Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][CH:12]=[C:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][C@@H:12]([CH3:1])[C@@H:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of cuprous iodide (950 mg) in dry ether (75 ml) under dry nitrogen at 0° was added a solution of methyl-lithium in ether (1.6M; 6 ml.) until the initially formed yellow precipitate just rediseolved to give a clear solution. To the stirred solution at 0° was added a solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (600 mg) in dry tetrahydrofuran (50 ml.). During the addition a bright yellow precipitate formed. The mixture was stirred at 0° for 30 minutes, and then poured into cold, saturated ammonium chloride solution (200 ml.) More ether (200 ml) was added and the organic layer was separated, washed with saturated ammonium chloride solution (200 ml) and with water (200 ml.) dried over sodium sulphate and purified by preparative t.l.c. in ethyl acetate to give a product which was further purified by preparative t.l.c. in ethyl acetate/chloroform, 1/1 to give a white solid (380 mg) which was recrystallised from ether/petrol to give title compound (248 mg) as colourless plates, m.p. 138°-140°, [α]D + 99°, (c 0.95).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C@@H:7]12[C:16](=O)[O:15][C:13](=[O:14])[C@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2.O>C(OCC)C>[OH:14][CH2:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[CH2:16][OH:15]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OC[C@@H]1CCCC[C@H]1CO
Yield: 70.7 %

Procedure:
To a mixture of lithium aluminum hydride (2.85 g; 75 mmol) and diethyl ether (50 ml), a solution of trans-1,2-cyclohexanedicarboxylic acid anhydride (1) (7.71 g; 50 mmol) in diethyl ether (150 ml) is dropwise added, and the resultant mixture is allowed to react at room temperature for 3 hours and then heated under reflux for 2 hours. After cooling, wet ether is dropwise added to the reaction mixture, followed by addition of water. The organic layer is collected by decantation, followed by concentration to give trans-1,2-bis(hydroxymethyl)cyclohexane (2) (5.1 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]([C:13](=O)[CH3:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[BH3-]C#[N:20].[Na+]>CCO>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]([CH:13]([NH2:20])[CH3:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ncc(Oc2ccc(F)cc2)cn1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(N)c1ncc(Oc2ccc(F)cc2)cn1
Yield: 94.3 %

Procedure:
1-(5-(4-fluorophenoxyl)pyrimidin-2-yl)ethanone (290 mg, 1.25 mmol), NH4OAc (1.9 g, 24.6 mmol), and NaBH3CN (314 mg, 5.00 mmol) were taken up in 20 mL 200 proof EtOH, and heated at 130 C for 3 minutes in a microwave apparatus. The mixture was concentrated to remove the EtOH. Crude was taken up in 30 ml water+25 mL EtOAc. 6N NaOH was added until aqueous pH was ˜10. Separated layers, and extracted aqueous with EtOAc (25 ml). The combined organic layer was washed with 25 mL brine and dried with Na2SO4. Filtered and concentrated with reduced pressure to give 275 mg crude tan oil, which was carried forward without further purification. Major product Anal. RP-HPLC tR=1.26 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 234.1 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]([N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][CH2:67]O)[CH2:61][CH2:60]1)(=[O:58])[CH3:57]>C(Cl)Cl>[C:56]([N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][CH2:67][O:34][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][C:30]=2[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]3[O:23][C:22]2[C:14]([F:13])=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH2:61][CH2:60]1)(=[O:58])[CH3:57]
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Diethyl azodicarboxylate (117 μl, 0.738 mmol) was added dropwise to a solution of 4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.2 g, 0.615 mmol), triphenylphosphine (0.242 g, 0.92 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.137 g, 0.738 mmol), (prepared as described for the starting material in Example 1 or Example 7), in methylene chloride (5 ml). After stirring at ambient temperature for 1 hour, triphenylphosphine (0.032 g), 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.022 g) and diethyl azodicarboxylate (20 μl) were added. The mixture was stirred for 1 hour at ambient temperature and evaporated under vacuum. The residue was purified by column chromatography, eluting with increasingly polar mixtures of methylene chloride and ethyl acetate followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was repurified by preparative LC/MS eluting with increasingly polar mixtures of acetonitrile and water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and pentane and the residue was filtered, washed with diethyl ether and dried under vacuum to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.057 g, 19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([C:7](=[O:17])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH3:6].[H-].[Na+].[CH:21](OC)=[O:22]>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:7]([N:5]([CH3:6])[C:4](=[CH:21][OH:22])[C:3]([O:2][CH3:1])=[O:18])=[O:17]
Reactant: COC(=O)CN(C)C(=O)C=Cc1ccccc1Cl
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(=CO)N(C)C(=O)C=Cc1ccccc1Cl

Procedure:
By a procedure analogous to that described in Example 1, part of the crude N-(o-chlorocinnamoyl)sarcosine methyl ester (6.99 g), methyl formate (30 ml) and sodium hydride (2.35 g) gave methyl N-(o-chlorocinnamoyl)-N-methyl-2-amino-3-hydroxypropenoate (4.56 g) as an off-white solid, m.p. 129°-130° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28](=[O:58])[CH2:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[CH:45]=[CH:46][CH:47]=2)=[CH:36][CH:35]=1)[C:31]([NH2:33])=O)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:58])[CH2:29][CH:30]([C:31](=[S:10])[NH2:33])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[CH:45]=[CH:46][CH:47]=2)=[CH:36][CH:35]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)CC(C(N)=O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C(N)=S)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
Lawesson's reagent (81 mg, 0.2 mmol) was added to a solution of compound 51.1 (50 mg, 0.1 mmol) in THF (2 mL). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched with water (5 mL). The reaction mixture was extracted with dichloromethane (3 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield compound 51.2 (40 mg) as a clear film. MS ESI (pos.) m/e: 516 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.67 (1H, s); 7.51-7.48 (3H, m); 7.31-7.28 (2H, m); 7.0-6.97 (2H, m); 5.14 (2H, s); 4.25-4.22 (1H, m); 3.51-3.46 (1H, m); 2.78-2.72 (1H, m); 1.38 (9H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:18](CC)CC.ClC(OCC)=O.N>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:18])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: CC(C)(COCc1ccccc1)C(N)=O
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a 0° C. solution of 2.4 g (11.4 mmol) of 3-benzyloxy-2,2-dimethyl-propionic acid and 1.65 ml (11.5 mmol) of Et3N in 80 mL of chloroform was added 1.04 mL (11.5 mmol) of ethyl chloroformate. After stirring for 15 min, NH3 gas was passed through the solution for 5 minutes. The resulting suspension was removed from the ice bath and allowed to stir overnight. The suspension was filtered and the filtrate was concentrated to near dryness. The resulting residue was crystallized from benzene/hexanes (16 mL/40 mL) mixture to provide 2.3 g of 3-benzyloxy-2,2-dimethyl-propionamide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:7]1([C:5]2[N:6]=[C:2]([NH:1][C:22]([NH:21][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[S:23])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1nc(-c2ccccc2)cs1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
3.10 g 2-amino-4-phenylthiazole (176 mmol) and 3.00 g benzoylisothiocyanate were heated in 50 ml acetone for 2 hours at reflux, during which a yellow solid was formed. The reaction mixture was subsequently stirred for 30 minutes at 5° C., the solid was suction-isolated and washed multiple times with n-pentane. After drying, 4.20 g of the target structure was obtained as an amorphous yellow solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[C:22]([C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12

Procedure:
0.32 g (7.62 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.94 g (2.54 mmol) of 3-methoxycarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.50 g of 3-carboxy-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 356 (M+•).
Reaction SMILES: [CH2:1]([C:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH2:1]([C:4]([C@:6]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C@@:8]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])=[O:5])[CH:2]=[CH2:3]
Reactant: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C=CCC(=O)[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@H](O)CO
Temperature: 25 °C
Yield: 28.7 %

Procedure:
1-allyl-D-arabinose 32 (75 g, 394 mmol) was dissolved in pyridine (800 mL) at 0° C., benzoyl chloride (101 mL, 867 mmol) was added over 2 h by addition funnel and the reaction was stirred while warming to room temperature for 16 h. The solvent was removed in vacuo, and the resulting residue was purified by silica gel flash chromatography (4:1 Hexanes:EtOAc to 3:2 Hexanes:EtOAc) to give 33 as a thick oil (45 g, 113 mmol, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[OH:26].[C:27]([O:32]C)(=[O:31])[C@@H:28]([CH3:30])O.BrBr>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[O:26][C@H:28]([CH3:30])[C:27]([OH:32])=[O:31]
Reactant: COC(=O)[C@@H](C)O
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br
Agent: BrBr
Product: C[C@@H](Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br)C(=O)O

Procedure:
Prepared from of 2-bromo-5-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11-yl)-phenol (Example 68) and commercially available (R)-lactic acid, methyl ester. White solid: mp 133-134.5° C.: MS (-ESI): [M-H]-, 2 bromine isotope pattern 553, 555, 557; Anal. Calc. for C25H16Br2O3S: C, 53.98, H, 2.90, N, 0.00. Found: C, 53.18, H, 2.82, N, 0.04.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11]CC)=[O:10])=[N:4]1)[CH3:2].[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1nn(CC)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1cc(C)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
A mixture of ethyl 1-ethyl-4-methyl-1H-pyrazole-3-carboxylate (8.60 g, 47.2 mmol), 8N aqueous sodium hydroxide solution (11.8 mL) and ethanol (30 mL) was stirred at room temperature for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (5.19 g, 71%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([CH2:46][CH:47](OCC)OCC)[C:12]([CH:14]([NH:27][C:28](=[O:45])[CH2:29][CH:30]([NH:34][C:35]([NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:31][CH:32]=[CH2:33])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(C)(C)C)=[CH:18][CH:17]=3)=[O:13])[C:4]=2[N:3]=[CH:2]1>C(O)=O>[CH2:38]([NH:37][C:35]([N:34]1[CH:30]([CH2:31][CH:32]=[CH2:33])[CH2:29][C:28](=[O:45])[N:27]2[CH:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:12](=[O:13])[N:11]([CH2:10][C:9]3[C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)[CH2:46][CH:47]12)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2scnc12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Solvent: O=CO
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc4scnc34)CC2N1C(=O)NCc1ccccc1
Yield: 40.7 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid [1-[benzothiazol-4-ylmethyl-(2,2-diethoxy-ethyl)-carbamoyl]-2-(4-tert-butoxy-phenyl)-ethyl]-amide (3.67 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give 2-Allyl-8-benzothiazol-4-ylmethyl-6-(4-hydroxy-benzyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.2 g, 3 step yield: 35%). 1H NMR (CDCl3, 300 MHz) δ 9.20 (s, 1H), 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.80 (m, 3H), 6.75 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 596 (M+H), 618 (M+Na).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:37])[N:22]([CH3:36])[C:23](S(C)(=O)=O)=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:37])[N:22]([CH3:36])[C:23]([O:12][CH2:11][CH2:10][CH2:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: OCCCc1ccccc1
Reactant: Cn1c(S(C)(=O)=O)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(OCCCc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oily suspension, 111 mg, 2.79 mmol) was added to a stirred solution of 3-phenylpropanol (387 mg, 2.85 mmol) in tetrahydrofuran (1 ml). After gas evolution ceased, 5-(4-fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-pyridyl)-4(3H)-pyrimidinone (100 mg, 0.279 mmol) was added and the mixture was heated at 60μ C. for 30 min. The reaction mixture was partitioned between dichloromethane and water. The organic solution was washed with brine, dried and evaporated. Column chromatography on silica gel (hexane-ethyl acetate=2:1) provided the title compound. MS (m/z): 416.1 (M+H)+; C25H22FN3O2 requir. 415.5.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3CC[C@@H]12
Yield: 56.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 137 mg (56%) of the title compound as a white solid. mp 86°-89°. FDMS: m/e=373 α[D]589 =+28.90 (c =1.04, chloroform).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([NH:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O.O1CCOCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C:14]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1NCCNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 100 °C
Yield: 89.4 %

Procedure:
Methyl 6-(benzenesulphonylmethyl)-2-[2-(t-butoxycarbonylamino)-ethylamino]-3-(furan-3-yl)benzoate (Intermediate 122, 0.115 g) was added to a solution of lithium hydroxide monohydrate (0.168 g) in water (1 ml) and dioxane (3 ml) and the mixture was heated at 100° C. for 1 hour. The reaction was cooled to room temperature, diluted with water and washed with diethyl ether. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM:MeOH:AcOH:water (350:20:3:2) to give 6-(benzenesulphonylmethyl)-2-[2-(tert-butoxycarbonylamino)-ethylamino]-3-(furan-3-yl)benzoic acid (0.1 g) as a pale yellow gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:20][CH2:21]OC(C)=O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1)#[CH:21]
Reactant: CCOC(C)=O
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C#Cc1cc(Oc2ccc(NC(C)=O)nc2C)ccn1
Temperature: 75 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of Example A5 (0.35 g, 1.260 mmol) in DMF (5 mL) was sparged with argon, treated with TEA (1 mL) trimethylsilylacetylene (0.531 mL, 3.78 mmol), copper(I) iodide (0.024 g, 0.126 mmol) and dichlorobis(triphenylphosphine)palladium(II) [Pd(PPh3)2Cl2](0.088 g, 0.126 mmol) and heated at 75° C. under argon for 16 h. The mixture was cooled to RT, treated with EtOAc, solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and H2O and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting material was dissolved in MeOH (20 mL), treated with K2CO3 (300 mg) and stirred at RT for 1 h. The mixture was concentrated to dryness, treated with EtOAc, sonicated, the solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (102 mg, 30%) as a light red solid. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H); 8.40 (d, J=5.8 Hz, 1H); 8.01 (d, J=8.8 Hz, 1H); 7.60 (d, J=6.0 Hz, 1H); 7.04 (d, J=2.5 Hz, 1H); 6.89 (dd, J=5.8, 2.6 Hz, 1H); 4.34 (s, 1H); 2.22 (s, 3H); 2.07 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).