Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[O:25]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:9][CH:10]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOC2CCc3ccccc3C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOC2CCc3ccccc3C2)cc1
Yield: 86.8 %

Procedure:
A mixture of rac.-alpha-oxo-4-[[2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.69 g) in hot methanol (10 mL) plus enough tetrahydrofuran to dissolve the solids, was treated with 1N sodium hydroxide (4 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.575 g of rac.-alpha-oxo-4-[[2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid as a colorless solid, mp 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH2:33]>>[CH2:31]([NH:34][C:35]([NH:30][C:29]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[N:13][C:12]=2[N:28]=1)=[O:36])[CH:32]=[CH2:33]
Reactant: C=CCN=C=O
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Product: C=CCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 26.2 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.186 g of allyl isocyanate according to the general procedure of Example 37. The product was purified by chromatography and crystallized from ethyl acetate to give 0.31 g of 1-allyl-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=529 (Base), 472, 446; mp 104-108° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:5])=[O:4].[BH4-].[Na+]>CO>[F:18][C:2]([F:1])([F:19])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-formyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 148, 540.0 mg, 1.82 mmols) in 7 mL MeOH at 0° C. was added NaBH4 (72.0 mg, 1.91 mmols). After stirring 2 hours at 0° C. the reaction was carefully quenched with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4), and concetrated under reduced pressure. The title compound was isolated by column chromatography (5-10% EtOAc-hexanes) as a colorless oil, 355.0 mg (90%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH2:24])[N:9]=1.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][C:44](O)=[O:45])=[CH:35]1.CN(C)CCCN=C=NCC.Cl.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH:24][C:44](=[O:45])[CH2:43][C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:34][CH:35]=2)[N:9]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: NCCCn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1c[nH]c2ccccc12)NCCCn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Reaction time: 16 h
Yield: 79.4 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenethyl)-4-benzyl-1-(3-aminopropyl)-5-oxo-1,2,4-triazole (Example 2, 0.500 g, 0.0010 mol) was dissolved in dichloromethane (20 ml) and indole-3-acetic acid (0.222 g, 0.00127 mol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide.HCl (0.244 g, 0.00127 mol), hydroxybenzotriazole (0.171 g, 0.00127 mol) and triethylamine (0.7 ml, 0.005 mol) added. The reaction was stirred for 16 hours, diluted with ethyl acetate (50 ml), washed with 10% citric acid solution, saturated sodium bicarbonate solution and brine. The organic layer was dried (MgSO4) and solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate then 1% methanol/ethyl acetate, to give the title compound as a pale yellow solid (0.500 g 80%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH2:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([CH:21]3[CH2:20][CH2:19][N:18]([CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: CCCN1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (23 mmol), 4-(1-propyl-piperidin-4-yl)-benzoic acid hydrochloride (23 mmol), HOBT (23 mmol), WSCD (23 mmol) and triethylamine (23 mmol) are dissolved in DMF (50 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale powder with mp. 198-200° C., Rf=0.34 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: COc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 160 °C
Yield: 53.1 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 5-hydroxy-2-methoxypyridine (Tyger Scientific, Ewing, N.J., USA; 24 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated to give 4-[4-(6-methoxy-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (34 mg, 54%) as a white powder. Mass spectrum (ES) MH+=427. HRMS Calcd. for C21H27N6O4 (MH+): 427.2089. Found: 427.2088.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:63][C@H:64]([C:69](O)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:63][C@H:64]([C:69]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:26])[NH:27][CH3:28])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67]
Reactant: CNC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.8 %

Procedure:
To a solution of 4-{[(1′S,2′S)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}-N-methylbenzamide (22, 150 mg, 0.38 mmol), DCC (94 mg, 0.45 mmol) and DMAP (5 mg, 0.038 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (134 mg, 0.38 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (180 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 75 mg (39%) of the title compound as an off white solid.
Reaction SMILES: [CH:1]1[C:2]([CH2:9][OH:10])([CH2:7][OH:8])[CH2:3][CH2:4][CH2:5][CH:6]=1.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21](OCC)(OCC)[O:22]CC)C>C(O)C.O>[CH2:3]1[C:2]2([CH2:9][O:10][C:21]3([O:20][CH2:18][C:11]4([CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]4)[CH2:17][O:22]3)[O:8][CH2:7]2)[CH2:1][CH2:6][CH:5]=[CH:4]1
Reactant: Cc1ccccc1
Reactant: OCC1(CO)C=CCCC1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CCO
Solvent: O
Product: C1=CCC2(CC1)COC1(OC2)OCC2(CC=CCC2)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a three-necked round-bottomed flask, equipped with a Dean-Stark trap (20 mL), a reflux condenser, a thermometer and a magnetic stir bar, was placed 2,2-cyclohexene-dimethanol 1 (15.78 g, 111 mmol) and 400 mL of toluene under an atmosphere of N2. The mixture was brought to reflux and maintained at reflux temperature for 2 hours to azeotropically remove any moisture. About 100 mL (5×20 mL) of azeotropic mixture was collected in the Dean-Stark trap. The mixture was then allowed to slowly cool to room temperature and 0.3 g of anhydrous para-toluenesulfonic acid (PTSA) was added, followed by dropwise addition of tetraethylorthocarbonate (TEOC, 11.7 mL, 56 mmol). The resulting mixture was brought to reflux to azeotropically remove ethanol generated during the reaction. The azeotropic mixture was shaken with salt water to determine the amount (volume) of ethanol collected. The reaction was monitored by GC (5 min at 105° C., a 20° C./min rise to 225° C.) and/or by TLC (silica gel, 15% ether/hexanes). After a total of 160 m L of azeotropic mixture (12.3 mL of ethanol) was collected, the reaction mixture was allowed to reflux for an additional 2 hours and then allowed to stir at 102° C. overnight. The reaction mixture was allowed to slowly cool to room temperature and then neutralized by the addition of 1 mL of triethylamine. The resulting mixture was allowed to stir at room temperature for an additional 30 min, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a light yellowish solid. The crude material was then purified by flash chromatography (silica gel, 15-25% ether/hexanes) or by recrystallization from refluxing ethyl ether/hexanes (v/v 1:1). The desired product 8,10,19,20-tetraoxatrispiro[5.2.2.5.2.2]henicosa-2,14-diene 2 (DCH) was obtained as white crystals in 80% yield. Mp (DSC) 118° C.; 1H-NMR (CDCl3, 300 MHz) δ126.20, 124.29, 114.82, 70.21, 30.62, 26.56, 21.42; IR (KBr pellet) (cm−1) 3020, 2920, 2850, 1630, 1440, 1365, 1250, 1225, 1190, 1100, 1025, 1000, 935, 920, 650; Anal. Calcd for C16H26O5: C, 69.84; H, 8.27; Found: C, 69.68; H, 8.42.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:19][C:20]([NH2:22])=[S:21].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>CCO>[NH2:22][C:20]1[S:21][C:8]([C:9]#[N:10])=[C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[N:19]=1
Reactant: NC(N)=S
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1sc(N)nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-fluorobenzoylacetonitrile (50 g, 306 mmol, 1 eq.) in EtOH (600 mL) was added pyridine (24.7 mL, 306 mmol, 1 eq.). The resulting mixture was stirred at 70° C. for 15 min then cooled to r.t. A previously stirred suspension of thiourea (46.7 g, 613 mmol, 2 eq.) and iodine (77.8 g, 306 mmol, 1 eq.) in EtOH (300 mL) was then slowly added. After 1 h at r.t. a cold 1 M Na2S2O3 solution (360 mL) was added under stirring. The resulting precipitate was filtered, washed with water, and finally dried under vacuo to afford 2-Amino-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.O[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:32])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1[N+:29]([O-:31])=[O:30])=[O:20]>O>[CH3:28][O:27][C:23]1[C:22]([N+:29]([O-:31])=[O:30])=[C:21]([C:19]2[O:20][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17](=[O:32])[CH:18]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(C(=O)CC(=O)c2ccccc2O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(-c2cc(=O)c3ccccc3o2)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
A solution of glacial acetic acid (15 mL), concentrated sulfuric acid (180 mL), and 1-(2-hydroxy-phenyl)-3-(3-methoxy-2-nitrophenyl)propane -1,3 -dione (770 mg, 2.43 mmol) is heated at reflux for 2.5 hours. The hot solution is poured onto crushed ice and H2O (200 mL), stirring vigorously for 30 minutes. The solution is cooled in a refrigerator. The resulting solid is filtered and washed with H2O to yield 2-(3-methoxy-2-nitrophenyl)-4-oxo-4H-[1]benzopyran (510 mg, 70%) as a brown solid.
Reaction SMILES: C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.[C:18]([Si:22]([O:25][CH2:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])([CH3:29])[CH3:28])([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CN([CH:40]=[O:41])C>O1CCCC1>[Si:22]([O:25][CH2:26][C:27]([C:30]1[C:31]([F:36])=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH:40]=[O:41])([CH3:29])[CH3:28])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:23])[CH3:24]
Reactant: CN(C)C=O
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
sec-Butyllithium (1.4M in cyclohexane, 3.54 mL) was added to dry tetrahydrofuran (10 mL) under nitrogen and the solution cooled to −78° C. N1-(2-(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine (0.859 g) was added slowly dropwise. A solution of tert-butyl(2-(2-fluorophenyl)-2-methylpropoxy)dimethylsilane (example 90, step e) (1.4 g) in dry tetrahydrofuran (3 mL) was then added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours at −78° C. DMF (2.69 mL) was added dropwise over 5 minutes and the mixture stirred at −78° C. for 1 hour followed by room temperature for 45 minutes. The reaction mixture was quenched by addition of water. Ethyl acetate (200 mL) was added and the organic washed three times with water followed by twice with 2M HCl and twice with water, then brine and dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 1 to 5% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.98 g.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:13][CH2:3][C:4](=[O:1])[CH2:5][CH2:6][CH2:7][CH2:2][CH3:12]
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCC(=O)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of the product obtained in Example IV (2.7 g, 0.017 mol) and p-toluenesulfonic acid monohydrate (0.023) g, 0.12 mmol) in dry toluene (200 ml) was allowed to reflux through a Soxhlet extractor for 2 hours. The Soxhlet thimble was charged with Type 4 A molecular sieves (16 g). After the solution was cooled to room temperature, anhydrous potassium carbonate (5 g, 0.036 mol) was added to the solution, and the mixture was stirred at room temperature for 30 min. The mixture was filtered and subjected to rotary evaporation to afford a slightly yellow wax at a 68% yield. Recrystallization from ethyl ether gave white crystals having a melting point of 69° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C([O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[CH:26](/C1C(O)=C(OC)C=C2C=1NC=CC2=O)=[CH:27]\CC.C(=O)([O-])[O-].[K+].[K+].C(I)C>C1(OC2C=CC=CC=2)C=CC=CC=1.CCOCC>[CH2:26]([O:1][C:2]1[CH:3]=[C:4]2[C:6]([C:14](=[O:13])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][NH:5]2)=[CH:7][C:8]=1[O:9][CH3:10])[CH3:27]
Reactant: COc1ccc(N)cc1O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC/C=C/c1c(O)c(OC)cc2c(=O)cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2cc(OCC)c(OC)cc2c1=O

Procedure:
3-Hydroxy-4-methoxyaniline (10.0 g) and diethyl ethoxymethylenemalonate (17.0 g) were condensed in the same manner as in the preparation of compound 72. The condensation product was O-ethylated with potassium carbonate (15.0 g) and ethyl iodide (7.0 ml) and then heated in diphenyl ether (70 ml) at a temperature of 240°-250° for 3 hours. After the mixture was left to cool, ether was added to the mixture. The resulting precipitate was collected by filtration, washed with water and dried to give 7-ethoxy-3-ethoxycarbonyl-6-methoxy-4(1H)-quinolone (10.2 g). The compound (5.0 g) was subjected to N-methylation and hydrolysis in the same manner as in Experimental Example 9 to obtain 3-carboxyl-7-ethoxy-6-methoxy-1-methyl-4(1H)-quinolone (compound 92, 4.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([N:13]=[N+]=[N-])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H][H].[C:19](OC(=O)C)(=[O:21])[CH3:20]>[Re]>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:13][C:19](=[O:21])[CH3:20]
Reactant: COC(=O)C(CSc1ccccc1)N=[N+]=[N-]
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: [Re]
Product: COC(=O)[C@H](CSc1ccccc1)NC(C)=O
Yield: 47 %

Procedure:
1.00 gram (4.22 mmoles) of the 2-azido-3-phenylmercapto-propionic acid methyl ester obtained in Example 2 was dissolved in 5 ml of acetic anhydride and then was added 1 mole % of rhenium VII sulfide based on the azido compound employed. Under vigorous stirring there was led hydrogen through the solution for 24 hours at 70° C. After the end of the reaction the solvent was drawn off under reduced pressure on the rotary evaporator, the product taken up in diethyl ether and the catalyst filtered off. Chromatography on a silica gel column with petroleum ether/ethyl acetate (volume ratio 1:1) gave 0.50 gram (47% of theory) of N-acetyl-S-phenyl-cysteine methyl ester as a colorless oil.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[I-].[I-].[Sm+2].[CH2:18]([C:20]([CH3:22])=[O:21])[CH3:19]>O1CCCC1>[OH:21][C:20]([C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][CH:6]=2)[CH:9]=[CH:10][CH:11]=[N:12]3)[N:1]=1)([CH3:22])[CH2:18][CH3:19]
Reactant: CCC(C)=O
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [I-]
Agent: [Sm+2]
Solvent: C1CCOC1
Product: CCC(C)(O)c1ccc2ccc3cccnc3c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
An embodiment of the process comprises mixing a stirred solution of 1,10-phenanthroline in tetrahydrofuran (THF) with a solution of the lanthanideII, samarium diiodide, in THF at a temperature of about 25° C. To the mixed solutions is added a solution of the ketone, methyl ethyl ketone, and the reaction mixture is stirred at about 25° C. for about 12 hours. The reaction is then quenched by the addition of a saturated aqueous solution of ammonium chloride and the mixture extracted with methylene chloride. The extract is washed with brine, dried and concentrated in vacao. The concentrate of product is purified by flash chromatography using alumina and ethyl acetate-hexanes as a gradient to provide racemic 2-[(1-hydroxy-1-methylpropyl)]-1,10-phenanthroline. (Formula 1, R=H, R1=ethyl, R2=methyl) This embodiment is depicted in the following reaction scheme wherein MEK is methyl ethyl ketone.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]1[N:32]=[CH:31][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:19]([CH3:30])[CH:18]=4)[C:10]=3[CH:9]=1)[CH2:6]2.C(N(CC)CC)C.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:30][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[CH:9]=[C:8]([N:5]4[CH2:4][CH:3]5[CH:7]([CH:2]5[NH:1][C:43]([CH:40]5[CH2:42][CH2:41]5)=[O:44])[CH2:6]4)[N:32]=[CH:31][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CC5C(N)C5C4)cc23)ccc1Oc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2ncnc3cnc(N4CC5C(C4)C5NC(=O)C4CC4)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 107.4 mg (0.25 mmol) of [6-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-pyrido[3,4-d]pyrimidin-4-yl]-(3-methyl-4-phenoxy-phenyl)-amine and 35.2 μL (0.25 mmol) of triethylamine in 0.5 mL of methylene chloride in an ice/brine bath was treated with 24.1 μL of cyclopropanecarbonyl chloride. The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with chloroform and washed with 2×50 mL of saturated sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was recrystallized from ethyl acetate to afford 91.7 mg (73%) of the title compound. 1H NMR (CDCl3): δ 8.78 (s, 1), 8.37 (s, 1), 7.63 (m, 1), 7.53 (m, 1), 7.26 (m, 2), 6.95 (m, 1), 6.89 (m, 3), 6.79 (s, 1), 3.87 (d, 2), 3.48 (m, 2), 2.38 (m, 1), 2.21 (s, 3), 184 (m, 2), 1.33 (m, 1), 0.89 (m, 2), 0.72 (m, 2). M.S. (m+1): 493; HPLC retention time (minutes): 6.672.