31 (t, J=6.7 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.53 (m, 4H), 2.51 (t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.13 (pentet, J=7.0 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.Br.Br.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:26])[F:27])[CH:14]=3)[CH2:25][CH2:24]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(NC2CCNCC2)c1
Reactant: Clc1ccc(Cl)nn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(NC2CCN(c3ccc(Cl)nn3)CC2)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
A mixture of 3 parts of 3,6-dichloropyridazine, 6.1 parts of N-[3-(trifluoromethyl)phenyl]-4-piperidinamine dihydrobromide, 6.4 parts of sodium carbonate and 180 parts of N,N-dimethylacetamide was stirred for 24 hours at 60° C. After cooling to room temperature, the reaction mixture was poured onto water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.5 parts (47%) of 1-(6-chloro-3-pyridazinyl)-N-[3-(trifluoromethyl)phenyl]-4-piperidinamine; mp. 117.9° C. (compound 148).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:25]#[N:26].C(O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]2[NH:30][C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[N:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To 4-phenoxybenzaldehyde (4.0 g, 0.020 mol) was added 20 mL of 40% NaHSO3 (aq). The mixture was stirred for 2 h at 25° C. 3,4-Diaminobenzonitrile (3.36 g, 0.0252 mol) and ethanol (50 mL) were added. The mixture was refluxed for 4 h. The reaction was then poured into water. The precipitate was filtered and recrystallized from ethyl acetate to afford 3.6 g (57%) of 2-(4-phenoxyphenyl)-1H-benzimidazole-5-nitrile.
Reaction SMILES: ClC(OCC)=O.[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38]>C(Cl)(Cl)Cl>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([C:24]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[O:35][CH3:34])=[O:26])[CH2:22][CH2:23]1
Reactant: O=C(O)C1CCN(CC2COc3ccccc3O2)CC1
Reactant: COc1ccccc1N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)C1CCN(CC2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.4 %

Procedure:
Ethyl chloroformate (0.1 g) was added dropwise to a stirred solution of 1-(1,4-benzodioxan-2-ylmethyl)piperidine-4-carboxylic acid (0.28 g) and triethylamine (0.12 g) in chloroform (10 ml) at 0° C. After 30 minutes a solution of 2-methoxyaniline (0.12 g) in chloroform (5 ml) was added and the mixture stirred at ambient temperature for 16 hours. The reaction mixture was then washed sequentially with water, aqueous sodium hydroxide solution (1M), hydrochloric acid (1M) and water. The solution was dried over magnesium sulphate, the solvent was removed in vacuo, and the residue was eluted through a silica column using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluant. The solvent was removed in vacuo to yield 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide as a solid (50 mg). This procedure was repeated on 9X scale with the following changes. The reaction was heated to 50° C. for 1 hour after being stirred at ambient temperature for 16 hours. The solvent was then removed in vacuo and the residue was eluted through a silica column as previously described. Further desired product (1.05 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29](F)=[C:28]([F:31])[C:27](F)=[C:26](F)[C:25]=3F)=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].[C:48](OC)(C)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:31])[C:29]=3[CH3:48])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)c(F)c(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Reactant: COC(C)(C)C
Product: Cc1c(F)cccc1CCCCOc1ccc(C#Cc2ccc(F)c3c(CCCC(=O)O)c(C)n(CCCC(=O)O)c23)cc1
Temperature: 25 °C

Procedure:
The compound (30 mg) prepared in Example 14 (2) was dissolved in methyl tertiary butyl ether (2.4 mL) at 60° C. The solution was cooled to room temperature to induce crystallization. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (24 mg).
Reaction SMILES: N[S:2]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH3:19])[C:6]=1[C:7]([N:9](CC)CC)=[O:8])(=[O:4])=[O:3]>C(O)(=O)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:5]2[C:6]=1[C:7](=[O:8])[NH:9][S:2]2(=[O:4])=[O:3])[CH3:19]
Reactant: CCN(CC)C(=O)c1c(C(C)[Si](C)(C)C)cccc1S(N)(=O)=O
Solvent: CC(=O)O
Product: CC(c1cccc2c1C(=O)NS2(=O)=O)[Si](C)(C)C
Yield: 0.1 %

Procedure:
To a solution of sec-BuLi (0.97M, 5.10 mL, 4.96 mmol) and TMEDA (0.75 mL, 4.96 mmol) in THF at -78° C. was added the amide (1.25 g, 4.50 mmol) in THF. Excess SO2 in THF was added quickly at -78° C. then warmed to room temperature. The THF was removed in vacuo and the residue treated at 0° C. with two equivalents of a 1:1 solution of sodium hydroxide (0.36 g, 9.0 mmol) and hydroxylamine-O-sulfonic acid (1.0 g, 9.0 mmol) in H2O. The reaction was stirred at room temperature for 4 hrs, extracted with EtOAc, dried over MgSO4, concentrated and flash chromatographed on silica gel with 20% ethyl acetate/hexane to give 0.62 g (41%) of 2-aminosulfonyl-N,N-diethyl-6-[1-(trimethylsilyl)-ethyl]benzamide. The benzamide (0.95 g, 2.66 mol) was refluxed in glacial acetic acid (20 mL) for 18 hr, stripped to dryness, triturated with hot cyclohexane (30 mL) and a trace of EtOAc (3 mL), cooled with scratching and filtered. There was obtained 0.81 g (85%) of 4-[1-(trimethylsilyl)-ethyl]saccharin, mp 123°-125° C.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:10]1=[O:29])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2>>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=2)[C:10]1=[O:29])[C:6](=[O:7])[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Reactant: Nc1ccc2c(c1)CNC2=O
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(c1)CNC2=O)[C@H]1OCCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Yield: 81.5 %

Procedure:
According to the Step 70-5 in the synthetic method for EXAMPLE 70, compound 73-3 (65 mg) was used instead of compound 70-4 to couple to 5-aminoisoindolin-1-one (25 mg) to obtain compound 74-1 (69 mg) as a white solid after reverse-phase (C18) purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:19]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1N
Product: COc1cccc(C(=O)Nc2ccccc2OC)c1
Yield: 100 %

Procedure:
Using o-anisidine (1.0 ml, 8.55 mmol) and m-anisoyl chloride (1.2 ml, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.2 g (100%) of the title compound in the form of brown oil.
Reaction SMILES: O=S1(=O)[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4]O1.[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:7]([NH:6][C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][F:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [F-]
Reactant: CC(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H](CF)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To an ice-cooled solution of (4S)-2,2-dioxo-3-benzyl-4-isopropyl-1,2,3-oxathiazolidine (1.9 g, 7.44 mmol) in THF (30 mL) was added a 1.0 M THF solution of tetrabutylammonium fluoride (14.88 mL, 14.88 mmol). The mixture was stirred for 1 h as ice bath melted and the reaction was gradually warmed to room temperature, then stirred overnight. The mixture was concentrated, and the remaining residue was treated with ether (25 mL) and 20% vol/vol aqueous sulfuric acid (25 mL). The reaction was stirred for 2 h at room temperature. The mixture was neutralized with 2 M NaOH (ca. 50 mL) and the layers were separated. The aqueous layer was extracted with ether (25 mL). The combined organic extracts were dried (MgSO4), filtered, then concentrated under vacuum to give the title compound (1.4 g) as a colorless oil. LCMS m/z=196.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.88 (oct, J=6.8 Hz, 1H), 2.57-2.66 (m, 1H), 3.80 (d, J=13.4 Hz, 1H), 3.88 (d, J=13.4 Hz, 1H), 4.34-4.59 (m, 2H), 7.22-7.36 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N-:13]=[N+]=[N-].[Na+].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[O:1]=[C:2]1[NH:13][CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCNC(=O)CC1
Temperature: 10 °C
Yield: 70 %

Procedure:
In a 250 ml three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 5.6 ml (5.98 g, 34 mmoles, 1 eq) of ethyl 4-oxocyclohexanecarboxylate 27 were dissolved in 50 ml of CHCl3. 6.65 g (102 mmole, 3 eq) of sodium azide were added, followed by 22.1 ml (32.8 g, 341 mmoles, 10 eq) of methanesulfonic acid dissolved in 20 ml of over 30 min. The mixture was heated to reflux for 1 hour and cooled down to 10° C. 200 nl of saturated sodium bicarbonate solution were added, the mixture decanted and the aqueous phase extracted with 3×150 ml of CHCl3, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (800 g SiO2, CH2Cl2/MeOH, 97/3) to give 5.1 g of crude compound. It was crystallised from 40 ml of diethylether to give 4.41 g of pure ester 28, 70% yield.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=3[C:8](=[O:9])[C:4]2=[C:5]([OH:7])[CH:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[CH:17]([C:24](=[O:26])[CH3:25])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 56.5 g (0.25 mol) of purified anthralin in 1750 cm3 of anhydrous toluene being stirred at room temperature, 27.3 cm3 (0.34 mol) of anhydrous pyridine was added first and then 21.4 cm3 (0.3 mol) of acetyl chloride was added dropwise by means of a dropping funnel. Slight heating occurred during addition then, after the end of addition, the mixture was heated to a temperature of around 90° C. for 1 hour. The mixture was cooled and 27.3 cm3 of pyridine and then, dropwise, 21.4 cm3 of acetyl chloride were again added at 30°-35° C. The mixture was then stirred for 1 hour at 85°-90° C. After a check to insure that the anthralin had been transformed to the 10-acetyl derivative, the reaction mixture was cooled to room temperature then washed 3 times with water (250 cm3). The toluene phase was decanted, dried over sodium sulfate and then concentrated to around 300 cm3. The solution was then deposited on a column of silica gel and eluted with toluene and a 1:1 mixture of toluene and methylene chloride. The first fractions were combined and then concentrated under vacuum. The solid obtained was then recrystallized from toluene to yield 21 g of bright-yellow crystals of 1,8-dihydroxy-10-acetylanthrone having a melting point of 146° C.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:15][CH2:14][C:13]([F:17])([CH3:16])[C:12]3[S:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[F:17][C:13]1([CH3:16])[C:12]2[S:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:8]=2[C:6]2[CH:7]=[C:2]([C:25]#[C:24][C@:26]3([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]3=[O:32])[C:3]([F:23])=[CH:4][C:5]=2[O:15][CH2:14]1
Reactant: CCOC(=O)c1nc2c(s1)C(C)(F)COc1cc(F)c(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CCOC(=O)c1nc2c(s1)C(C)(F)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (170 mg) was reacted similarly to as described in General Procedure P with non-critical modifications to afford 130 mg (76%) of ethyl 9-bromo-4,8-difluoro-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-4,8-difluoro-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (122 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 4,8-difluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 7.2 mg and 6.9 mg (11% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-fluorine substitution position for each isomer was not determined.
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[CH2:30]([Mg]Br)[CH3:31]>O1CCCC1>[CH3:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][C:17]1[O:18][C:14]2[CH:15]=[CH:27][C:11]([C:7]3[CH:6]=[C:5]([C:4](=[O:28])[CH2:30][CH3:31])[CH:10]=[CH:9][CH:8]=3)=[CH:12][C:13]=2[CH:16]=1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
The product from Example 145 (20 mg, 0.05 mmol) was dissolved into tetrahydrofuran (900 μL), cooled to 0° C., and treated with 1.0 M ethylmagnesium bromide in tetrahydrofuran (150 μL, 150 μmol). The reaction mixture was then stirred at room temperature overnight, quenched by the addition of saturated aqueous NH4Cl, and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc, and the combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min.] to provide the title compound (44% yield). MS (ESI APCI) m/z 362 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H), 1.21 (t, 3H), 1.39-1.53 (m, 1H), 1.74-1.87 (m, 2H), 1.95-2.09 (m, 1H), 2.24-2.37 (m, 1H), 2.42-2.61 (m, 2H), 2.94-3.18 (m, 4H), 3.20-3.35 (m, 2H), 6.63 (s, 1H), 7.50-7.52 (m, 2H), 7.58 (dd, 1H), 7.77-7.79 (m, 1H), 7.87 (ddd, 1H), 7.96 (ddd, 1H), 8.22 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH2:12][CH3:13])[NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5]([CH2:12][CH3:13])=[N:4][N:3]2[C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:16]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c(N)n[nH]c1CC
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CC)nn2c(-c3cccnc3)ccnc12

Procedure:
As for Example 2, 1.83 g. of 3-amino-4-carboethoxy-5-ethylpyrazole is heated at reflux temperature for 16 hours with 1.76 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 1.20 g. of the product of the example as colorless crystals, m.p. 119°-120° C.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH:32]([C:34]1[S:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33]>>[CH2:19]([C:12]1([CH2:15][CH2:16][CH2:17][CH3:18])[C:13]2[CH:14]=[C:2]([C:37]3[S:38][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=3)[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][C:9]([N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:8][CH:7]=2)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(Br)ccc1-2
Reactant: O=Cc1ccc(B(O)O)s1
Product: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(-c3ccc(C=O)s3)ccc1-2

Procedure:
As shown in Scheme 2, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21). Then, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a). Finally, in acetonitrile, 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-Cyano-3-[5-(9,9-dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (23a).