Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C(O)(=O)C>[CH3:1][C:2]1[N+:6]([O-:7])=[C:13]([C:12]2[CH:15]=[CH:16][C:9]([Br:8])=[CH:10][CH:11]=2)[O:5][C:3]=1[CH3:4]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)C(C)=NO
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(Br)cc2)[n+]([O-])c1C
Yield: 74.1 %

Procedure:
A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and 4-bromo-benzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooled to 0° C. and then gaseous HCl was bubbled through the solution for 35 min while the reaction was stirred in an ice bath. Diethyl ether (500 mL) was then added to the reaction to precipitate the product and the resultant slurry stirred 45 min at 0° C. before being filtered. The solids were rinsed with Et2O (50 mL), taken up in water (1 L) and conc. NH4OH (60 mL) added to the slurry. This mixture was extracted with CHCl3, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give 97.4 g (74%) of 4,5-dimethyl-2-(4-bromophenyl)-oxazole oxide as a white solid. The compound should be used directly within 24-48 h: 1H NMR (500 MHz, CDCl3) 8.34 (d, J=9.0 Hz, 2H), 7.61 (d, J=9.0 Hz, 2H), 2.35 (s, 3H), 2.20 (s, 3H); 13C (125 MHz, CDCl3) 142.1, 131.9, 129.5, 126.3, 124.1, 122.2, 11.1, 6.2; IR (KBr) 1685, 1529, 1418, 1377, 1233, 1165 cm−1; UV (EtOH)max 307 nm (24371); HRMS (TOF) m/z calculated for C11H1179BrNO2: 267.997, found 267.9951.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>>[CH3:10][CH:9]([N:12]=[C:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)[CH3:11]
Reactant: CC1CCCC(=O)C1
Reactant: CC(C)N
Product: CC1CCCC(=NC(C)C)C1
Reaction time: 8 h

Procedure:
To a mixture of 112 g. 3-methyl cyclohexanone and 120 g. isopropylamine are added 100 g. Linde Type 3A molecular sieves. The mixture is allowed to stand overnight at room temperature, after which the sieves are removed by filtration and the excess of isopropylamine is removed in vacuo at room temperature. The oil residue is 1-methyl-N-(3-methylcyclohexylidene)-ethylamine, b.p. 36 at 0.5 mm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH:17](OC)(OC)[O:18][CH3:19]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/[O:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(=O)NC2=O
Reactant: COC(OC)OC
Solvent: CC(=O)O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Temperature: 90 °C
Yield: 79 %

Procedure:
An amount 200 mg (0.92 mmol) of 6-tert-butylisoquinoline-1,3(2H,4H)-dione is dissolved in acetic acid 1.0 mL followed by addition of trimethyl orthoformate (25 uL, 2.3 mmol). After, the mixture is heated at 90° C. for 1 h, and cooled to room temperature. The yellow solution evaporated to dryness. Small amounts of anhydrous ether is added and hexane. The yellow solid is collected with hexane to give 188 mg (79% yield) MS (ESI) m/z 260.2 (M+1). 1H NMR (300 MHz, DMSO-d6) 1.346 (S, 9H), 4.178 (S, 3H), 7.472-7.505 (dd, J=1.8 Hz, J=1.8 Hz 1H), 8.007 (d, J=8.52 Hz 2H), 8.31 (d, J=1.71 Hz 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([CH3:37])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=2)[CH3:2].Br[CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:52])[CH:48]=2)[N:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:39])[C:5]([CH3:38])([CH3:37])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:13][C:12]([O:21][CH2:41][C:42]1[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[C:47]([F:52])[CH:48]=3)[N:43]=1)=[CH:11][CH:10]=2)[CH3:2]
Reactant: Fc1ccc2nc(CBr)ccc2c1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To 3-{3-tert-Butylsulfanyl-5-hydroxy-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (D-2; 6.5 g, 11.9 mmol) in MeCN (75 mL) was added 2-bromomethyl-6-fluoro-quinoline (3.14 g, 13.1 mmol), and Cs2CO3 (9.7 g, 29.8 mmol). The reaction was stirred at room temperature overnight, after which LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (D-3, 7.6 g).
Reaction SMILES: C(O/[N:5]=[C:6](/[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C:6]1[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][N:5]=1
Reactant: COc1ccc(/C(=N\OC(C)=O)c2cc(F)ccc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3cc(F)ccc3F)noc2c1
Reaction time: 0.75 h

Procedure:
To a mixture of 34 g of E-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime in 70 ml dimethylformamide at 65° C., 18.2 g of potassium carbonate is added. The mixture is stirred for 45 min and poured into water. The precipitate is collected and dried. Recrystallization from ether gives 3-(2,5-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 121°-122° C.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH2:8]([O:10][C:11](=[O:24])[CH2:12][CH2:13][C:14]1[C:22]2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][CH:15]=1)[CH3:9].COC(OC)OC.[OH-].[Na+]>O.C(OCC)(=O)C>[CH2:8]([O:10][C:11](=[O:24])[CH2:12][CH2:13][C:14]1[C:22]2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][C:15]=1[CH:3]=[O:4])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CCc1c[nH]c2c1C(=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: CCOC(=O)CCc1c(C=O)[nH]c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a trifluoroacetic acid solution (47 mL) containing 3-(3-ethoxy-3-oxopropyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole (4, 10.0 g, 42.5 mmol) was added with trimethylorthoformate (13.6 g, 128 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min, warmed up to room temperature and stirred for 2.0 h. The solution was added with ethyl acetate (250 mL), water (200 mL) and NaOH (18 g). The organic layer was collected and washed with saturated aqueous NaHCO3 (200 mL), dried over MgSO4 (s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (50% EtOAc in hexanes) to give 3-(3-ethoxy-3-oxopropyl)-2-formyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (5, 2.1 g, 8.0 mmol) as yellow solids in 19% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]=1)([OH:12])=[O:11]
Reactant: CCCCCBr
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
Indole 3-carboxylic acid (3 g, 18.62 mmol) was added to a suspension of sodium hydride (60% in oil) (1.11 g, 1.5 eq) in dry DMF (30 ml) under a nitrogen atmosphere. The mixture was stirred at room temperature for 45 min (H2 evolving has ceased) and to this was added 1-bromopentane (4.62 ml, 2 eq) in dry DMF (10 ml) dropwise. The mixture was stirred at room temperature overnight. The solvents were removed in vacuo and to the residue was added water (30 ml) and ethyl acetate (30 ml). The ethyl acetate portion was separated, dried over sodium sulphate, filtered and evaporated to dryness. The crude residue was purified by column chromatography (silica gel: 20% ethyl acetate in hexane) to give the title compound (2.12 g, 49%) as a cream solid.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][C:11]2[C:16](Br)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[F:26])=[O:9])=[C:6]([F:27])[C:5]([O:28][CH2:29][CH3:30])=[CH:4][CH:3]=1>CN(C=O)C.O.[Cu]>[CH2:29]([O:28][C:5]1[CH:4]=[CH:3][C:2]2[C:16]3[C:11](=[C:12]([F:26])[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:14][CH:15]=3)[O:10][C:8](=[O:9])[C:7]=2[C:6]=1[F:27])[CH3:30]
Reactant: CCOc1ccc(Br)c(C(=O)Oc2c(Br)ccc(OCc3ccccc3)c2F)c1F
Agent: [Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1F)c(=O)oc1c(F)c(OCc3ccccc3)ccc12
Yield: 20.9 %

Procedure:
103 g (0.188 mol) of 3-benzyloxy-6-bromo-2-fluorophenyl 6-bromo-3-ethoxy-2-fluorobenzoate were dissolved in 1 l of DMF and refluxed for 72 hours in the presence of 119 g (1.88 mol) of copper powder. The batch was subsequently diluted with water and extracted with ethyl acetate, and the combined extracts were dried over sodium sulfate and evaporated. Crystallisation of the crude product from THF gave 15 g (21% of theory) of 8-ethoxy-4,7-difluoro-3-benzyloxybenzo[c]chromen-6-one as pale-yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([NH:28][C@H:29]([CH2:32][N:33](C)[C:34](OCC[Si](C)(C)C)=O)[CH2:30][OH:31])=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH2:1]([C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([NH:28][C@H:29]([CH2:32][NH:33][CH3:34])[CH2:30][OH:31])=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)N[C@@H](CO)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)N[C@@H](CO)CNC)C1
Temperature: 50 °C
Yield: 37.9 %

Procedure:
To a solution of (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-1-hydroxy-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (10.0 mg, 0.01 mmol) in acetonitrile (1.0 mL) was added excess tetraethylammonium fluoride. The resulting solution was heated at 50° C. for 2 h, and concentrated under vacuum. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-1-hydroxy-3-(methylamino) propan-2-yl)piperidine-1-carboxamide (2 mg) as its TFA salt. 1H NMR (400 MHz, CD3OD) 7.62 (d, 1 H), 7.32 (d, 1 H), 7.04-7.20 (m, 4 H), 6.74 (d, 1 H), 6.56 (d, 1 H), 4.40 (d, 1 H), 4.00 (m, 1 H), 3.92 (d, 1 H), 3.60 (m, 1 H), 3.54 (m, 1 H), 3.26 (t, 2 H), 3.24 (s, 3 H), 3.22 (m, 1 H), 3.04 (m, 1 H), 2.82 (m, 1 H), 2.64 (s, 3 H), 2.62 (q, 2 H), 2.42 (m, 2 H), 1.94 (m, 1 H), 1.24-1.64 (m, 7 H), 1.08 (t, 3 H), 0.98 (m, 1 H); MS m/z 528 (M+H+).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:10]=1
Reactant: CC(=O)C(C)(C)C
Reactant: Clc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, is charged with 100.0 g of sodium t-butoxide and 300 mL of dry toluene. The mixture is stirred at 23-27° C. and added to a solution of 1.48 g of palladium acetate and 125.0 g of 4-bromochlorobenzene in 850 mL of dry toluene. The mixture is heated to a temperature at 95-100° C. using a heating mantle temperature set at about 95-125° C. over a period of 40 minutes. A solution of 98.1 g of pinacolone in 300 mL of toluene is added over a period of 45 minutes to 1 hour while maintaining the internal temperature at 95-100° C. The mixture is stirred for an additional 9 hours, then cooled to an internal temperature at 23-25° C. over a period of 30 minutes. Six hundred (600) g of 15% ammonium chloride solution is added over a period of 10 minutes while maintaining the internal temperature at 20-27° C. The mixture is stirred, the organic layer separated, and washed with 600 mL of saturated sodium chloride solution. The organic layer is charged into a 5 L, 4-necked, round-bottomed flask equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, and a solution of 150.0 g of L-cysteine in 900 mL of water is added. The mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes to achieve reflux, then stirred for an additional 5 hours. After cooling, the aqueous layer is removed, and the organic layer filtered over a Buchner funnel containing a pad of 20.0 g of Celite. After washing the Celite pad with 200 mL of toluene, and saving the filtrate, to the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water. The mixture is heated to an internal temperature at 78-82° C. White solids formed gradually. The triphasic mixture is stirred at this temperature for an additional 5 hours, then cooled, and the organic layer is separated. The organic layer is filtered over a pad of 20.0 g of Celite and the pad is washed with 200 mL of toluene. The combined filtrates is washed again with 400 mL of saturated NaCl solution. The organic layer is filtered and concentrated to collect about 800 mL of solvent to afford about 1.0 L of crude 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone in toluene, which is used directly in the next step, theoretical Yield: 137.6 g (Pd 2 ppm).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:21])([CH3:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:21])([CH3:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:26]#[C:25][C:23]([OH:27])([CH3:24])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1nc2c(s1)C(C)(O)COc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 9-Bromo-4-hydroxy-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (387 mg, 1.04 mmol), 2-methyl-3-butyn-2-ol (699 mg, 8.32 mmol), Pd(OAc)2 (23 mg, 0.104 mmol), CuI (39 mg, 0.208 mmol) and PPh3 (82 mg, 0.312 mmol) in Et3N (15 mL) was degassed with N2, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester as a yellow solid (312 mg, 80%). LC-MS (ESI & APCI): 374.3 (M+1).
Reaction SMILES: [OH:1]O.[C:3]([OH:10])(=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]>O[W](O)(=O)=O.C(O)(C)(C)C>[OH:1][CH2:8][CH:7]1[O:10][C:3](=[O:9])[CH2:4][CH2:5][CH2:6]1
Reactant: C=CCCCC(=O)O
Reactant: OO
Agent: O=[W](=O)(O)O
Solvent: CC(C)(C)O
Product: O=C1CCCC(CO)O1
Temperature: 70 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A total of 2 ml of 30% by weight hydrogen peroxide aqueous solution was added dropwise to a stirred mixture of 1.12 g (10 mmol) of 5-hexenoic acid, 25 mg (0.1 mmol) of tungstic acid, and 15 ml of t-butyl alcohol at room temperature, followed by stirring at 70° C. for 8 hours. As a result, δ-hydroxymethyl-δ-valerolactone was produced in a yield of 72%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NC1CC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC3CC3)cc2c1=O
Yield: 31 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with cyclopropylamine according to the GPA affording 10 mg (31%) of a red powder. Rt=3.15 min.
Reaction SMILES: O.NN.[C:4]1([C:10]2[CH:50]=[CH:49][CH:48]=[CH:47][C:11]=2[C:12]([NH:14][C:15]2[CH:46]=[CH:45][C:18]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]4[CH2:31][C@@H:32]([N:34]5C(=O)C6=CC=CC=C6C5=O)[CH2:33][C@H:23]4[CH2:22]3)=[O:20])=[CH:17][CH:16]=2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[NH2:34][C@@H:32]1[CH2:31][N:24]2[C:25]3[C:30]([N:21]([C:19](=[O:20])[C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C:11]5[CH:47]=[CH:48][CH:49]=[CH:50][C:10]=5[C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=5)=[CH:46][CH:45]=4)[CH2:22][C@@H:23]2[CH2:33]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@H](N4C(=O)c5ccccc5C4=O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: N[C@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3N2C1
Yield: 86.1 %

Procedure:
Hydrazine monohydrate (0.41 g) was added to a solution of (2S, 3aS)-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-2-phthalimido-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline (1.0 g) prepared in Reference Example 65 in ethanol (10 ml) and the mixture was heated under reflux conditions for one and half hours. After cooling the reaction solution, the ethanol was removed through concentration. The resulting residue was dissolved in chloroform, the resulting solution was washed with a 5% aqueous solution of sodium hydroxide and water, died over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/methanol (95/5) to give 0.68 g (yield 86.0%) of the title compound as amorphous powder.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19]C)=[CH:12][C:11]=1[CH3:21])=[O:9].Cl.O>C(Cl)Cl>[Cl:5][C:6]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[CH:12][C:11]=1[CH3:21])=[O:9]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c([N+](=O)[O-])cc1C(=O)c1c(Cl)cccc1Cl
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Aluminumchloride (1.5 g; 11 mmol) is added to a solution of 2,6-dichloro-5'-nitro-4'-methoxy-2'-methyl-benzophenone (1.8 g; 5.3 mmol) in methylenechloride (6 ml). The mixture is stirred for 30 minutes at 20° C. and for 1 hour at 45° C., 5 ml conc. hydrochloric acid/ice are added. After shaking with 20 ml of methylenechloride the organic layer is treated with 2N hydrochloric acid and with water. After drying the solvent is evaporated, the residue purified by chromatography (flash column filled with 30 g of silicagel, elution with toluene). The residue from the main fraction is treated with diisopropylether to give yellow crystalls; (1.2 g; 73% y); mp. 170° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[O:4]1.O=[C:35]1[CH2:38][CH:37]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:35]4[CH2:38][CH:37]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:36]4)[O:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: COC(=O)CC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)CC1CC(NC[C@H]2O[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A solution 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 0.88 mmol) and methyl 2-(3-oxocyclobutyl)acetate (100 mg, 0.70 mmol) [prepared using the procedure found in US Patent Application Publication 2009/0118287] in 1,2-dichloroethane (12 mL) was treated dropwise with acetic acid (50 uL, 0.88 mmol). The solution was treated with sodium triacetoxyborohydride (260 mg, 1.2 mmol) in one portion and allowed to stir at room temperature until complete by HPLC. After 4 h, HPLC indicated the reaction was about 80% complete. An additional 20 mg of ketone was added and stirring was continued for 2.5 h. The reaction mixture was diluted with 30 mL CH2Cl2 and washed with 15 mL sat NaHCO3. The aqueous phase was washed with 15 mL CH2Cl2 and the combined organic phase was dried over Na2SO4. The organic phase was filtered and concentrated to yield a light yellow glass that was purified by flash chromatography (70 g silica gel; 2% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (270 mg, 66%) as a colorless glass: MS (ESI+) for C30H39N5O7 m/z 582.2 (M+H)+; HPLC purity >95% (ret. time, 2.88 min).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[CH2:12][CH2:11][O:10][CH:9]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH2:8]1.[OH-].[Na+].C(Cl)(Cl)Cl>O1CCCC1>[CH3:20][N:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH:9]2[O:10][CH2:11][CH2:12][NH:7][CH2:8]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CNCCO2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(CC2CNCCO2)CC1
Temperature: 60 °C
Yield: 66 %

Procedure:
Lithium aluminum hydride (150 mg, 4.10 mmol) was suspended in tetrahydrofuran (5 mL), and the suspension was mixed with a solution of tert-butyl 4-morpholin-2-ylmethylpiperazinecarboxylate (390 mg, 1.37 mmol) prepared as an intermediate according to Process Step 2 of Reference Example 19 in tetrahydrofuran (5 mL) added dropwise under ice-cooling, followed by heating at 60° C. under reflux for two hours. An aqueous sodium hydroxide solution (2 mol/L, 10 mL) and chloroform (50 mL) were added under ice-cooling, followed by separation. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to thereby yield the title compound (180 mg, in a yield of 66%).