Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8])(=O)C.[Na].[OH-:12].[Na+:13]>O>[CH2:6]([S:7]([O-:9])(=[O:8])=[O:12])[CH2:5][S:4][S:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:8])=[O:9].[Na+:13].[Na+:13]
Reactant: [OH-]
Reactant: CC(=O)SCCS(=O)(=O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=S(=O)([O-])CCSSCCS(=O)(=O)[O-]

Procedure:
The ongoing S-acetyl-2-mercaptoethane sulfonic acid, sodium salt (20 g) is dissolved in water and added 1N sodium hydroxide to adjust the pH to 9.0. The reaction mixture is the then stirred while bubbling oxygen for 48 hours. The aqueous portion is then concentrated and crystallized out the product directly. Yield is found to be 80%. The product is characterized by NMR and corroborated the structure with the authentic sample.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](CC(NC3C=C4C(=CC=3)C[C@@]3(C(=O)NC(=O)N3C)C4)=O)[C:13](=[O:35])[C:12]([CH3:37])([CH3:36])[S:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH:9]2[NH:14][C:13](=[O:35])[C:12]([CH3:37])([CH3:36])[S:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN3C(=O)C(C)(C)SC[C@H]3c3cc(F)cc(F)c3)cc1C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)SCC(c2cc(F)cc(F)c2)NC1=O
Reaction time: 2 h

Procedure:
To a solution of 2-[(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxo-4-thiomorpholinyl]-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamide (Example 2) in 1.5 mL chloroform at 0° C., was added 3-chloroperoxybenzoic acid (21 mg with a purity of 77%, 0.121 mmol). An LCMS of the reaction mixture after two hours showed that all starting material was consumed. Calcium hydroxide (14 mg, 0.185 mmol) was added to the reaction and stirred for fourty minutes. The mixture was then vacuum filtered through filter paper and the solid was washed with chloroform (3×10 mL). The filtrate was concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2-1:99 to 5:95, to give the title compound. MS: m/z=545 (M+H). HRMS: m/z=545.1653; calculated m/z=545.1665 for C26H26F2N4O5S.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].O=P(Cl)(Cl)[Cl:17]>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: Cc1c(S(=O)(=O)O)sc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Cl)sc2ccccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 115.5 %

Procedure:
The 3-methylbenzothiophene-2-sulfonic acid (45 mg, 0.20 mmol) was mixed with POCl3 (2 mL, 20 mmol) and CH2Cl2 (2 mL) and heated at 70° C. for 6 h. The reaction mixture was diluted with CH2Cl2 before the reaction was quenched with ice and stirred at room temperature for 1 h. The organic phase was separated. Evaporation of the solvents afforded 57 mg the title compound (91%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][NH:33][C:32](=[O:41])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:38]4[CH2:37][CH2:36][C:35]5([O:30][CH2:31][C:32](=[O:41])[NH:33][CH2:34]5)[CH2:40][CH2:39]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)CNC(=O)CO4)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 1-oxa-4,9-diazaspiro[5.5]undecan-3-one (61 mg, 0.36 mmol) and molecular sieves (4 Å, powdered, 255 mg) in DCE (5 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) to afford 394 as a cream solid (116 mg, 83%). LCMS (Method G): RT=5.76 min, M+H+=546. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.77 (m, 1 H); 7.32-7.24 (m, 2 H); 5.93 (bs, 1 H); 4.35 (m, 4 H); 4.18 (s, 2 H); 3.90-3.84 (m, 7 H); 3.82 (bs, 2 H); 3.37 (q, J=7.5 Hz, 2 H); 3.27 (m, 2 H); 2.72 (m, 2 H); 2.59 (m, 2 H); 2.05-1.93 (m, 2 H); 1.68 (m, 2 H) and 1.46 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]#[N:16])=[CH:7][CH:6]=1.[Li+].[OH-]>CO>[C:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([CH2:4][C:3]([OH:17])=[O:2])=[CH:6][CH:7]=1)#[N:16]
Reactant: COC(=O)Cc1ccc(C#N)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
To a solution of compound 2A (6.20 g, 26.7 mmol) in MeOH (100 mL) was treated with saturated aqueous LiOH (15 mL), and the reaction mixture was stirred at rt overnight (˜16 h). The resulting mixture was concentrated in vacuo to dryness and partitioned between a mixed solvent (50% Et2O:50% EtOAc) and H2O. The H2O layer was acidified to pH 2-3 and extracted with EtOAc (3×20 mL). The EtOAc was dried over Na2SO4 and concentrated in vacuo to give a yellow solid (2.1 g) in 38% yield.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH3:15])[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH3:15])[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: Cc1ncsc1CCC1(C(C)C)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3scnc3C)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one (Example E-1; 0.22 g, 0.78 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2, 0.33 g, 0.90 mmol), potassium carbonate (1.0 g, 7.2 mmol), and DMF (4 mL). The product was chromatographed on silica gel, eluting with 10% MeOH in CH2Cl2, to give the title compound, mp 138-141° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:73][O:72][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:24][C@@H:23]([O:25][C@@H]7O[C@H](CO[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@@H](O[C@@H]8O[C@@H](C)[C@H](O)[C@@H](O)[C@H]8O)[C@H](O)[C@H]7O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[CH2:22][CH2:21][C@:20]6([CH3:69])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:70])[C@H:7]3[C@@H:6]2[CH3:71])[CH2:4][CH2:3]1.C(O)(C)C.Cl.C>O.C1(C)C=CC=CC=1.CCCCCC>[CH3:1][C@@H:2]1[CH2:73][O:72][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:69])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:70])[C@H:7]3[C@@H:6]2[CH3:71])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O[C@@H]6O[C@H](CO[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@@H](O[C@@H]7O[C@@H](C)[C@H](O)[C@@H](O)[C@H]7O)[C@H](O)[C@H]6O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A mixture of 1004 parts of crude sarsasaponin, 1560 parts of isopropanol, 225 parts of water and 298 parts of concentrated hydrochloric acid is heated at reflux for 2 hours. Then, an additional 166 parts of concentrated hydrochloric acid dissolved in 400 parts of water is added and refluxing continued for a further 1.5 hour. The reaction mixture is diluted to 12,000 parts by volume with water and ice and the resulting precipitate collected, washed with water and air-dried to afford crude sarsasapogenin in an 89% yield. This crude material is dissolved in toluene with warming, treated with 190 parts of alumina, 45 parts of charcoal, and filtered hot. The toluene solution is then cooled to room temperature and refiltered. The toluene is removed in vacuo to leave a volume of about 1,000 parts. This solution is diluted with n-hexane to about 3,500 parts by volume causing the separation of a dark precipitate. The solution is filtered, treated with charcoal, warmed to about 60° C., and filtered through diatomaceous earth under vacuum. Cooling affords crystals which are separated, washed successively with 1,500 parts by volume of the mother liquors and 1,000 parts of n-hexane and dried in a steam oven. Recrystallization from a mixture of acetone and n-hexane affords sarsasapogenin, identical to the product of Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2].O.Cl>CO.[Fe]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]=[CH:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([OH:26])=[C:7]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:8]=1
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(C=Cc2ccccc2N)cc(C(C)(C)C)c1O
Yield: 69.8 %

Procedure:
To a solution of 2,6-di-tert-butyl-4-(2-nitrostyryl)phenol (1.1 g, 3.1 mmol) in methanol (15 ml) was added water (4 ml), conc. hydrochloric acid (0.2 ml) and iron powder (1.7 g, 30 mmol) and the mixture was heated under reflux for 5 hrs. After filtration, followed by extraction with ethyl acetate and water, the extract was washed with water, dried over MgSO4 and concentrated. Purification of the residue by a silica gel column chromatography followed by recrystallization from hexane afforded 4-(2-aminostyryl)-2,6-di-tert-butylphenol (0.70 g, 70%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:23])([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]1=[O:24])CCC.[CH2:25](N1C2C(=CC=CC=2)C(=O)C1=O)[CH:26](C)[CH3:27].C(C1C=CC=CN=1)(=O)C>>[OH:23][C:7]1([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:1][CH:26]([CH3:27])[CH3:25])[C:6]1=[O:24]
Reactant: CC(C)CN1C(=O)C(=O)c2ccccc21
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Agent: CC(=O)c1ccccn1
Product: CC(C)CN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 1-isobutylindoline-2,3-dione and commercially available 2-acetyl pyridine (Fisher Scientific). 1H-NMR δ 8.70 (ddd, 1H), 8.13 (td, 1H), 7.92 (dd, 1H), 7.56 (ddd, 1H), 7.34-7.28 (m, 2H), 7.07-7.02 (m, 2H), 6.85 (d, 1H), 3.77 (d, 1H), 3.56-3.42 (m, 3H), 2.15 (m, 1H), 0.97 (dd, 6H). calculated mass for C19H20N2O3, 324.15. Observed, 325.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccccc1-n1cccn1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccccc4-n4cccn4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 45.5 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Pyrazol-1-yl-benzaldehyde (28 mg, 0.163 mmol) were reacted to produce 33 mg (45%) of the title compound. mp: 120° C., 1H NMR (300 MHz, DMSO-d6): 12.88 (s, 1H), 8.00 (s, 1H), 7.82 (d, J=8 Hz, 1H), 7.77 (s, 1H), 7.66 (m, 3H), 7.60 (m, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.37 (s, 1H), 6.22 (s, 1H), 6.10 (s, 1H), 4.87 (t, J=8 Hz, 1H), 3.32 (s, 1H), 2.80 (s, 1H), 2.16 (d, J=8 Hz, 1H), 1.31 (d, J=8 Hz, 1H). MS: 490, 492 (M+H), HPLC: 2.28 min (G method).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(C1[N:9]([CH:42]([CH3:44])[CH3:43])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:41])(=[O:40])[N:27]([CH2:36][CH2:37][O:38][CH3:39])COCC[Si](C)(C)C)=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:12]=1)=O>CCCCCC.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:2]([C:1]1[N:9]([CH:42]([CH3:44])[CH3:43])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([S:26](=[O:40])(=[O:41])[NH:27][CH2:36][CH2:37][O:38][CH3:39])=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][N:12]=1)=[CH:3][CH3:4]
Reactant: [Li]CCCC
Reactant: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C=O)n3C(C)C)n2)cc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
n-Butyl lithium (656 μl of a 1.6 N solution in hexane, 1.05 mmol), was added dropwise to a solution of ethyl triphenylphosphonium iodide (437 mg, 1.05 mmol), in anhydrous THF (15 ml), under nitrogen at 0° C. A solution of 4-(2-formyl-1-isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 105; 300 mg, 0.523 mmol), in THF (5 ml), was then slowly added. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The volatiles were removed by evaporation and the residue dissolved in EtOAc (40 ml), washed with water (2×15 ml), brine (15 ml), and dried. The solvent removed by evaporation to give a crude product (254 mg), as a yellow foam. The crude product was purified by chromatography on silica-gel eluting with 3% MeOH in DCM), the semi-pure product (70 mg), was dissolved in TFA/H2O (1:1, 10 ml), and stirred for 1 hour. The TFA was removed by evaporation, the resulting aqueous solution neutralised with saturated NaHCO3, and the product extracted with DCM (3×5 ml). The extracts were combined, dried and the solvent removed. The residue was purified by preparative reverse phase HPLC, eluting with acetonitrile/H2O, 0.01% formic buffer. Pure fractions were neutralised with 2N aqueous sodium hydroxide solution. The resulting white precipitate, was collected by filtration and dried to give the title compound (1:2.5 mixture of E:Z isomers), as a white solid (5 mg, 2%). NMR: Z isomer 1.51 (d, 6H), 2.09 (d, 3H), 2.92 (t, 2H), 3.17 (s, 3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.05 (m, 1H), 6.51 (m, 1H), 7.1 (br s, 1H), 7.16 (d, 1H), 7.57 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.48 (d, 1H), 9.47 (s, 1H); E isomer 1.51 (d, 6H), 1.94 (d, 3H), 2.92 (t, 2H), 3.17 (s, 3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.60 (m, 1H), 6.67 (m, 1H), 7.1 (br s, 1H), 7.13 (d, 1H), 7.47 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.44 (d, 1H), 9.47 (s, 1H); m/z: 457.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=2[F:27])[N:20]=[C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:18]=1[CH3:35].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:25]1[CH:24]=[C:23]([F:28])[CH:22]=[C:21]2[C:26]=1[C:17]([NH:15][C:14]1[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:10][CH:11]=[CH:12][CH:13]=1)=[C:18]([CH3:35])[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[N:20]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1ccccc1-c1ncccc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ncccc1Nc1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of 2-(2-methoxyphenyl)-3-pyridinamine (30.8 mg, 0.15 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-pyridinyl)quinoline (67.8 mg, 0.23 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (15.5 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (0) (14.5 mg, 0.016 mmol), and sodium tert-butoxide (45.1 mg, 0.47 mmol) in dry toluene (2.0 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layers were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on basic alumina (0-30% EtOAc in hexanes) to afford an light yellow solid as 5,7-difluoro-N-(2-(2-methoxyphenyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (1H, m), 8.31 (1H, d, J=4.5 Hz), 7.82 (1H, m), 7.70 (1H, m), 7.54 (3H, m), 7.30 (1H, m), 7.18 (1H, m), 7.06 (2H, t, J=7.5 Hz), 7.01 (1H, m), 6.87 (1H, ddd, J=13.2, 8.7, 2.0 Hz), 3.86 (3H, s), 1.82 (3H, br. s.). Mass Spectrum (pos.) m/e: 455.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15]C1)[CH2:6][CH2:5]2.C(N)(=[O:21])C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[C:8]3[CH2:15][CH2:16][C:17](=[O:21])[NH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cc1Cl)CCC(N1CCCC1)=C2
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC2=C(CCc3cc(Cl)c(Cl)cc32)N1

Procedure:
A melt of 10.1 g (0.038 mol) of 1-(6,7-dichloro-3,4-dihydro-2-naphthyl)pyrrolidine, 5.36 g (0.075 mol) of acrylamide and 0.3 g of p-toluenesulfonic acid is stirred under nitrogen at 100° for 2 hours and at 150° for 2 hours. Recrystallization of the melt cake from ethanol yields 8,9-dichloro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one with melting point 260°-261°.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: Sc1ncccn1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ncccn3)C(=O)O)cc2)cc1

Procedure:
Example 45 is prepared from 2-mercaptopyrimidine and 1d using the procedure described for compound 20.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CCCCC=CCC=CCCCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCC=CCC=CCCCCCCCCC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 10,13-octadecadienoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(10,13-octadecadienoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-hydroxy-4-(10,13-octadecadienoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate. By catalytic hydrogenation of 3-hydroxy-4-(10,13-octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(octadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl methanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:22][CH:23]2[CH2:25][O:24]2)[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:22][CH:23]([OH:24])[CH2:25][C@@H:12]1[C:11](=[O:13])[N:10]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH2:9]2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1CC(CC2CO2)(C(=O)OC(C)(C)C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC(O)C[C@@H]2C1=O
Yield: 25.5 %

Procedure:
3-(Oxiran-2-ylmethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.2 g, 12.16 mmol) was dissolved in tetrahydrofuran (50 mL). A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (18 mL, 1.5 equivalents) was added in an argon atmosphere at −78° C., and the mixture was gradually heated. When the reaction temperature reached about room temperature, the reaction was quenched with an ammonium chloride solution, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1→2:1→1:1→1:2) to give 1.07 g (26%) of the title compound having a single isomer as a colorless oil. 1.0 g (24%) of the raw material was collected. 1.20 g (29%) of a four-membered ring-closed compound as a by-product was obtained as a diastereomer mixture.