Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=O>O1CCCC1.[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH:10]1([C:9]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH3:5])[CH:8]=2)[CH2:2][CH2:1]1
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: [Zr+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(C2CC2)cc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of zirconocene dichloride (1.76 g, 6.02 mmols) in dry tetrahydrofuran (25 ml), was slowly added ethylmagnesium bromide (12 ml, 1 M in tetrahydrofuran, 12 mmol) at −78° C. The green solution was stirred for 15 minutes at −78° C. and then warmed to 2° C. until the reaction color turned red (15 minutes). A solution of 3,4-dimethoxy-benzaldehyde (1.00 g, 6.02 mmol) in dry tetrahydrofuran (20 ml) was added and the reaction was allowed to warm up to room temperature over 1.5 hours. Solvent was removed under reduced pressure, and dichloromethane (20 ml) was added. The reaction mixture was cooled to 0° C. and titanium chloride (IV) (6 ml, 1M in dichloromethan, 6 mmol) was added. The reaction was allowed to warm up to room temperature over 30 minutes, and quenched with saturated ammonium chloride solution. The mixture was filtered through celite and portioned between dichloromethane and water. The combined dichloromethane was washed with saturated aqueous solution of ammonium chloride, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 8% to 30% ethyl acetate in hexane) to yield 4-cyclopropyl-1,2-dimethoxy-benzene as yellow oily residue (0.2 g, 19%). Ref: Vincent Gandon et al. Eur. J. Org. Chem. 2000, 3713.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=Cc1ccc(O)cc1Br
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C/c1ccc(O)cc1Br
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed 2-bromo-4-hydroxybenzaldehyde (2.0 g, 9.95 mmol, 1.00 equiv), ethyl (triphenylphosphoranylidene)acetate (5.22 g, 14.98 mmol, 1.51 equiv), Tol (50 mL). The resulting solution was stirred overnight at 90° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column, eluting with ethyl acetate/petroleum ether (1:4). This resulted in 2.2 g (77%) of ethyl (2E)-3-(2-bromo-4-hydroxyphenyl)prop-2-enoate as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:59]([F:60])=[CH:58][C:12]2[N:13]([CH2:43][C:44]([N:46]([CH:55]([CH3:57])[CH3:56])[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)=[O:45])[C:14](=[O:42])[CH:15]([CH2:25][C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28](C(OC(C)(C)C)=O)[N:27]=3)[C:16](=[O:24])[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1>>[F:8][C:9]1[C:59]([F:60])=[CH:58][C:12]2[N:13]([CH2:43][C:44]([N:46]([CH:55]([CH3:57])[CH3:56])[C:47]3[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=3)=[O:45])[C:14](=[O:42])[CH:15]([CH2:25][C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][N:27]=3)[C:16](=[O:24])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
To a solution of 5.0 mL trifluoroacetic acid under nitrogen is added 0.500 g of 2-[7,8-difluoro-3-(1-tertbutoxycarbonyl-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 67, (0.697 mmol). After stirring for 1.5 hrs., the trifluoroacetic acid is removed in vacuo and the residue is partitioned between methylene chloride and aqueous sodium hydroxide (1N) and transferred to a separatory funnel. The layers were separated and the organic layer is back-extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, evaporated in vacuo to a residue and then triturated with hexane. Hexane is removed in vacuo and the remaining solid is dried under high vacuum to provide 430 mg of the title compound as an off-white solid: 1H NMR (300 MHz, CDCl3) δ7.93 (d, 1H, J=8.2), 7.51 (m, 2H), 7.41 (m, 2H), 7.29 (m, 7H), 7.15 (m, 1H), 7.00 (m, 2H), 6.82 (m, 1H), 5.01 (m, 1H), 4.36 (m, 1H), 4.32 (d, 1H, J=17.1), 4.19 (d, 1H, J=16.7), 3.88 (s, 3H), 3.87 (m, 1H), 3.74 (dd, 1H, J=6.0, 16.1), 1.10 (d, 6H, J=6.8); low resolution MS (FAB)m/e 624 (MH+).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27]Cl)=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:29]([OH:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C(N(CC)CC)C>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([O:37][CH2:27][O:26][C:24]([NH:23][CH2:22][CH2:21][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:9]=2)=[O:25])=[O:36])[CH:31]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)OCCl)cc1OC(=O)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)OCOC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C
Reaction time: 96 h

Procedure:
The chloromethyl carbamate prepared in Example 112 (1.26 g, 3.04 mmol) was combined with 10 mL of dry dimethylformamide and that mixture was added to a premixed solution of nicotinic acid (375 mg, 3.04 mmol) and triethylamine (445 mL, 5% excess) in 15 mL of dry dimethylformamide at room temperature. The reaction mixture was stirred for 4 days, then the precipitate which formed was removed by filtration. The filtrate was evaporated to dryness and the residue was taken up in 20 mL of methylene chloride. That solution was washed twice with 10 mL portions of water. Removal of the solvent in vacuo afforded the title compound of the formula: ##STR141## The identity of the product was confirmed by NMR.
Reaction SMILES: [NH2:1][C:2]([C:4]1([NH:17]C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3]>[Pd].CCO>[NH2:17][C:4]1([C:2]([NH2:1])=[O:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Reaction time: 24 h
Yield: 104.6 %

Procedure:
10% Palladium on carbon (200 mg) was added to a solution of tert-Butyl 4-(aminocarbonyl)-4-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate (430 mg, 1.14 mmol) in EtOH (20 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 24 h, the mixture was filtered though celite and concentrated to give the title compound (0.29 g).
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.CCOCC>C(O)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Agent: C=O
Agent: Cl
Solvent: O=CO
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 111.9 %

Procedure:
Formaldehyde (12M, 37% in water, 35 ml, 420 mmol) was added to a solution of ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35 g, 89 mmol) in formic acid (35 ml). After stirring at 95° C. for 3 hours, the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and 3M hydrogen chloride in ether (40 ml, 120 mmol) was added. After dilution with ether, the mixture was triturated until a solid was formed. The solid was collected by filtration, washed with ether and dried under vacuum overnight at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, quant.).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]2=[N:6][C:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[CH:14]=[CH:13][C:5]3=[N:6][C:7]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[N:4]3[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1ccc2nc3c(n2n1)CCCC3
Reactant: C1COCCN1
Product: c1cc2nc3c(n2nc1N1CCOCC1)CCCC3
Temperature: 0 °C

Procedure:
A mixture was prepared by adding 5.0 g of 2-chloro-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole to 30 ml of morpholine and this was stirred and heated at reflux for 24 hours. It was then poured into 200 ml of ice water. A tan solid formed and this was separated by filtration to give 2-(4-morpholinyl)-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole melting at 187.5°-188.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 102 mg of 4-Ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.13 (t, 3H, J=7.6 Hz), 2.54 (q, 2H, 14.8 Hz, 7.6 Hz), 7.08 (d, 2H, J=8.8 Hz), 7.35-7.43 (m, 4H), 7.46 (d, 1H, J=2.4 Hz), 7.55-7.63 (m, 4H), 7.69 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). m/z 445.3 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]3)=[CH:20][CH:19]=2)[CH2:15][CH2:14][C:13](=[O:16])[NH:12]1)=O>C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]3)=[CH:20][CH:19]=2)[CH2:15][CH2:14][C:13](=[O:16])[NH:12]1
Reactant: Nc1ccccc1NC(=O)C1(Cc2ccc(C3CC(=O)NS3(=O)=O)cc2)CCC(=O)N1
Solvent: CC(=O)O
Product: O=C1CCC(Cc2ccc(C3CC(=O)NS3(=O)=O)cc2)(c2nc3ccccc3[nH]2)N1
Temperature: 120 °C
Yield: 58.9 %

Procedure:
N-(2-aminophenyl)-2-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)benzyl]-5-oxopyrrolidine-2-carboxamide (6.6 mg, 0.01 mmol) was stirred in acetic acid (0.5 mL) and heated to 120° C. for 60 seconds in a microwave. Purification by preparative LCMS gave the title compound as a white solid, (2.5 mg, 42%), 1H NMR (400 MHz, CD3OD): δ 7.80 (m, 2H), 7.62 (m, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H, 5.20 (m, 1H), 3.50 (m, 2H), 2.65 (m, 1H), 2.50 (m, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 2.03 (m, 1H), 1.70 (m, 1H); LCMS found for C21H20N2O4S (M+H)+: m/z=425.
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([C:18]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: CCOC(=O)c1nsc(=O)o1
Product: CCOC(=O)c1nsc(-c2ccc(C)cc2)n1
Yield: 41.5 %

Procedure:
A solution of 7.48 g (0.0427 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate and 50.0 g (0.427 mol) of p-tolunitrile (redistilled) was held at 190° C for 72 hours. The reaction mixture, which contained the product in 16% yield, was concentrated under vacuum to 90° C (0.5 torr) to give 4.4 g of black residue. Elution chromatography of this material on 200 g of silica gel (Woelm, for dry column chromatography) with benzene gave 1.7 g of product. Crystallization of this material from hexane (charcoal) gave 0.72 g (7%) of solid, mp 65°-66.5° C.
Reaction SMILES: C[N+](C[C@H](O)CC#N)(C)C.[Cl-].C[N+](CC(O)=O)(C)C.[CH3:20][N+:21]([CH2:24][CH:25]([OH:30])[CH2:26][C:27]([OH:29])=[O:28])([CH3:23])[CH3:22].[Cl-]>Cl>[OH:30][C@H:25]([CH2:26][C:27](=[O:28])[O-:29])[CH2:24][N+:21]([CH3:23])([CH3:20])[CH3:22]
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: C[N+](C)(C)CC(=O)O
Agent: C[N+](C)(C)C[C@H](O)CC#N
Agent: Cl
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]

Procedure:
13.5 kg L-carnitine nitrile chloride was dissolved in 22 liters concentrated hydrochloric acid and hydrolyzed to L-carnitine chloride, as described in Example 2. It was subsequently reacted to betaine in the highly basic ion exchanger (Amberlite IRA-416). After appropriate reprocessing, 11.1 kg colorless L-carnitine with (α)D20 =-30.8° and an HPLC concentration of 99.7% was isolated.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C([O-])(C)(C)C.[K+].ClCCl>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1Nc1ccc(OC(F)(F)F)cc1
Temperature: 110 °C

Procedure:
To 374 μL of 2-fluoro-nitrobenzene in 2 mL of DMSO are added 962 μL of 4-trifluoromethoxyaniline (2 equivalents) and 636 mg of potassium tert-butanolate (1.6 equivalents). The whole is heated to 110° C. for 3 hrs. Once the reaction is completed, the medium taken up in a minimum of dichloromethane is hydrolyzed and then extracted. The organic phase is successively washed with water and then with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated under reduced pressure. A silica gel chromatography of the residue (cyclohexane and then cyclohexane/ethyl acetate: 99/1) allows 575 mg of the desired product to be isolated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCCC1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>CCOCC.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:22])=[CH:16][CH:15]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1)N1CCCCC1

Procedure:
A solution of 120 g of dry pyridine, 103.2 g of piperidine and 1.5 liters of dry ether was stirred vigorously as 215.7 g of freshly distilled 4-chlorophenyl acetyl chloride in 250 ml of ether was added dropwise. After 4 hours the mixture was diluted with one liter of water and the organic phase collected. The aqueous phase was extracted with ether and the ether phases were combined, washed successively with 0.1N hydrochloric acid twice, 5% sodium hydroxide twice, saturated sodium chloride twice, dried and concentrated in vacuo. The residual oil was taken up in dichloromethane and percolated through a bed of neutral alumina with additional solvent. The resulting oil was crystallized from carbon tetrachloride:hexane (1:9), giving 243 g of N-(4-chlorophenylacetyl)piperidine as yellow crystals, mp 85°-85.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[CH3:14]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:14])[C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(n1)CCC(=O)N2
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(n1)CCC(=O)N2C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
A solution of 1.2 g (6.7 mmol) 6-methoxy-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 15 ml of DMF was cooled to 5° C. and to this solution was slowly added 6.7 ml (6.7 mmol) of potassium t-butoxide (1M solution in THF). The mixture was stirred for 10 minutes followed by addition of 0.46 ml (7.4 mmol) methyl iodide. After addition was complete, the reaction mixture was stirred for 1 hour at 5° C. The reaction mixture was poured into saturated NaCl. The mixture was extracted with ethyl acetate. The ethyl acetate extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using 5:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 0.83 g of 6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one. TLC Rf=0.6 (1:10 ethyl acetate/chloroform). 1H NMR (CDCl3) δ 7.2 (d, 1H), 6.6 (d, 1H), 3.9 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass Spectrum: m/e 193.2 (p+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-])=O)=[C:11]([CH:14]=2)[CH2:12][OH:13])[CH:4]=[CH:5][N:6]=1>[Pd].CO>[NH2:15][C:10]1[CH:9]=[CH:8][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:14][C:11]=1[CH2:12][OH:13]
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])c(CO)c1
Agent: [Pd]
Solvent: CO
Product: Cc1nccn1-c1ccc(N)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of 5-(2-methylimidazol-1-yl)-2-nitrobenzylalcohol (308 mg), 10% Pd/C(84 mg) and methanol (5.0 ml) was hydrogenated at 1 atmosphere. The mixture was stirred at room temperature for 2 hours and filtered to remove the catalyst. The filtrate was diltilled under reduced pressure to give 268 mg (100%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=O)[N:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CC(O)=O.CC(N(C)C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([CH2:17][N:27]4[CH2:28][CH2:29][CH:24]([N:23]([CH3:30])[CH3:22])[CH2:25][CH2:26]4)[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Reactant: CN(C)C1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CN(C)C1CCN(Cc2cccc(Nc3nccc(-c4ccc(Br)s4)n3)c2)CC1
Yield: 7.1 %

Procedure:
A solution of 3-[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-benzaldehyde (25 mg, 0.069 mmol) and 4-dimethylaminopiperidine (13.3 mg, 0.104 mmol) in 25% HOAc in DMA was mixed for 2 h and then treated with MP-CNBH3 (2.5 eq.) for 18 h. The reactions were filtered and purified directly by LCMS to afford title compound (2.3 mg, 7%) for 2 steps. MS: m/z 472 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 1.37 (br q, J=11 Hz, 2H), 1.70 (br d, J=12 Hz, 2H), 1.94 (br t, J=11 Hz, 2H), 2.04 (br t, 1H), 2.87 (br d, J=11 Hz, 2H), 3.33 (s, 2H), 6.89 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.33 (dd, J=1, 5 Hz, 1H), 7.37 (m, 1H), 7.55 (br d, J=8 Hz, 1H), 7.86 (m, 1H), 7.89 (br s, 1H), 8.51 (dd, J=1.5, 5 Hz, 1H), 9.68 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[OH-:22].[Na+]>Cl>[OH:15][CH2:14][CH:13]([CH2:18][OH:17])[CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: [OH-]
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 72 %

Procedure:
2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)-ethyl]purine (3.74 g, 12 mmol) in hydrochloric acid (2.0 M, 12 ml) was heated under reflux for 1.5 hours. The solution was neutralised with aqueous sodium hydroxide (10%) and then allowed to cool. The solution was filtered and the solid washed with water to afford 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine as a white crystalline solid (2.18 g, 72%), m.p. 275°-277° C.; (Found: C, 47.31; H, 6.02; N, 27.81%; C10H15N5O3 requires C, 47.43; H, 5.97; N, 27.65%).
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH:12]=1)=[O:7].[F:31][CH:32]([F:41])[O:33][C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:4][O:5][C:6]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:32]([F:41])[F:31])=[CH:35][CH:36]=3)=[CH:19][CH:20]=2)[CH:12]=1)=[O:7]
Reactant: COC(=O)c1cc(CSc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(CSc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (12.8 mg) was added to a degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulphanylmethyl]-furan-2-carboxylic acid methyl ester (151) (200 mg, 0.516 mmoles), 1-difluoromethoxy-4-iodo-benzene (153 mg, 0.568 mmoles) and 2M aqueous cesium carbonate (4.12 ml) in 1,4-dioxan (15 ml). The mixture was placed under an argon atmosphere and was heated at 100° C. for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water, and the mixture adjusted to pH=2 with 1M aqueous hydrochloric acid. The organic phase was washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography, using heptane/ethyl acetate 9:1 v/v as eluent, to afford compound 152 (126 mg) as a white solid. LC/MS System A; Rt=4.17 mins.
Reaction SMILES: C[O:2][C:3]1([CH3:12])[O:9][CH:8]2[CH:5]([CH2:6][C:7]2([CH3:11])[CH3:10])O1.C[Si](C)(C)[I:15]>C(Cl)Cl>[I:15][C@@H:5]1[CH2:6][C:7]([CH3:11])([CH3:10])[C@H:8]1[O:9][C:3](=[O:2])[CH3:12]
Reactant: COC1(C)OC2CC(C)(C)C2O1
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](I)CC1(C)C
Yield: 75 %

Procedure:
34.4 g (0.2 mol) of 3-methoxy-3,6,6-trimethyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 44.0 g (0.22 mol) of trimethyliodosilane are heated to the reflux in 150 ml of methylene chloride for 15 hours. Concentration and fractional distillation in vacuo give 40.2 g (75%) of trans-1-iodo-2-acetoxy-3,3-dimethyl-cyclobutane. Boiling point0.1 38°-39°, nD20 1.5008.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:42]1[CH2:41][CH2:40][N:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH2:44][CH2:43]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(C3CCN(C)CC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(1-methylpiperidin-4-yl)piperazine (85 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 615 (M+H).